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European Commission

Major Diseases Research - Catalogue of Research Projects (2003-2005) in the Sixth Framework Programme

Luxembourg: Office for Official Publications of the European Communities

2005 – 233 pp. – 21.0 x 29.7 cm

ISBN 92-894-8153-6

Interested in European research?

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EUROPEAN COMMISSION

Directorate-General for ResearchDirectorate F – HealthUnit F.2 – Major Diseases

Contact: Alain Vanvossel

European CommissionOffice CDMA 2/22B-1049 Brussels

Tel. (32-2) 29 62 578Fax (32-2) 29 55 365



Major Diseases ResearchCatalogue of Research Projects (2003-2005)

in the Sixth Framework Programme

Directorate-General for ResearchLife Sciences, Genomics and Biotechnology for Health

EUROPEAN COMMISSION

Edited by Alain Vanvossel

2005

catalogue-E-14phase.qxd 12/12/05 15:58 Page 1

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Major D i seases Research (2003-2005)3

Table of contents

Foreword 7

Introduction 9

Overarching projects 11Eicosanox 12ECRIN-RKP 14

Cardiovascular 17Bloodomics 18EVGN 20MOLSTROKE 24EuroClot 26Myocardial Repair 28

Diabetes 31Diabesity 32EXGENESIS 34EUGENE2 36TONECA 39IMMIDIAB 41

Rare diseases 43Eumitocombat 44Euroglycanet 47GENESKIN 49EuroWilson 52PWS 56EUGINDAT 58EURAPS 60AUTOROME 62Orphanplatform 64


Anti-Microbial Drug Resistance 67EUR-INTAFAR 68ActinoGEN 70VIRGIL 73PNEUMOPEP 75AMIS 77PREVIS 79COBRA 82micro-MATRIX 85

Brain, neurological and psychiatric diseases 87PROMEMORIA 88NEWMOOD 90APOPIS 93GENADDICT 95EUROSCA 97NeuroNE 100BrainNetEurope II 102AUTISM MOLGEN 106SYNSCAFF 108EUROHEAD 111SPASTICMODELS 113NCL-models 116NEUROKCNQPATHIES 118X-ALD 120PainGenes 122GRIPANNT 124STRESSPROTECT 126INTERDEVO 129NeuroDisseminator 131EUROMEMO 132ESNI course 2003 135FENS Forum 2004 137RABRE 139

Human development and ageing 141MIMAGE 142GEHA 144EMBIC 146Cells into Organs 148




LINK-AGE 150ANABONOS 152OSTEOGENE 154AGEACTION 156

Cancer 159INTACT 162BIOCARE 164Angiotargeting 166PRIMA 168Active p53 170EMIL 173TRANSFOG 176FIRST 179CANCERDEGRADOME 182STROMA 185Mutp53 187MOL CANCER MED 191EUROXY 194MAESTRO 195CCPRB 196eTUMOUR 198TRANSBIG 200European LeukaemiaNet 202DNA METHYLATION 206European MCL Network 209BRECOSM 212MetaBre 214ENACT 217PROTHETS 219P-MARK 221EUSTIR 223EUROCAN +PLUS 225

Indexes 227Index by acronym 228Index by contract number 230Index by project coordinator 232



Millions of European citizens battle with chronic diseases every day.The ultimateobjective of any health research funding is to eliminate such diseases.The task ishuge - major diseases,such as cardiovascular,brain diseases and cancer,are immenselycomplex and can often only be tackled by multidisciplinary teams from differentcountries.For over a quarter of a century,European Union Framework Programmeshave supported research in life sciences,providing opportunities for research fundingand the training of scientists.Europe is fortunate to have excellent research centresactive in these fields – the challenge is to ensure their further development and tofacilitate the creation of effective and durable partnerships between them.

The current Sixth Framework Programme focuses on major diseases as part of its first thematic priority 'Lifesciences, genomics and biotechnology for health', with an emphasis on the field of genomics which has usheredin a new era in medical research.

This publication illustrates the EU's essential commitment to major disease research, featuring the 87 projectssupported under the first and second calls for proposals in the actual Framework Programme, representing aglobal budgetary effort of about €380 million.

Let us not underestimate this collaborative research effort, bringing together the best teams in Europe in basicresearch,molecular biology,clinical expertise,epidemiology and bioinformatics. It must be recognised that,throughthe research Framework Programmes,the EU has the largest experience in the world thanks to such multinationaland multidisciplinary co-operation which is essential because of the scale of the problems faced.These multi-skilled approaches are needed to generate important advances in our scientific knowledge and ultimately to leadus towards new drugs, therapies and treatments for the benefit of the patients and for public health in general.

Research must become embedded in healthcare. As sure as research delivers solutions to some problems, it alsoopens up further questions.The current work being funded should also help to point us in the right direction aswe prepare for the Seventh Framework Programme, now expected to embrace even broader ambitions andobjectives for co-operation in health research.As Commissioner for Research, I am convinced that increasedsupport in (health) research is a key element for Europe's industrial growth and a cornerstone of the knowledgebased economy and society.

Janez Potoc¬nik


Foreword



The current Sixth Framework Programme (FP6 – 2002-2006) is dedicating around €800 million to supportingresearch in the area of 'Combating major diseases:application-orientated genomic approaches tomedical knowledge and technologies' with the aim of improvingpatient health and quality of life in Europe and around the world.

Under FP6,five possible funding instruments provide support to largeror smaller projects with different objectives. Integrated Projects (IP)and Specific Targeted Research Projects (STREP) are aimed atgenerating, demonstrating and validating new knowledge throughresearch and development. Networks of Excellence (NoE) supportstrategic research coordination through extensive networking.Coordination Actions (CA) and Specific Support Actions (SSA)promote collaboration and coordination of smaller scale projects,andother activities such as conferences and studies.

Collaboration between industry and academia is strongly encouraged.Emphasis is placed on the participation of small and medium-sizedenterprises (SMEs) in all FP6 initiatives, including this part of theprogramme, in recognition of their important and proven innovativepotential.

This catalogue features 87 projects selected under the first and secondFP6 calls for proposals, presented by scientific area, for a totalcontribution of about €380 million provided by the EU.

Several excellent projects have incorporated innovative post-genomicand proteomics approaches.They are identifying genes,collecting dataand applying innovative bioinformatics techniques – including the useof model organisms – to elucidate cellular and molecular mechanisms,and to elaborate clinical aspects of diseases with a strong potentialfor new diagnostics.

This part of the FP6 thematic priority 'Life sciences, genomics andbiotechnology for health' (TP1) covers a large spectrum of majordiseases and, as such, supports research to combat cardiovasculardiseases, diabetes and rare diseases; tackles the problem of anti-microbial drug resistance; studies the brain and neurological andpsychiatric diseases; enhances knowledge about molecularmechanisms of human development and healthy ageing; and finally,combats cancer.

Cardiovascular diseases claim more lives in Europe than any othermedical condition.The World Health Organisation estimates that theycause some 30% of mortality worldwide.Despite the growing numberof interventional and pharmacological approaches, much remains tobe done. Some of the main aspects of cardiovascular diseases havealready been addressed by the first two FP6 calls for proposals,namelycoronary artery disease, vascular diseases, atherothrombosis andthrombotic stroke, heart failure, arrhythmias and myocardial repair.

Europe has seen an explosive increase in diabetes over the past twodecades.Today, an estimated 20 million people in the EU (about 4%of the population) suffer from this debilitating disease, excludingundiagnosed cases.This figure is expected to grow to at least 26 millionby 2030. Diabetes lowers the life expectancy of sufferers by up to 15

years and increases the risk of cardiovascular disease by two to fourtimes. Projects funded under the first two FP6 calls for proposals aretackling the prediction of type 1 diabetes while, with respect to type2 diabetes (TP2D), projects are addressing the treatment of obesity,the effects of exercise and the genetics of TP2D in migrant population.

'Rare diseases' (RDs),by definition,affect only small groups of people.In Europe, RDs are defined as those affecting less than one person in2 000.These conditions are often genetic in nature, usually severelydebilitating and life-threatening.Their low prevalence,the only featureshared by all RDs, confirms the undeniable added value of teamworkand pooling of resources and patient data at the European level. Rarediseases and disorders covered by the first two calls include disordersof mitochondrial oxidative phosphorylation,glycosylation and plasmamembrane amino acids transporters; rare skin diseases; Wilson'sdisease; Prader-Willi syndrome; and autoimmune diseases. Someprojects take a broad approach,addressing personalised medicine andplan for the coordination of early clinical trials.

Over time,bacteria,viruses,and other microscopic predators mutateinto new strains resistant to existing medications.The problem ofresistance to antimicrobials has grown into a major health concernand now threatens to impede advanced medical interventions as wellas treatment of common infections.Mortality due to drug resistancehas increased, while costs for medical care due to treatment failureshave escalated. Some of the major aspects of this problem havealready been addressed in the first two calls through projects focusingon the design of new antibiotics (addressing new molecular targets)and new alternative treatment approaches (addressing virulencefactors and stimulating the immune response), improvedunderstanding of the molecular mechanisms behind antibioticresistance, and the establishment of a vigilance network to controland predict the development of antiviral drug resistance.

The brain may well be the most complex organ in the human body.One-third of our genes and proteins are specific to the brain alone,providing the basis for our unique intellectual capabilities.The morewe understand about how the brain works, the more we can unravelthe causes of the many devastating neurological and psychiatricdisorders and diseases, and try to find new treatments or even cures.Neurodegenerative diseases have been tackled on a broad scale underthe first two calls for proposals.

Two large initiatives, an IP and a NoE, are addressing all relateddisorders displaying abnormal protein aggregation, includingAlzheimer's, Parkinson's and Huntington's diseases, motor neuronediseases and prion diseases.The NoE on 'Human brain tissue research'is addressing brain banking. One project covers a rare geneticneurological disorder, spinocerebral ataxia, which causes progressivemovement disorders.


Introduction


Important funded research projects in areas such as affectivedisorders, mechanisms of addiction or mechanisms of learning andmemory, migraine and pain in general, are now expected to generatemajor impacts through the use of recently available genome data.Other projects cover drug development related to cytoprotectionand inhibition of stress.

Growing old is a normal part of life, but it brings its own particularhealth challenges with it. The EU seeks to help Member Statesencourage good health for European citizens from the cradle to oldage – as the ranks of the 'silver generation' grow, addressing theirspecific medical needs will become ever more important.The area of'human development and ageing' is meant to provide a strongknowledge base for medical needs and good health throughout apatient's lifetime.The study of healthy ageing has been addressed bythe first two FP6 calls, specifically with respect to genetic aspects andthe role of mitochondria. One NoE and one IP, addressing thedevelopment of organs and embryo-implantation, respectively, tacklequestions of human development. Bone formation, anabolism andosteoporosis are also covered.

Cancer is likely to remain one of the biggest killers of the beginningof the 21st century. In Europe, almost 1 million people die of cancerevery year, and 2 million new cases of cancer are diagnosed. Canceris an elusive enemy. Its multiple causes – including geneticpredisposition, environmental and life-style influences, infectiousagents and ageing – and their complex interactions represent a majorchallenge for basic and clinical research. So far, the budget allocatedspecifically to the calls in the 'Combating cancer' section has enabledthe funding of 27 projects. A number of these focus on the analysisof molecular targets, such as cell-cycle regulators, kinases,phosphatases, telomerase, proteases, DNA repair molecules, p53protein,and mitogen-activated protein kinase (MAPK) signalling, andon molecular mechanisms surrounding angiogenesis, epigenetics and hypoxia.

Research is also being funded on biomarkers for early detection,prognosis and responsiveness to treatment.Moreover,therapies,suchas viral therapy, stem cell therapy, gene therapy, radiotherapy, noveltechnologies, together with the development of new drugs, are beingcovered by the funded projects. In addition, research on molecularimaging is being supported by EU funding.There are also a numberof studies specific to particular types of cancer, such as leukaemia,lymphoma, myeloid cell leukaemia, melanoma, colon cancer, breastcancer, pancreatic cancer, prostate and childhood cancers.

Finally, one large IP has been funded on the topic of functionalgenomics and proteomics of the pathways of nitric oxide andeicosanoid signalling and their interactions.This initiative is overarchingseveral diseases, ultimately aiming to develop new therapies andtreatments for cardiovascular, cerebral and neoplastic diseases.

As can be seen from the catalogue, these 87 projects represent amassive effort from the EU scientific community involved in lifesciences research for the ultimate benefit of both the patient and theEuropean citizen.

AcknowledgmentThis catalogue has been produced thanks to essential input from allproject coordinators involved and the efficient co-operation of allmembers of Unit F2 'major diseases', in particular Catherine Berens,Philippe Cupers, Dambrauskaite Virginija, Mary Fitzgerald, Olaf Kelm,Elengo Manoussaki, Elmar Nimmesgern, Jürgen Sautter, NathalieVercruysse, Jan Van de Loo, Maria Vidal, Christian Wimmer, all underthe inspiring coordination of Thomas Jussen and Ludovica Serafini andthe guidance of Alain Vanvossel.



• Eicosanox 12

• ECRIN-RKP 14

Overarching projects


SummaryThe eicosanoids and nitric oxide (NO) are important signalling

molecules in many physiological and pathological processes,

including cardiovascular, cerebral and neoplastic disorders.

Together, these diseases account for the vast majority of deaths in

Europe and represent an enormous health problem with a major

socio-economic impact. We have assembled a large consortium,

positioned at the forefront of eicosanoid and NO research. The

partners will carry out a multidisciplinary project, aiming to increase

the knowledge of these autacoids, and to develop novel therapeutic

strategies and medical treatments. We will carry out molecular

studies on key enzymes and receptors to elucidate biochemical

properties, catalytic mechanisms and structure-function

relationships. We will address the functional genomics of the

Eicosanoid and NO cascades to characterise gene expression

profiles and regulation under normal and disease states, and identify

novel potential drug targets.New genes will be characterised using

proteomics, structural genomics and model organisms. In parallel,

the partners will conduct cell biological work on gene regulation,

gene silencing, signalling systems and cross-talk between pathways.

This information will be used in studies of disease mechanisms such

as inflammation, immune responses and angiogenesis. In turn, these

insights in pathology will be translated into investigations of diseases

using animal models and clinical applications. The basic research

together with applied and clinical studies will act in synergy to

identify novel targets for pharmacological intervention and drug

design for the treatment of patients suffering from cardiovascular,

cerebral and neoplastic disorders.

ProblemEicosanoids and NO are involved in a number of severe endemic diseasesthat plague the Western world, e.g.atherosclerosis,myocardial infarction,thrombosis, dementia and cancer. In fact, cardio- and cerebrovasculardisorders alone, such as coronary heart disease and stroke, are theleading cause of death in Europe.Together with cancer, these diseasesaccount for the vast majority of mortality and morbidity among adultsin Europe.The project will increase our knowledge of these commonand deadly diseases and the mechanisms by which eicosanoids and NOtrigger and maintain pathophysiological processes, with the long-termgoal of developing novel drugs and therapeutic strategies.

AimThe project’s goal is to generate new knowledge about cardiovascular,cerebral and neoplastic diseases.The work involves basic molecularstudies of proteins, investigations of gene regulatory mechanisms,cellular signalling mechanisms and functional genomics and proteomicsapproaches to identify new genes. In turn, this work will be translatedinto applied and clinical research activities.Together with evaluationsin animal models, clinical patient studies and programmes on drugdesign,we expect to develop novel therapeutic strategies and medicaltreatments for several severe diseases. We will also create a long-lasting infrastructure for R&D activities, education, training,exploitation and dissemination of results to users at multiple levels,such as research organisations, funding agencies, patient associations,industry, and society in general.

Expected resultsIt is envisaged that molecular work, including biochemistry, proteinchemistry, studies of structure function relationships and enzymeregulation will generate basic knowledge of the molecularproperties of the key proteins in the eicosanoid and NO cascades.We will take advantage of the human genome sequence and employfront-line technologies in functional genomics and proteomics

Eicosanox

Eicosanoids and nitric oxide: Mediators of cardiovascular,cerebral & neoplastic diseases

OVERARCHINGPROJECTS



research to identify genes that participate in the biologicalresponses elicited by eicosanoids and NO.Thus, we will carry outa large integrated programme on systematic microarray analysesfor mRNA profiling of regulated genes in a variety of in vitro and invivo model systems for disease processes. Using a proteomicsapproach, new genes will be characterised at molecular andfunctional level, using an array of biochemical and biophysicalmethods, structural genomics and model organisms. These jointactivities are expected to generate important insights to theregulated expression of genes in the eicosanoid and NO cascades,cross-talk between the pathways, and identification of novel genesinvolved in the regulation and action of these autocoids, i.e. novelpotential drug targets.

Along with this work, we will conduct work on cellular regulationof eicosanoid and NO biosynthesis and action, includingcomplementary tasks on gene regulation, gene silencing expressionand function of receptors, intracellular signalling mechanisms andcross-talk between pathways. This knowledge will in turn betranslated into studies of basic pathophysiological mechanisms, inparticular inflammatory and immune reactions, as well asangiogenesis. Insight into the role of eicosanoids and NO in basicpathology will be connected to direct investigations ofcardiovascular, cerebral and neoplastic diseases,using animal modelsand clinical applications on human tissues and patient studies.Thus,the basic research and applied and clinical studies will act in synergyand facilitate efforts to identify novel targets for pharmacologicalintervention and drug design. These joint efforts will allowdevelopment of novel therapeutic strategies and medicaltreatments for patients suffering from diseases of the cardiovascularand central nervous systems and cancer.

Potential applicationsOur project will increase our knowledge about these common anddeadly diseases and the mechanisms by which eicosanoids and NOtrigger and maintain pathophysiological processes. In addition, weintend to identify new drug targets,evaluate the therapeutic potentialof recently developed lead structures, improve existing therapies anddevelop novel drugs and therapeutic strategies.

OVERARCHINGPROJECTS

Major D i seases Research (2003-2005) 13

Coordinator Prof. Haeggström, Jesper Z.

Division of Chemistry 2

Department of Medical Biochemistry and Biophysics

Karolinska Institutet

Stockholm, Sweden

Phone: +46 8 524 87612

Fax: +46 8 736 0439

Email: [email protected]

Project web-site: http://www.eicosanox.org

Key words: eicosanoids, nitric oxide, cardiovasculardisease, brain disease, neoplasia,inflammation, angiogenesis, drugdevelopment, therapy, molecular biology, cellbiology, genomics, proteomics

PartnersKarolinska Institutet, Sweden

University of Frankfurt, Germany

Università degli Studi di Milano, Italy

Fondazione Università Gabriele DÁnnunzio, Italy

Wolfson Institute for Biomedical Research, UnitedKingdom

Queen Mary & Westfield College, University of London,United Kingdom

National University of Ireland, Ireland

Nicox Research Institute Srl, Italy

Universidad Autonoma de Madrid, Spain

Biolipox AB, Sweden

Queens University, Canada

University Clinics Charité, Humboldt University, Germany

Acronym: EicosanoxProject number: LSHM-CT-2004-005033EC contribution: €10 700 000 Instrument: Integrated ProjectDuration: 60 monthsStarting date: 01/01/2005


OVERARCHINGPROJECTS

ECRIN-RKP


SummaryBased on the interconnection of national networks of clinical research

centres (CRCs) and clinical trial units (CTUs) the European Clinical

Research Infrastructures Network (ECRIN) programme is designed

to develop an infrastructure allowing for bottom-up harmonisation

of support, training, and practice of clinical research. ECRIN aims at

providing public or private (mainly biotechnology SME) sponsors with

a support for translational research and multicentre clinical studies

in Europe.The ECRIN consortium is based on national networks of

CRC / CTUs together with the European Forum for Good Clinical

Practice (EFGCP).A major objective of ECRIN consists of stimulating

and facilitating the creation of centres and national networks,especially

in the new member states, for their subsequent connection to the

European network. Connecting these national networks within a

broad European network will contribute to the critical mass at the

European level needed for the implement of European standards and

training regarding clinical research. The European Consortium of

clinical research infrastructures currently includes eight networks of

CRCs and CTUs, covering six European countries representing 260

million citizens (Denmark, France,Germany, Italy, Spain, and Sweden),

and comprising 112 different medical centres and hospitals conducting

1500 clinical studies.

Objectives The ECRIN-RKP project is designed to exchange informationregarding the organisation of national networks and theirenvironment. This ECRIN-RKP project is the first step of a widerECRIN programme designed to build up an infrastructure promotinga harmonised implementation of the EU Directives regarding clinicalresearch, and providing academic or biotechnology sponsors with asupport for the conduct of multinational clinical studies/trials inEurope (the ECRIN Infrastructure project). Optimising the ECRINInfrastructure project requires an in-depth reciprocal knowledge ofall partners and of their national environment, leading to refinementof the content of items specific for infrastructure projects, namelythe networking activities, the transnational access activities and thejoint research projects. Prepared by national workshops, the ECRIN-RKP action is therefore based on a diagnostic step devoted to acomparative analysis (a workshop in Brussels on 16-17 December2004,with three representatives per network), followed by a closuremeeting (on 14-15 February 2004, in Brussels,with one representativeper centre) designed to discuss which points require harmonisationand which services could be proposed for transnational access.

Potential outcomeThe ECRIN-Infrastructure project will be developed later and willconsist of the build-up of an infrastructure facilitating transnationalclinical studies and including networking activities allowing for harmo-nisation of training, tools and practice.

Networking activities are designed to promote a harmonisedimplementation of good clinical practice, according to Directive2001/20/EC and Member State legislation, a harmonised training andpractice in clinical research, and communication with investigators,patients and citizens.Workgroups will cover the impact of nationallegislation on clinical studies, ethical issues, good clinical practice andharmonisation of SOPs, data management and quality controlprocedures.Topic-specific subnetworks,collection of biological material,and transnational cohorts will be promoted, while circulation ofinformation will target the main actors of clinical research, i.e.,investigators and researchers, scientific associations, the CochraneCollaboration, funding agencies, and industry partners, as well aspatients and patients associations. European Correspondents in eachnational network will participate in such networking activities.

Transnational access activity will facilitate the realisation ofmultinational studies through a panel of flexible services proposed tothe sponsors (however ECRIN will not act as a sponsor by itself).Services provided will rather include consulting for centre selection,funding opportunities, protocol review, ethical review, biostatistics,data and safety monitoring committees, and insurance, whereassupport will be provided for regulatory affairs,drug dispensation,datamonitoring, pharmacovigilance and management of SAE, and datacustody and intellectual property. Transnational access to ECRINfacilities will be delivered, after scientific, methodological and ethicalreview, through a Co-ordination Team whose role consists of solvingproblems raised by transnational studies with the help of EuropeanCorrespondents in each national network.

Joint research projects aim at improving the quality of the servicesdelivered by the ECRIN-Infrastructure. This is achieved through aEuropean joint research programme in ethics, informed consent, andgender issues.

European Clinical Research Infrastructures Network(ECRIN) - Reciprocal Knowledge Programme (RKP)


The project is designed on a progressive growth model of the initialnetwork through the addition of new national networks (with specialattention provided to the new Member States),thereby increasing theefficiency of the infrastructure.

In addition, this SSA allowed to participate in the preparation of theFP7 Technology Platform 'Innovative Medicines for Europe' (Barcelonaworkshop). ECRIN also participated in the debate on transparencyin clinical trials, and will co-ordinate a communication event on clinicalresearch, targeting EU citizens and patients associations.

Participants The ECRIN consortium is designed to provide a European not-for-profit platform for the investment and realisation of trans-Europeanclinical research projects. ECRIN is not directed towards a specificspeciality or disease category,but will foster transfer of best researchpractice from speciality to speciality all over Europe.

1 - CRCs and CTUs

The development of Clinical Research Centres (CRCs) in Europeoccurred in the 1990s in some countries with the support of health orresearch ministries, of universities, hospitals, and government agencies,and of foundations.Allowing investigation through a team of study nurses,physicians, specific beds and equipment, each centre acts as a facilityproviding support for research projects, acting through strongconnections with physicians from various medical fields involved in thedesign of the project, in its realisation, and in the enrolment of patients.Clinical research centres also provide expertise for drug registration,and represent a bench-to-bedside link between research laboratoriesand clinical studies,either through clinical applications of new strategies,or through the investigation of patients for genotype/phenotype, orpathophysiological studies.

The concept of Clinical Trial Units (CTUs) developed earlier and hasextended in Europe over the past ten years.Not necessarily based in ahospital, their main activities consist in providing specialist knowledgefor planning, conducting, and reporting clinical trials (including phase I,phase II, and phase III trials) that may include from several patients toseveral thousands of patients.Their task includes design of the trials,implementation of the randomisation of the patients, case record form(CRF) development and collection, database building and checking,analysis of the data, and reporting of the results. Their staff includesstatisticians,project managers,data managers, and computer engineers.They are closely collaborating with clinicians, supporting them in all thesteps of clinical trials.Most of the CTU are also performing other typesof clinical studies (diagnostic evaluation for instance) and epidemiologicalstudies. Medical teams participating in the trial may be helped for datacollection by study nurses or research assistants, or by CRCs. Thisillustrates the complementarity between both structures, CTUs oftenprovide CRCs with methodological and data management support.ManyCRCs are mainly involved in the early phases of drug and devicedevelopment, CTUs in later ones.

2 – National networks of CRCs/CTUs

In most countries,the organisation of the first national networks onlyappeared recently, permitting critical mass achievement, and leading tothe standardisation of practice in these countries, and the facilitation of

national multicentre studies alongside the interconnection of skills andlogistics. However, some EU countries still lack such networks.

3 - ECRIN network

The ECRIN consortium of clinical research infrastructures includeseight networks of clinical research centres (CRCs) and clinical trial units(CTUs),covering all the medical fields.Currently, these networks coversix countries representing 260 million citizens.Therefore they reach thecritical mass both at their country level and at the EU level.No equivalentinfrastructure exists in Europe.

In addition, the Canadian participant (FRSQ-GEREQ) extends thecapacity of ECRIN to perform clinical studies on the North Americancontinent, using data management tools compatible with FDArequirements.

Closely associated with scientific associations and investigators, actingthrough disease-specific networks of practitioners, these centres havethe capacity to enrol patients in a wide range of clinical studies,particularly in rare diseases, orphan drugs, paediatrics, biotherapy.

OVERARCHINGPROJECTS


Coordinator Demotes-Mainard, Jacques CIC INSERM-CHU de BordeauxCHU Haut-Lévèque,Avenue de Magellan33604 PESSAC, FrancePhone: +33 55765 6170Fax: +33 55765 6168Email: [email protected] web-site: www.ecrin.orgKey words: clinical research, infrastructures, harmonisa-

tion, transnational studies

Partners Clinical Research Centres / Clinical Trial Units Network,Denmark Réseau Français des Centres d’Investigation CliniqueINSERM-Hôpitaux, FranceRéseau Français d’unités d’essais cliniques, France Netzwerk der Koordinierungszentren für Klinische Studien,GermanyConsorzio Italiano per la Ricerca in Medicina, ItalyIstituto Mario Negri. Italy Spanish Clinical Research Network, SpainClinical Research Centres / Clinical Trial Units Network,SwedenEuropean Forum for Good Clinical Practice

Acronym: ECRIN-RKPProject number: LSHM-CT-2004-511963EC contribution: €225 000Instrument: Specific Support Action Duration: 12 monthsStarting date: 13/05/2004



• Bloodomics 18• EVGN 20• MOLSTROKE 24• EuroClot 26• Myocardial Repair 28

Cardiovascular


SummaryCoronary artery disease and atherothrombosis cause more deathsin Europe than any other disease.About 600 000 people are diagnosedwith myocardial infarction (MI) yearly, with 50% of cases being fataland many of the survivors experiencing a reduction in quality of life.Early identification of individuals at risk has proven difficult in the past.With state-of-the-art tools and technologies at hand,the Bloodomicsproject aims at discovering markers associated with a higher risk forarterial thrombus formation and MI.

In the post-genome era, the Bloodomics project makes use of thecompleted human genome sequence as well as employing highthroughput platforms for sequencing, genotyping for single nucleotidepolymorphisms (SNPs), gene expression analysis, proteomics andRNA interference. Integrating the knowledge generated with thesedifferent platforms with clinical information from MI patients will leadto the identification of genetic markers for atherothrombosis.

The Bloodomics project focuses on the genetics and cell biology ofplatelets,since we hypothesise that the response of platelets is criticalin determining whether thrombus formation will lead to arterial bloodvessel occlusion. Initially, we will identify platelet genes and genevariants that contribute to atherothrombosis. Later we will determinethe physiological role of the corresponding proteins and characterisethe signalling pathways involved. This comprehensive approach willprovide new insights into the causes of coronary artery disease andatherothrombosis, eventually leading to the development of newstrategies for prevention and novel anti-platelet drugs for treatment.

The Bloodomics consortium has brought together a multi-disciplinaryteam from 14 world leading academic centres across Europe. Fiveleading clinical coronary artery disease units,groups specialized in cellbiology and signalling, haematopoiesis and proteomics will worktogether with Europe's premier genome centre in this challengingdiscovery programme.The programme will be underpinned by a teamof ten bioinformaticians and four statisticians. In addition, two youngcompanies,Domantis Ltd,an antibody engineering company and TriumAnalysis Online, a company developing online solutions forbiostatistics, epidemiology and informatics, will make criticalcontributions. By adding 30 new positions to the existing 160 staff inthe affiliated institutes, Europe’s commitment to basic andtranslational research in coronary artery disease andatherothrombosis will be strengthened.

The clinical challengeThe risk of cardiovascular disease is determined by the interplaybetween an individual’s genetic background, lifestyle and environment.Twin studies have clearly demonstrated a genetic component forcardiovascular disease and several risk genes have already beendiscovered. However, genetic markers to predict the risk ofatherothrombosis are currently not available. The absence of suchmarkers means that there is a risk of an excess of preventativetreatment. As an example, long-term aspirin use can cause bleedingand its benefits for the population at large become marginal if it isused too widely.

AimThe Bloodomics project aims to discover genetic markers for theprediction of thrombus formation in coronary artery disease and todesign better anti-thrombotics for improved prevention andtreatment.

Expected resultsDuring the course of the project, 300 candidate platelet genes thatare potentially associated with arterial thrombus formation will beidentified using complementary approaches.Three different routes willbe used to discover candidate genes. First, we will define the plateletresponse to several well-characterised agonists in a large group ofhealthy individuals and then identify differences in mRNA and proteinabundance using microarray and proteomics in extreme end samples.Second, we will compare the transcriptome of platelets from MIpatients and controls. Finally, we will discover novel genes importantfor platelet function by studying rare pedigrees with unexplainedautosomal recessive bleeding disorders of the platelet type.

Based on the common disease-common alleles hypothesis,the geneticvariants in the 300 candidate genes will be identified by exonresequencing in a reference panel of 48 individuals.This will lead tothe discovery of common alleles.To determine whether certain allelesdo confer a statistically significant risk to coronary artery disease orrelated events,we will analyse the frequency of these polymorphismsin a Phase-I case-control study using the DNA of 2 000 well-characterised patients and 2 000 common controls. By this directapproach alleles that may confer a relative risk of at least 1.5 will bediscovered.These putative risk genes (predicted to be 5-10% of theinitial 300 candidate genes) will require further investigation in a Phase-II case-control study with another 3 000 patients and controls.Wewill be able to achieve this because the Bloodomics DNA repositoryprovides access to samples and clinical phenotype information fromover 10 000 patients with coronary artery disease and 10 000common controls.

Identification of risk genes for atherothrombosis in coronary artery disease by transcriptome and proteomeanalysis and high throughput exon resequencing

CARDIOVASCULAR


Bloodomics


We will integrate the results obtained in functional and cell signallingstudies with the transcriptome, proteome and genetic data of a largenumber of healthy individuals and patients. It is expected that this willresult in a library of platelet functional signatures and geneticfingerprints.This integrated library will be a powerful tool towardspersonalised medicine in coronary artery disease.

Finally, the application of RNA interference in human haematopoieticstem cells will further allow us to gain insight into the function ofnovel platelet proteins that are discovered within the candidate geneprogramme. In combination with an antibody production pipeline, itis expected that we may identify novel targets for drug development.

Potential applicationsIdentification of individuals at risk is paramount for an effectivepreventative health care strategy that aims at reducing the morbidityand mortality of heart disease. Future improvement in coronary careis also dependent on new and safe drugs.The Bloodomics project willmake contributions in both of these areas. First, genetic risk markersfor atherothrombosis will be discovered. Second, novel targets willbe identified and development of anti-thrombotic drugs will besupported by structural studies. Finally, the project will generatepopulation genetics data from large cohorts of patients and controlsfrom different European member states.

Structure of the VWF-bindingdomain of GpIba: Ribbon

representation of GpIba.TheNH2-terminal ß hairpin, calledß finger, is coloured blue; theeight leucine-rich repeats aregreen.The COOH-terminal

flanking region is coloured redand contains a disorderedloop (residues 227-241)called ß switch. Disulfide

bridges are indicated in yellowball-and-stick representation.

CARDIOVASCULAR


Coordinator Dr.Willem H. Ouwehand

European Cardiovascular Genetics Foundation (ECGF),Department of Hematology,University of Cambridge,Long Road

Cambridge CB22PT, United Kingdom

Phone: +44-1223-548 037

Fax: +44-1223-548 136


Project website: www.bloodomics.org

Key words: coronary artery disease, atherothrombosis,myocardial infarction, platelet, RNAi,microarray, proteomics, genotyping,sequencing, case-control study, clinical cohort

PartnersThe Chancellor, Master and Scholars of the University ofCambridge, United Kingdom

European Cardiovascular Genetics Foundation, Cambridge,United Kingdom

Genome Research Ltd/Wellcome Trust Sanger Institute,Hinxton, United Kingdom

Universitair Medisch Centrum Utrecht,The Netherlands

Academisch Ziekenhuis bij de Universiteit van Amsterdam,The Netherlands

Katholieke Universiteit Leuven, Belgium

Stichting Sanquin Bloedvoorziening, Amsterdam,The Netherlands

LURIC Datenbank Gesellschaft bürgerlichen Rechts,Freiburg, Germany

Associazione per lo studio della trombosi in cardiologia,Pavia, Italy

Trium Analysis Online GmbH, Munich, Germany

Medical Research Council/Biostatistics Unit, Cambridge,United Kingdom

Domantis Ltd, Cambridge, United Kingdom

University of Leicester, United Kingdom

University College Dublin, Ireland

Subcontracting: National Institute for Biological Standardsand Control, Potters Bar, United Kingdom

Acronym: Bloodomics

Project number: LSHM-CT-2004-503485

EC contribution: €8 879 155

Instrument: Integrated Project

Duration: 48 months

Starting date: 01/06/2004


SummaryCardiovascular disease (CVD) caused 51% of deaths in Europe in 2001.

Coronary heart disease and stroke,which result from atherosclerosis,

constitute 80% of CVD.Better prevention and treatments have halved

age-specific incidence, but the ageing population and adverse trends in

obesity and diabetes threaten these improvements.There is also an

alarming increase in heart failure, the end stage of coronary heart

disease.Future advances depend on developing entirely new strategies.

Genomics and proteomics together open up fresh horizons for

molecular understanding of cardiovascular disease, for identifying new

diagnostic measurements and developing new pharmacological, gene

and cell-based therapies.The European Vascular Genomics Network

(EVGN) assembles the necessary critical mass and promotes

multidisciplinary interactions by uniting 25 world-leading basic and

clinical institutions from nine European countries.It focuses on the three

areas with greatest therapeutic potential:

1) endothelial dysfunction,an early critical event in atherosclerosis and

hence a target for prevention;

2) plaque instability,responsible for precipitating thrombosis and hence

most life-threatening acute events; and

3) therapeutic angiogenesis,either conventional or cell-based to recover

ischemic organ function and reduce heart failure. Our research

armoury spans genomics,proteomics,molecular biology,cell biology,

gene transfer and genetic modification in mice, and integrative

pathophysiology in man.The EVGN will maximise the scientific and

commercial potential of European vascular biology by electronic

data-sharing and communication networks, shared research tools,

and exchange and training programmes. The EVGN will train

tomorrow’s lead investigators through a European training

programme for PhD students,which will also address adverse gender

balance and encourage excellence in eastern Europe, which suffers

high prevalence of CVD.

Expression of the adhesion molecule VCAM-I (in brown) by the endotheli-um of a mouse fed an atherogenic diet for 10 days. Lumen on the right

European Vascular Genomics Network

CARDIOVASCULAR EVGN



ProblemCardiovascular disease is the leading cause of death in the EuropeanUnion, accounting for over 1.5 million deaths each year (5 millionin Europe).Nearly half (42%) of all deaths in the EU (51% in Europe)in 2001 were from cardiovascular disease,while cancer caused 20%.Ischemic heart disease and stroke, which have a predominantvascular origin resulting from atherosclerosis, account for mostdeaths from cardiovascular disease (80%). Age-specific incidencerates for cardiovascular disease have fallen by half over the past 30years in the economically advanced European nations, as the resultof better prevention and treatments based on growing knowledgeof vascular biology. Although these measures are becoming widelydisseminated, an additional dramatic effect on cardiovasculardisease incidence and mortality is unlikely to be achieved withoutthe development of entirely new therapeutic and preventivestrategies. Recent advances in genomics open new avenues tounderstand the molecular basis for cardiovascular disease andhence design new diagnostic tests and classes of drugs based onhitherto unknown target genes.Therapeutic approaches includingDNA vaccination, gene therapy and cell therapy may revolutionisethe prevention and treatment of atherosclerosis. Accordingly, theEuropean Vascular Genomics Network (EVGN) is a timely initiativeaimed at maximising the impact of the post-genome era on vascularbiology so as to optimise the conversion of research results intoconcrete health, social and economic benefits.

Aim1.The EVGN networks and structures the leading European groups

already involved in an uncoordinated way in applying genomics tovascular biology research, so as to maximize their potential. Thenetwork focuses on the 3 research areas, endothelial dysfunction,unstable atherosclerosis and therapeutic angiogenesis that appear mostlikely to generate benefits for patients.

a) Endothelial dysfunction is an early prognostic marker andimportant pathological mechanism underlying the developmentof atherosclerosis.A major goal of the EVGN is to develop newdiagnostic tools and means to correct endothelial dysfunction,which could have a major impact on atherosclerosis prevention.

b) Potentially fatal myocardial infarctions and strokes areprecipitated by acute atherosclerotic plaque instability, eithersurface erosion or rupture of the fibrous cap.The EVGN is aimedat identifying the genes that mediate plaque instability in humans,designing diagnostic tests to identify high-risk individuals anddeveloping drugs to decrease risk of rupture.

Atherosclerotic plaques (in red) at the surface of the aorta from a mouse deficient in apolipoprotein E

CARDIOVASCULAR



c) Insufficient neoangiogenesis is an integralcomponent of loss of organ functionfollowing chronic ischaemia or acuteischaemic injury due to atheroscleroticplaque rupture and myocardial infarction.Therapeutic angiogenesis promoting thegrowth of new vessels from existing vesselwall cells, in conjunction with therecruitment of circulating endothelialprogenitor cells (EPCs), is therefore viewedas a highly promising strategy torevascularise ischaemic tissues and therebyimprove functional recovery of injuredorgans. A major goal of the EVGN is toidentify genes involved in differentiation,homing and expansion of EPCs.

2.The EVGN acts as an interface between basicscientists and clinician scientists to promoteand accelerate the transition of knowledge invascular biology to improve diagnosis andtreatment of atherothrombotic diseases.

3.The EVGN provides enriched and continued education in vascularbiology. The EVGN proposes to train tomorrow’s leadinginvestigators by creating a European training programme in vascularbiology for PhD students based in part on a summer school.

4.The EVGN jointly manages,disseminates and promotes exploitationof the knowledge generated and accumulated within the network.

Expected results1.To define the molecular mechanisms underlying endothelial and

smooth cell dysfunction and discover new preventive strategies inatherosclerosis.

2.To develop and standardise new animal models of plaque rupture,to improve non-invasive in vivo detection of unstable plaques, andto identify molecular targets whose selective activation/inhibitionwill tend to limit plaque progression or promote atheroscleroticplaque stability.

3.To identify novel genes, gene products, or signalling pathways thatare involved in, and could be targets for, selective modulation ofangiogenesis/vasculogenesis

4.To define the most suitable preventive and/or therapeutic strategiesfor use in clinical care of ischaemic vascular diseases.

Potential applicationsThe chosen study areas 1) endothelial dysfunction,2) atheroscleroticplaque instability and 3) therapeutic angiogenesis represent threephases of the cardiovascular disease continuum. Endothelialdysfunction underlies atherosclerosis progression and is a fertile areafor early diagnosis and prevention.Atherosclerotic plaque instabilityprecipitates most life-threatening manifestations of atherosclerosisand as such is a key unexplored area for novel therapies, not basedon risk factor modification but on targeting the pathology.Therapeuticangiogenesis is a leading edge new technology that promises toameliorate end organ damage following acute cardiovascular events.In particular it may tackle the alarmingly escalating incidence of heartfailure. Each of the three priority areas is ripe for the genomicapproach, since each depends on understanding complex regulatorypathways in molecular detail. Each has potential for the developmentof new diagnostic and therapeutic strategies that will providepermanent benefits for patients.

Expression of the Tissue Factor,the main initiator of thrombus

formation in myocardial infarction (in red), in a human

atherosclerotic plaque that contains debris from apoptotic

cells (in brown)

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Coordinator Dr Tedgui,Alain

Inserm U541

Hôpital Lariboisière

41 blvd de la Chapelle

75475 Paris - Cedex 10, France

Tel: +33 1 44 63 18 66

Fax: +33 1 42 81 31 28

Email:[email protected]

Project web-site: http://www.evgn.org/

Key words: cardiovascular disease, vascular biology, ather-osclerosis, endothelium, angiogenesis, inflam-mation

PartnersBristol Heart Institute,The University of Bristol,United Kingdom

Klinikum der J.W.Goethe-Universität, Germany

Chancellor, Masters and Scholars of the University ofCambridge, Addenbrooke’s Centre for ClinicalInvestigation, United Kingdom

Department of Pharmacology, Cardiovascular ResearchInstitute Maastricht (CARIM),The Netherlands

Center for Molecular Medicine, Karolinska Institutet,Sweden

Fondazione IFOM Istituto FIRC di Oncologia moleculare,Italy

University Hospital, Zürich, Switzerland

Department of Vascular Biology and Thrombosis research,Medical University of Vienna, Austria

Medizinische Klinik und Poliklinik, Johannes Gutenberg-Universität Mainz, Germany

Klinik und Poliklinik Innere Medizin III, Universität desSaarlandes, Germany

Institute for Cardiovascular Research (ICaR-VU),VU Medical Centre,The Netherlands

Centre for Biopharmaceutical Sciences, University ofLeiden,The Netherlands

Department of Biochemistry,Academic Medical Center,University of Amsterdam,The Netherlands

Universita Vita-Salute San Raffaele, Italy

Institut fuer Pathophysiologie, Medizinische, UniversitaetInnsbruck, Austria

A.I.Virtanen Institute, University of Kuopio, Finland

Institute for Cancer Research and Treatment, Universityof Torino, Italy

Experimental Medicine and Gene Therapy Section,National Institute of Biostructures and Biosystems, Italy

St George's Hospital Medical School, University ofLondon, United Kingdom

Department of Molecular Biology, Institute ofMicrobiology,The Hebrew University of Jerusalem, Israel

Department of Reproductive and Vascular Biology,University of Birmingham, United Kingdom

University College London, United Kingdom

Division de Cardiologie, Fondation pour RecherchesMédicales, University Hospital of Geneva, Switzerland

Centre Européen de Recherche en Biologie et enMédecine, IGBMC, Illkirch, France

Ark Therapeutics Group Limited, London, UnitedKingdom

Technoclone GmbH,Vienna,Austria

Inserm-Transfert SA, Pons, France

Acronym: EVGNProject number: LSHM-CT-2003-503254EC contribution: €9 000 000Instrument: Network of ExcellenceDuration: 60 monthsStarting date: 01/01/2004

CARDIOVASCULAR



SummaryStroke kills about 5 million people annually and is also the leading

cause of disability and dementia in adults. Early recognition of

individuals at risk for stroke would significantly alleviate the heavy

social and economical burdens due to stroke. Advances in

identification of vulnerable individuals require development of

entirely new strategies. Stroke is triggered by thrombosis occurring

after rupture of atherosclerotic plaques, and MOLSTROKE focuses

on identifying pathogenetic molecular mechanisms and vascular

protagonists defining vulnerable plaques and contributing to plaque

rupture. MOLSTROKE assembles seven partners with

multidisciplinary backgrounds and exploits innovative technological

approaches together with testing of novel pathogenetic hypotheses.

The priority research areas of MOLSTROKE consist of 1)

concomitant wide genomic and histoproteomic screening of lesional

vascular tissue to identify novel pathogenetic markers, 2) early

inflammatory events, which are the key to atherosclerosis

progression and hence primary prevention, and 3) atherosclerotic

plaque instability,which leads to the acute clinical thrombotic events.

The proposed investigations will implement novel technologies of

differential display of unknown genes and vascular tissue arrays.Thus,

weighted identification of stroke denominators can be accomplished

and thereby lead to improved diagnostic and treatment modalities.

The research armoury spans genomics, tissue arrays, molecular

biology, cell biology, immunology, biochemistry, gene transfer, animal

models and integrative bioinformatic software tools.

MOLSTROKE will maximise the scientific, educational and

commercial potential of the proposal by electronic data-sharing,

communication networks, shared research tools, and training

programmes.

ProblemStroke is a major killer since about 5 million people die each year ofthis disease. Stroke is also the major cause of disability in adults, andthe second most important cause of dementia in western countries.Among those who survive a stroke,the risk of a second stroke is veryhigh. Currently known risk factors for stroke (age, cardiovasculardiseases, atrial fibrillation, arterial hypertension, diabetes mellitus,carotid stenosis) are of low sensitivity and specificity. It is important

to identify new markers to more appropriately predict the possibledevelopment of stroke and to identify those subjects with potentialbenefit from preventive therapy.

Ischemic strokes account for 83% of all strokes and thrombotic strokesrepresent 52% of all ischemic strokes. Thrombotic stroke is aconsequence of atherosclerotic disease and is caused by destabilisationof atheromatous plaque with ensuing thrombosis and vessel occlusionlocally or distally due to embolism.A large body of data supports thatinflammation plays a major role in the pathophysiology of atherosclerosisand stroke.Understanding the mechanisms responsible for the initiation,establishment, maturation and persistence of atherosclerotic lesions isfar from being fully accomplished. The current research focus is thedefinition of new criteria to recognise vulnerable plaques and vulnerablepatients. These criteria should be based on better definition of thepathogenetic mechanisms of plaque rupture. They should utiliseinexpensive and relatively non-invasive screening methods that arecapable of adding predictive value to measurements of established riskfactors.Moreover, they should be readily applicable to an asymptomaticpopulation.

AimThe main scientific and technological goals of MOLSTROKE are toidentify mechanisms and molecular protagonists that participate inthe vascular pathological events leading to thrombotic stroke.MOLSTROKE addresses objectives using two concomitantstrategies.

The first strategy is non-hypothesis driven and will use wide-screeningtechnologies together with novel bioinformatics tools to identify genesand proteins preferentially expressed in atheromatous plaques as wellas molecular,biochemical, and cellular patterns potentially involved inplaque rupture.

The second strategy is based on hypothesis-driven studies,taking intoconsideration current knowledge of the pathogenesis of vascularlesions at the level of molecular protagonists and mediators ofinflammation and vascular cell responses to inflammation.

Expected results• identification of genes of potential pathogenetic importance

• generation and use of novel bioinformatics tools

• localise and quantify differentially expressed proteins in symptomaticatherosclerosis

• identify molecular targets of novel therapeutic approaches toprevent symptomatic atherosclerosis and stroke

• strategy for immunotherapy of atherosclerosis and strokeprevention

Molecular basis of vascular events leading to thrombotic stroke

CARDIOVASCULAR MOLSTROKE



• strategy for lipid-based immunomodulation of atherosclerosis

• development of new therapeutic strategies (anti-inflammatoryand/or anti-angiogenic) for prevention of thrombotic stroke

• translational impact to other diseases in which inflammation andexcessive angiogenesis occur (e.g. cancer, diabetic retinopathy,arthritis, psoriasis)

Potential applicationsPrevention and therapy of stroke.

Coordinator Prof. De Libero, GennaroExperimental ImmunologyDepartment of ResearchUniversity Hospital Basel4030 Basel, SwitzerlandPhone: +41 61 2652365Fax: +41 61 2652350Email: [email protected]. Resink,ThereseSignal TransductionDepartment of ResearchUniversity Hospital Basel4030 Basel, SwitzerlandEmail:[email protected] Project web-site: to be constructedKey words: stroke, atherosclerosis, inflammation, angio-

genesis, lipids, plaque instability

PartnersDr Biedermann, BarbaraDepartment of Internal MedicineUniversity Hospital BruderholzBinningen, SwitzerlandProf. Hansson, Goran. K.Department of MedicineKarolinska Hospital and Center for Molecular Medicine Karolinska InstituteStockholm, SwedenDr Bochkov,ValeryDepartment of Vascular Biology and ThrombosisResearchUniversity of ViennaVienna,AustriaProf. Ricciardi Castagnoli, PaolaUniversità Milano BicoccaMilan, ItalyProf.Wick, GeorgInstitute for Biomedical Ageing ResearchAustrian Academy of SciencesInnsbruck,Austria

Acronym: MOLSTROKEProject number: LSHM-CT-2004-005206EC contribution: €2 300 000Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/01/2005

Work flow in the MOLSTROKE project

CARDIOVASCULAR



SummaryThrombotic stroke is a disabling condition affecting an estimated 650,000

Europeans annually, with considerable mortality and costing over €30

billion/yr. This project aims to unravel the genetic basis of thrombotic

stroke leading to new diagnostics and drug targets.

ProblemGenetic factors account for a substantial component of the incidenceand mortality of stroke.There is little effective therapy.EuroClot aimsto identify and validate potentially therapeutically useful genesassociated with thrombotic stroke using a novel approach. Stroke isa complex end-point disease involving the interaction of manypathologic processes, such as vessel wall atheroma, hypertension,platelet function & coagulation. EuroClot focuses on uncovering thegenes that control the end-stage of the coagulation process that leadsdirectly to the production of the thrombus (clot) that causes vascularobstruction and tissue death.Clinical studies indicate that alterationsin fibrin structure and/or function create a prothrombotic phenotype,which increases vascular risk.Twin studies have shown a substantialgenetic component to levels of activation peptides and the finalcommon pathway of thrombus (fibrin structure/function).

AimWe aim specifically to identify the major genes involvedin variations of the end-stage clotting process andinvestigate the role of these novel genes (and existingcandidate genes) in the pathogenesis of stroke acrossEurope. EuroClot will study stroke intermediatephenotypes in over 3000 twins from theGenomEUtwin project involving eight countries and700 subjects from extended families. Genes will bevalidated in 1000 stroke cases including those from thelarge European prospective MORGAM study. Cross-European differences in allelic frequencies will beexamined along with their relative impacts.Phenotypingwill be standardised and harmonised and a Europeandatabase established. Close links with European SMEswill ensure that all findings from EuroClot aremaximally exploited to develop future novel diagnosticsand therapeutic targets.

Expected results• Identification of susceptibility loci and genes for the

end stages and final common pathways of clotting.

• Assessment of the importance of these geneticfactors in the general European population.

• Discovery of how identified genetic variants vary in influence andfrequency of stroke in Northern and Southern Europe.

• Identification of genes controlling fibrin formation or activation thatwill become important diagnostic tests used in conjunction withother markers or genes.

• Better understanding of the mechanisms involved providing potentialnew drug targets for the prevention or treatment of early stroke.

• Collaboration with SMEs to exploit findings for clinical benefit.

• Generation of genotypic and phenotypic data for concordant anddiscordant twin pairs for future studies evaluating environmentaleffects on stroke pathogenesis and expression.

• Stimulation of interest in thrombotic stroke research.

• Development of the clinical, genetic, and experimental EuroClotdatabase.

• Position European researchers as leaders in clotting and strokeresearch.

Genetic regulation of the end-stage clotting process that leads to thrombotic stroke


CARDIOVASCULAR EuroClot


Potential applications • Potential new drug targets for the prevention of or treatment of early

stroke by reducing the tendency to clot.

• Development of novel therapeutic targets for the prevention ofthrombotic stroke using translational approaches in collaborationwith appropriate SMEs in Europe.

• Development of potential novel diagnostic tests for stroke risk usingcombinations of clotting factors and genetic tests in collaborationwith SMEs in Europe.


CARDIOVASCULAR

Coordinator Prof. Spector,Tim

Twin Research Unit

St Thomas’ Hospital

Lambeth Palace Road

London SE1 7EH, United Kingdom

Phone: + 44 20 7188 6765

Fax: + 44 20 7188 6718


Project web-site: in development

Key words: cardiovascular system, stroke, genetic, clottingfactors

PartnersProf. Grant, Peter

Academic Unit of Molecular Vascular Medicine

Leeds Institute of Genetics, Health and Therapeutics

Leeds General Infirmary

Leeds, United Kingdom

Prof. Rosendaal, Frits

Department of Clinical Epidemiology

Leiden University Medical Centre

Leiden,The Netherlands

Prof. Palotie,Aarno

Finnish Genome Centre

University of Helsinki,

Helsinki, Finland

Prof. Evans,Alun

Department of Epidemiology and Public Health

Mulhouse Building

Belfast, United Kingdom

Dr Stazi,Antionia

Centro Nazionale di Epidemiologia

Sorveglianza e Promozione della Salute (CNESPS)

Rome, Italy

Prof. Pedersen, Nancy

Department of Medical Epidemiology and Biostatistics

Stockholm, Sweden

Prof. Soria, Jose Manuel

Thrombosis and Haemostatis Unit

Hospital de la Santa Creu i Sant Pau

Barcelona, Spain

Acronym: EuroClotProject number: LSHM-CT-2004-005268EC contribution: €1 500 000 Instrument: Specific Targeted Research Project Duration: 36 monthsStarting date: 01/01/2005


SummaryHeart failure caused by ischaemic heart disease is one of the most

common causes of morbidity and mortality across Europe. It is

especially high among elderly people, but post-infarction myocardial

injury is also a major cause of disability in younger survivors from

myocardial infarction.The project is dedicated to stimulate state-of-

the-art research on the clinical applications of autologous stem cells,

including bone marrow-derived stem cells as well as myoblasts, to the

regeneration of heart muscle in irreversibly damaged post-infarction

regions.The consortium includes most experienced European clinical

researchers in the field, which already had accomplished the phase I

clinical trials in participating centres.

The researchers from participating centres have agreed to coordinate

their future clinical trials on stem cell transplantation for myocardial

regeneration in patients with post-infarction heart failure, as a result

of the proposed project.This will include analysis of pooled clinical

data obtained in participating centres, reciprocal exchange of

information on cell culture and cell preparation for transplantation.

This will also include standardisation of clinical protocols aiming at

evaluation of the clinical efficacy of myocardial replacement therapy

as well as hands-on training of different techniques of cell delivery,

including percutaneous cell transplantations, in particular trans-

coronary arteries bone marrow stem cell delivery protocols as well

as trans-ventricular and trans-cardiac-veins myoblast injection

techniques.As a result of further integration of the consortium, it is

expected to stimulate formation of a common future phase III studies

at international level, especially with an option of submitting future

Integrated Project application within the 6th Framework Programme.

The current project of a Specific Support Action project is focused

on coordination of individual studies and integration for future pan-

European research. Thus, the continuation of the current clinical

experiments within phase I and II studies will be performed with

resources from each participating centre.The intention of this SSA

project is to enable the consortium to make appropriate exchanges

of information, reciprocal training visits as well as co-operative

analyses of pooled data. Summary of existing pooled data will be

submitted for publication by participating team leaders. In addition,

two international conferences on stem cell therapies and three

workshops for practitioners will be organised.

ProblemHeart failure due to myocardial infarction is a result of myocardialtissue loss. Preclinical research and initial clinical experience suggestsa possibility of myocardial regeneration by cell transplantation.

AimThe purpose of the project is to enhance the exchange of informationon clinical experience with cell transplantation between leadingresearch groups and to summarise the European experience withmyoblast and bone marrow-derived cells transplantation in patientswith post-infarction heart failure.

Expected resultsIt is assumed, that as a result of the proposed project, the exchangeof information and co-operative reciprocal visits in participatingcentres would further advance clinical research aiming at the myoblasttransplantation in comparison to other totipotent cells as bonemarrow cells for myocardial regeneration.

Potential applicationsEstablishing clinical protocols for the use of cell transplantation forthe treatment of post-infarction heart failure.

Clinical experience with bone marrow cells andmyoblasts transplantation for myocardial repair

CARDIOVASCULAR Myocardial Repair



Coordinator Siminiak,Tomasz

University School of Medical Sciences, Poznan

Department of Cardiology

Ul. Juraszow 7/19

60-479 Poznan, Poland

Phone: +48 61 8212422

Fax: +48 61 8212 319

[email protected]

Project web-site: under construction

Key words: cardiology, medicine, muscle system, stemcells, organ regeneration, cell therapy

PartnersHôpital Européen Georges Pompidou, Paris, France

Instut de Ciencias del Corazon,Valladolid, Spain

University of Rostock, Germany

3rd Medical School, Charles University Prague, CzechRepublic

University Hospital, Clermont-Ferrand, France

Vilnius University, Lithuania

Polish Academy of Science, Poznan, Poland

University of Rotterdam,Thoraxcenter,The Netherlands

Acronym: Myocardial RepairProject number: LSSM-CT-2004-511992EC contribution: €400 000Instrument: Specific Support ActionDuration: 30 monthsStarting date: 01/01/2005

CARDIOVASCULAR




• Diabesity 32• EXGENESIS 34• EUGENE 2 36• TONECA 39• IMMIDIAB 41

Diabetes


SummaryThe Diabesity project brings together basic and clinical scientists with

the joint aim of identifying new genes implicated in obesity and diabetes

(diabesity) and to develop strategies for validating these genes as targets

for future pharmacological manipulation.We will study how these genes

interact with hypothalamic pathways that regulate appetite and

metabolism using multiple approaches to establish the functional role

of genes in regulating metabolism,body weight and composition.Using

this approach we aim to identify several novel, validated drug targets

for the treatment and prevention of diabesity.

ProblemThe rapid increase in the prevalence of obesity, type-2 diabetes, andassociated complications is a major global health problem. In Europealone, approximately 33 million adults will be suffering from diabetesby 2010. Obesity, which is a major recognised risk factor for type-2diabetes, is itself rapidly increasing in prevalence resulting in a ‘diabesity’epidemic.The current cost of type-2 diabetes in the European Unionis €15 billion per year,and medical complications arising from diabetesaccount for up to 8% of total health costs in Europe. For most people,neither dieting nor current pharmacological interventions are effectivein achieving long-term weight reduction. Dieting is largely ineffectivebecause once a chronically overweight state has been attained,the braininterprets dieting as a threat to survival, and the hypothalamic controlsystems of the brain reduce our metabolism and attempt to maintainbody weight, i.e.our brains ‘defend’ our existing energy stores.Thus toprevent and treat diabesity, we must develop approaches to modulatethe ways in which the brain controls metabolism, body weight andcomposition.

AimDiabesity aims to combine neurophysiological,neuroanatomical, andsystems physiological approaches to establish the functional role ofgenes in regulating body composition, in order to understand howmanipulation of gene activity impacts upon whole body physiology,endocrinology and phenotype. We will identify novel genes andprocesses linked to the pathogenesis of diabesity and thereby findpotential molecular drug targets. Characterisation of those drugtargets, in particular by using molecular physiological studies andintegrative human biology, will be followed by target validationresulting in the identification of several novel, validated drug targetsfor the treatment and prevention of diabesity.

Expected resultsUsing a combination of invertebrate and mammalian genetics,Diabesity expects to firstly identify several genes involved in thepathogenesis of diabesity.These potential drug targets will then becharacterised by molecular and physiological studies resulting in thelocalisation of the site of expression of the targets and an understanding of their functional roles in diabesity. Once characterised,potential targets will (by molecular genetics and phenotypicalanalyses) be identified as playing major roles in diabesity, therebyproviding validated novel drug targets and pharmaceutical therapiesthat appropriately address diabetes and obesity.

Potential applicationsNew knowledge generated by Diabesity, primarily novel drug targetsand potential pharmaceutical therapies, will be translated intoapplications that directly enhance human health by bringing basicknowledge through to clinical application. To this end, bothfundamental and applied research will be supported,with an emphasison integrated, multidisciplinary, and coordinated efforts that addressthe present fragmentation of European research and increase thecompetitiveness of the European biotechnology industry.By identifyingpotential new drug targets for the treatment and prevention ofdiabesity we will provide pharmacological and biotechnological SMEswith the possibility to develop novel pharmaceutical therapies.

Novel molecular targets for obesity and type 2 diabetes

DIABETES Diabesity


Coordinator Prof. Dickson, Suzanne L.

Prof. Dickson, Suzanne L.

Department of Physiology, Medicinaregatan 9A

Göteborg University

Box 434

405 30 Göteborg, Sweden.

Phone: +46 31 773 3568


Project web-site: www.eurodiabesity.org/

Key words: diabetes, obesity, metabolism, drug targets, dia-besity

PartnersProf.Astrup,ArneThe Royal Veterinary & Agricultural University

Department of Human Nutrition, Rolighedsvej 30

Frederiksberg C, Denmark


DIABETES


Dr Barroso, InêsThe Wellcome Trust Sanger InstituteThe Wellcome Trust Genome CampusHinxton, Cambridge, United KingdomProf. Bloom, SteveDepartment of Metabolic MedicineImperial College School of MedicineHammersmith Hospital, London, United Kingdom Dr Steuernagel,ArndDeveloGen AG Göttingen, Germany,Prof. Brüning, Jens CKlinik II und Poliklinik für Innere Medizin der Univesität zuKölnCologne, GermanyDr Cox, Roger DMRC Mammalian Genetics Unit, Medical Research CouncilHarwell, Oxfordshire, United KingdomProf. Dieguez, CarlosUniversidad de Santiago de Compostela SpainProf. Enerbäck, SvenMedical Genetics, Department of Medical Biochemistry,Göteborg University, SwedenProf. Ghigo, EzioDivision of Endocrinology and Metabolism,Department of Internal Medicine,University of TurinTorino, Italy,Dr Grosse, JohannesIngenium Pharmaceuticals AG, Munich, Germany,Dr Hager, JorgIntegraGen SA, 4,Evry, FranceProf. Hebebrand, JohannesChild and Adolescent Psychiatry of the RheinischenKliniken of the University of Duisburg-Essen,GermanyProf. Jansson, John-OlovDivision of EndocrinologySahlgrenska Hospital, Göteborg UniversitySweden Prof. Leng, GarethSchool of Biomedical and Clinical Laboratory SciencesUniversity of Edinburgh College of MedicineEdinburgh, United KingdomProf. Liposits, ZsoltInstitute of Experimental MedicineLaboratory of Endocrine Neurobiology,

Budapest, HungaryProf. Meister, BjörnDepartment of Neuroscience, Karolinska InstituteStockholm, SwedenDr Mercer, JulianMolecular Neuroendocrinology GroupAppetite and EnergyBalance Division, Rowett Research Institute, BucksburnAberdeen, United Kingdom Prof. Nolan, JohnMetabolic Research Unit, Dept of Clinical Medicine(Endocrinology)Trinity College Dublin, St James’s HospitalDublin, IrelandProf. O’Rahilly, SteveUniversity of CambridgeDepartment of Clinical BiochemistryAddenbrooke’s HospitalCambridge, United KingdomDr Pagotto, UbertoEndocrine UnitDept. of Internal Medicine and GastroenterologyS.Orsola-Malpighi General HospitalBologna, ItalyProf. Ricquier, DanielFaculté de Médecine Necker-Enfants MaladesParis, FranceProf. Rohner-Jeanrenaud, FrançoiseLaboratory of Metabolic ResearchDivision of Endocrinology, Diabetology and NutritionDepartment of Medicine and of MorphologyGeneva, SwitzerlandProf. Seckl, JonathanMolecular Medicine CentreWestern General Hospital,Edinburgh, United KingdomProf. Staels, BartInstitut Pasteur de LilleLille, FranceProf.Treier, MathiasEuropean Molecular Biology LaboratoryDevelopmental Biology ProgrammeHeidelberg, GermanyProf.Tschöp, MatthiasDept. of Pharmacology, German Institute of HumanNutritionPotsdam-Rehbrücke, Germany

Acronym: DiabesityProject number: LSHM-CT-2003-503041EC contribution: €11 700 000Instrument: Integrated ProjectDuration: 60 monthsStarting date: 01/01/2004


SummaryEurope faces an epidemic of obesity, Type 2 diabetes and the metabolic

syndrome. Obesity and insulin resistance, which can be regarded as

precursors of Type 2 diabetes,arise due to an imbalance between energy

intake and energy expenditure. Regular exercise, combined with an

improved diet, provides protection against, and an effective treatment

for, these conditions.This Integrated Project aims to provide a better

understanding of the molecular mechanisms involved in the protective

effects of exercise and a healthy diet,especially in terms of the signalling

pathways,and the changes in gene expression,involved.These improved

insights should allow the more rational design both of new

pharmaceutical interventions, and of policies designed to improve the

health of the population through improvements in lifestyle.

ProblemThe European Union, like the rest of the developed and developingworld, is facing a major epidemic of three inter-related chronicconditions, i.e.Type 2 diabetes, obesity and the metabolic syndrome.Unless steps are taken to alleviate this crisis, the cost of treating thelong-term consequences of these conditions could overwhelm ourhealthcare systems. Although genetic factors increase the risk ofdeveloping these conditions, their rapid current global rise can onlybe due to environmental factors.Obesity and insulin resistance, bothof which can be regarded as precursors of Type 2 diabetes, arise dueto an imbalance between energy intake and energy expenditure.Thisin turn may be due to two features of the modern urban lifestyle:

(i) frequent consumption of processed foods with high energy andlow fibre content;

(ii) reduction in the amount of exercise taken due to changes in socialand transport patterns. It is now well established that regularexercise, combined with an improved diet, provides protectionagainst the development of these conditions, as well as a first lineof treatment.

AimRecent major scientific advances (in which partners in this projecthave played a prominent part) have begun to unravel the signallingpathways,and changes in gene expression, in muscle and other tissuesthrough which the beneficial effects of regular exercise arise.The aimof this proposal is to establish a major European consortium that will

capitalise on these new advances and begin the process of convertingthem into new measures for prevention or treatment of disease.

Our proposal would establish a consortium that will execute anIntegrated Project on this topic in a truly multidisciplinary manner.Our combined academic expertise ranges across molecular and cellbiology,use of animal models including transgenic mice,human musclephysiology, diabetic medicine, and human epidemiology, genetics andinterventional studies. Some of the methodologies we use include:

1) Molecular biological manipulation of signalling pathways in culturedcells and in animal models, such as in vivo tranfection of DNA intomouse muscle (e.g. Fig. 1)

2) Metabolic studies of muscle during exercise and after exercisetraining in male and female human volunteers, both in healthysubjects or those with Type 2 diabetes (e.g. Fig. 2)

3) Collection of clinical data, and DNA samples for genetic analysis,from families containing subjects with and without Type 2 diabetes,across large European regional populations (e.g. Fig. 3).

The consortium also includes two major European companiesinvolved in pharmaceutical and food production, and two small-to-medium enterprises involved in developing new technologies relevantto our aims.

Studies of changes in protein localisation in live muscle fibres, usingfluorescent proteins

Health benefits of exercise: identification of genes and signalling pathways involved in effects of exercise oninsulin resistance, obesity and the metabolic syndrome

DIABETES EXGENESIS



Expected results1) Identify and delineate the intracellular signalling pathways that

mediate the effects of exercise in skeletal muscle of males andfemales.

2) Identify the mechanisms leading to release by muscle duringexercise of extracellular factors,such as cytokines,that affect insulinresistance and transmit effects of exercise to other sites such asadipose tissue,the liver and endothelial cells,and study their actionat those sites.

3) Identify the signalling mechanisms stimulating release of fatty acidsand cytokines (adipokines) from adipose tissue during exercise andfasting.

4) Establish whether mutations affecting any of the signalling pathwaysinvolved in effects of exercise could predispose to Type 2 diabetes,obesity or the metabolic syndrome in humans.

5) Delineate patterns of expression of genes and proteins in humansat risk of developing Type 2 diabetes and in cohorts of monozygoticand dizygotic twins of known health status.

6) Validate potential new drug targets identified during the research,using small molecule inhibitors or activators, expression ofconstitutively active or dominant negative mutants,siRNA techno-logy, or gene targeting in mice.

7) Develop technologies that enable screening of drugs usingimmortalised human muscle cells, and more effective long-termmonitoring of human physical activity and cardiac function.

Potential applicationsNew insights gained in this project will provide an evidence base to allowthe more rational design of measures aimed at reducing the large burdenof Type 2 diabetes,obesity and the metabolic syndrome in the population.

These measures could take the form of new pharmaceuticalinterventions based on the identification of signalling pathways orproteins responsible for the health benefits of exercise,or of new policiesat local, national or EU level that produce beneficial changes in thelifestyles of the population, especially in terms of diet and exercise.

Metabolic studies during exercise in female and male volunteers

CoordinatorProf. Hardie, D Grahame

Division of Molecular Physiology

Faculty of Life Sciences

University of Dundee

Wellcome Trust Biocentre

Dow Street

Dundee DD1 5EH, Scotland, United Kingdom

Phone: +44 1382 344253

Fax: +44 1382 345783


Project web-site:http://www.dundee.ac.uk/lifesciences/exgenesis/

Key words: exercise, genes, signalling pathways, diabetes,obesity, metabolic syndrome

Partners5 Denmark

1 Belgium

2 France

1 Finland

3 Sweden

5 United Kingdom

2 Spain

1 Switzerland

1 Czech Republic

1 The Nederlands

1 Italy

1 Germany

1 Poland

Acronym: EXGENESISProject number: LSHM-CT-2004-005272EC contribution: €12 700 000Instrument: Integrated ProjectDuration: 60 monthsStarting date: 01/01/2005

DIABETES



SummaryEUGENE2 is a Network of Excellence focused on functional genomics,

genomics, proteomics and bioinformatics to unravel the complex

pathogenesis of Type 2 diabetes and the specific role of the skeletal

muscle, fat and the liver. This involves the dedication and the

development of common research infrastructures in human and rodent

genomics and bioinformatics combined with cohesive research efforts

in proteomics, transcriptional regulation, insulin signalling and action in

the target tissues. A concerted effort in applying functional genomic

approaches in target cells,rodents,and humans will generate information

necessary to make advances in health care,pharmaceutical development

and public health policies.

ProblemType 2 diabetes is a complex polygenic disease where geneticsusceptibility interacts with environmental factors.An early event inthe development of Type 2 diabetes is insulin resistance, i.e., animpaired effect of insulin in the target tissues (muscle, adipose tissueand liver).

Although the metabolism and function of all these tissues are alteredin the diabetic state, it is currentlyunknown if, and to what extent, thesechanges are secondary to the diabetic stateor if they are initiating events in thedevelopment of the disease.

To comprehensively study thepathogenesis of as complex a disease asType 2 diabetes requires a broad array ofexperimental technologies, access todifferent experimental models (cells andanimals), expertise in muscle, adiposetissue and liver biology as well as well-characterised human populations with thedisease and genetically predisposedindividuals who have not yet developedType 2 diabetes. Consequently, no singleresearch group in Europe has the capacityto comprehensively study such acomplicated disease. The existingfragmentation of diabetes research inEurope is an important obstacle tosuccess.

EUGENE2 integrates top scientists indiabetes research in Europe, thereby

bringing together specific expertise in the required areas of cell-and molecular biology, rodent models, biology of target organs forinsulin action (skeletal muscles, adipose tissue and liver) as well ascombined access to unique patient populations allowing functionalgenomic and genetic studies. The establishment of commonresearch protocols, technical platforms and databases will promotedurable and sustainable integration.The increased critical mass andthe joint efforts of scientists with complementary expertise willallow EUGENE2 to advance the current state of the art and providenew insights into the pathogenesis of Type 2 diabetes and toimprove existing therapy.

AimMany steps are taken to strengthen European diabetes research and toreduce fragmentation.These include indirect integrating activities basedon jointly executed research (JER), and direct integrating activities:

• coordinated programming of research in order to strengthen thecomplementarity of the participants

• sharing of common research tools and platforms

• joint use of infrastructures

• exchange of staff and training programmes

• integrated management of knowledge and intellectual property andimplementation of a Joint Strategy for Immaterial Property rights.

European network on functional genomics of Type 2 Diabetes

DIABETES EUGENE2


The Joint Programme of Activities of EUGENE 2


• reinforcement of electronic information and communicationnetworks.

The jointly executed research is focused on generating new knowledgeto fill existing gaps as well as to develop platforms for common use.

A JER programme is, by definition, an instrument for integration.Although intensive research has been focused on the genetics of Type2 diabetes during many years,major genes contributing to this diseaseremain largely unknown.

Each partner in EUGENE2 will bring unique expertise to theproject together with particular models or experimentaltechniques such as:

• unique patient populations and phenotyping procedures combinedwith functional genomics and/or genetics

• unique animal models and their characterisation

• signal transduction and engineered cell models

• peptide synthesis and drug discovery.

Expected results1. Promoting integration through the establishment of common

research platforms for bioinformatics,novel reagents and cell lines,RNA and DNA samples, proteomics and engineering andphenotyping animal models.

2. Jointly executed research to identify novel genes related to Type 2diabetes. Success in this endeavour will have major healthimplications for both the diagnosis and treatment of Type 2 diabetes.

3. Characterising the function of genes related to insulin resistanceand Type 2 diabetes as well as their genomic associations and/orlinkage.

4. Establishing joint training programmes and scientist exchangeprogrammes to strengthen European research expertise in this field.

5. Strengthening the European pharmaceutical and biotechnologyindustries through research collaboration and policy for protectionof knowledge.

DIABETES


Graphical presentation of the research components of EUGENE 2 and their relationships


DIABETES



Section of Integrative Physiology

Dept. of Surgical Science

Stockholm, Sweden

Prof. Joost, Hans-Georg

Dept. of Pharmacology

German Institute of Human Nutrition Potsdam-Rehbruecke

Potsdam-Rehbrücke, Germany

Prof. Beguinot, Francesco

Dipartimento di Biologia e Patologia Cellulare e Molecolare (DBPCM)

II Facoltà di Medicina

Naples, Italy

Prof.Van Obberghen, Emmanuel

Inserm Unité 145 – Faculté de Médecine

Nice, France

Prof.Auwerx, Johan

Institut Clinique de la Souris

Illkirch, France

Prof. Bosch, Fatima

Center of Animal Biotechnology and Gene Therapy (CBATEG)

Universitat Autònoma de Barcelona (UAB)

Bellaterra, Spain

Director Levens, Nigel

Biovitrum AB,

Stockholm, Sweden

Coordinator Prof. Smith, Ulf

Lundberg Lfaboratory for Diabetes Research, Dept. ofInternal Medicine, Sahlgrenska Academy at GöteborgUniversity

413 45 Göteborg, Sweden

Phone: +46 31 3421104

Fax: +46 31 829138


Project web-site: www.eugene2.com (to beestablished).

Key words: diabetes, insulin resistance, cardiovasculardisease, adipose tissue, liver, skeletal muscles

PartnersProf. Laakso, Markku

Department of Medicine

University of Kuopio

Kuopio, Finland

Prof. Häring, Hans-Ulrich

Medizinische Universitätsklinik

Tübingen, Germany

Prof. Sesti, Giorgio

Department of Experimental and Clinical Medicine

University Magna Graecia of Catanzaro

Catanzaro, Italy

Prof. O’Rahilly, Stephen

Clinical Biochemistry

Addenbrooks Hospital

Cambridge, United Kingdom

Prof. Pedersen, Oluf

Steno Diabetes Center

Gentofte, Denmark

Prof. Zierath, Juleen R

Acronym: EUGENE2Project number: LSHM-CT-2004-512013EC contribution: €8 000 000Instrument: Network of ExcellenceDuration: 48 monthsStarting date: 01/11/2004


SummaryType 1 diabetes mellitus (T1DM) imposes a heavy burden of morbidity

and premature death on more than 2 million inhabitants in Europe.To

identify new targets for prevention, diagnosis and treatment of T1DM,

greater understanding of its aetiology and pathology is crucial. This

requires the elucidation of the cellular and molecular mechanisms

responsible for T1DM through bringing together leading European

centres of expertise in the field of clinical and experimental T1DM

research.The capabilities of the European groups participating in this

coordination action (CA) provide the required technical skills and

innovative advances.European diabetes research expertise in T1DM as

assembled in this CA proposal will enable the coordination of RTD

projects which are already in receipt of funding for the research part.

The research topics to be coordinated in this CA deal with (a) molecular

mechanisms of beta cell death and signalling pathways of apoptosis in

T1DM; (b) the impact of environmental factors upon the genetically

based regulation and progression of T1DM; (c) the use of established

and new animal models to unravel the molecular mechanisms of the

aetiology and pathology of T1DM; (d) the role of the cellular immune

system in the pathogenesis of T1DM.The financial support for this CA

will allow the running of the coordination activities.This will make it

possible to better understand the underlying causes of T1DM with the

aim of identifying targets for prevention, diagnosis and treatment.

ProblemType 1 diabetes mellitus (T1DM) is a complex multigenic disease witha large socio-economic impact. It is the most frequent metabolicdisease in children and affects around two million children and adultsin Europe.In many areas of Europe the incidence of T1DM is increasingand affecting children at a progressively younger age.

AimThe aim of this CA is to use advanced genomics to detect triggersof autoimmunity and regulators of progression as well as mechanismsof � cell death in well-characterised patient cohorts and experimentalmodel systems with the aim of identifying targets for prevention,diagnosis and treatment.

To achieve this aim the CA will promote and support the networkingand coordination of research and innovation activities in the field ofT1DM in Europe.

This will be achieved in particular through

• Coordination of common clinical and experimental studies andexperiments on T1DM.

• Organisation of conferences,workshops and expert group meetings.

• Organisation of the exchange of personnel.

• Exchange and dissemination of ethical principles and good practicein clinical and experimental diabetes research through setting upcommon information systems and expert groups.

• Running of a central network resource for collection,quality control,storage and dissemination of biological materials.

Expected resultsThe results of this CA will be:

• Increased knowledge and new expertise in T1DM research.

• Education of young and advanced scientists in T1DM research.

• Exploitation of the acquired knowledge for the development of newtherapeutical concepts for the prevention, diagnosis and treatmentof T1DM.

The new knowledge achieved through this CA will be, in particular,a better understanding of:

• Molecular mechanisms of immune mediated beta cell death andsignalling pathways of apoptosis in T1DM, oxidative stress andcytokines.

• Impact of environmental factors upon the genetically basedregulation and progression of T1DM.

• Role of the cellular immune system in the pathogenesis of T1DM,the role of the T cells and the identification of triggering factors ofthe autoimmune reaction.

• Both in human studies and through the use of established and newT1DM animal models, unraveling the molecular mechanisms of theaetiology and pathology of T1DM.

Potential applicationsDue to the increasing incidence of T1DM in Europe there is an urgentneed for the development of new preventive and curative therapiesof this disease.The activities of this Coordination Action will allowthe identification of new targets for prevention, diagnosis andtreatment of T1DM. This understanding will help to provide therational basis for the development of new pharmaceutical and genetherapies against this serious disease.

Coordination action on the aetiology, pathology and prediction of Type 1 diabetes in Europe


DIABETESTONECA



DIABETES

College Dublin, Ireland

INSERM Unit 457, Robert Debré Hospital, Paris, France

Development & Reproductive Biology, BiomedicumHelsinki, Finland

Steno Diabetes Centre, Gentofte, Denmark

Department of Immunohaematology & Blood Tranfusion,Leiden University Medical Centre, the Netherlands

Department of Endocrinology and Metabolism, Universityof Pisa, Italy

Enterovirus Laboratory, National Public Health Institute,Helsinki, Finland

LEGENDO, UZ Gasthuisberg O&N, Leuven, Belgium

Department Medical Biochemistry, Ernst-Moritz-Arndt-University, Germany

Endocrine Unit, Hospital Universitari de Bellvitge,Barcelona, Spain

Dept of Medical Cell Biology, Uppsala University, Sweden

Institute of Biomedical & Clinical Science, PeninsulaMedical School, United Kingdom

Coordinator Lenzen, Sigurd

Institute of Clinical Biochemistry

Hannover Medical School

30625 Hannover, Germany

Phone: + 49 511 532 6525

Fax: + 49 511 532 3584


Project web-site:http://www.mhhannover.de/institute/clinbiochemistry/toneca

Key words: Type 1 diabetes, beta cell apoptosis,autoantibodies, immunology, animal models

PartnersDepartment of Pharmaceutical Sciences,AstonUniversity, United Kingdom

School of Biomedical Sciences, University of Ulster,United Kingdom

CeeD, Centre européen d’étude du Diabète, France

Diabetes & Metabolism Unit, Medical School, SouthmeadHospital, Bristol, United Kingdom

School of Pharmacy & Biomolecular Sciences, UnitedKingdom

Endocrinology & Diabetes Unit, University of BarcelonaMedical School, Spain

Immunology of Diabetes Unit, San Raffaele ScientificInstitute, Milan, Italy

Pharmacy and Biomolecular Sciences, University ofBrighton, United Kingdom

Dept. of Internal Medicine – Endocrinology, University ofSiena, Italy

Laboratory of Pharmacodynamics, Université Libre deBruxelles, Belgium

Laboratory of Experimental Medicine, Universite Libre deBruxelles, Belgium

GKT School of Biomedical Sciences, King’s CollegeLondon, United Kingdom

Department of Molecular Medicine, Karolinska Hospital,Stockholm, Sweden

Children´s Hospital, University of Tübingen, Germany

Lilly Research Laboratories, Hamburg, Germany

Department of Biochemistry Institution, University

Acronym: TONECAProject number: LSHM-CT-2004-503245EC contribution: €1 000 000 Instrument: Coordination ActionDuration: 48 monthsStarting date: 01/06/2004


Summary

The epidemiology of Type 2 diabetes and its complications vary

significantly between ethnic groups. Immigrants in western Europe,

particularly from the South-Asian countries, appear to represent the

epidemic challenge to understand the genetic predisposition and its

interfaces with the adaptability to new environmental conditions for

the development of Type 2 diabetes mellitus (T2DM). Communities

undergoing transitory lifestyles offer an ideal opportunity to gain

insight to the patterns of genetic predispositions and their complex

interplay with lifestyle that may explain the increasing prevalence of

obesity and T2DM in Europe and the rest of the world today.

The relationships between the conditions like obesity, T2DM and

insulin resistance and impaired insulin secretion are complex.They

may have some common genetic traits and endocrinological features

but the pathophysiology responsible for the development of

hyperglycaemia in Type 2 diabetes is yet to be established. Obesity

stands out as a risk factor for T2DM, but lean Type 2 diabetes was

also observed in India and Bangladesh. Recent observations of

extremely lean, lipoatrophic models have revealed a similar

predisposition to developing diabetes as with those with increased

adiposity. Further investigations are needed in the adipose tissue and

its dysfunction in the pathogenesis of diabetes.

Proteomics are necessary in these investigations. The thrifty

phenotype hypothesis, introduced by Hales and Barker in 1992,

proposed the concept that environmental factors acting in early life

might influence later risk of Type 2 diabetes.This may obviously have

played a role in the increased development of Type 2 diabetes among

immigrants to Europe. Reduction of obesity is the core point in the

treatment of diabetes in all ethnic groups.Reduced calorie intake and

increased physical activity are the main treatment issues for both the

conditions. Individualisation of treatment may be enhanced by further

studies in genetic epidemiology.

The understanding of the etiology and mechanism causing increased

hyperglycaemia in this population will provide clues to more effective

treatment and prevention of diabetes and obesity. Furthermore, the

information may help in understanding the pathophysiology of T2DM

in other population and thereby methods of treatment and prevention

in general.Since the ethnic mix of the European population is changing

rapidly,the identification of the mechanism involved in Type 2 diabetes

is also important for the other ethnic groups.

There is a need to organize cohesive efforts from various specialties

like obesity and T2DM in genetics, bioinformatics, cell biology, clinics,

epidemiology, and prevention.

ProblemTo understand the genetic predisposition and its interfaces with theadaptability to new environmental conditions for the development ofType 2 diabetes mellitus.

Complex interplay with the lifestyles that may explain the increasingprevalence of obesity and T2DM in Europe and the rest of the worldtoday.

To explain the pathophysiology responsible for the development ofhyperglycaemia in T2DM.

To provide clues to more effective treatment and prevention ofdiabetes and obesity.

AimCreate a network of specialists of obesity and T2DM in genetics,bioinformatics and cell biology, clinics, epidemiology and preventionthrough three workshops,two training program and one internationalconference:

1. to train new researchers;

2. to conduct a small-scale genetic study of obesity and T2DM and oflifestyle in available immigrant populations in Oslo, London andHelsinki (funded outside the present project);

3. to contribute to develop bioinformatics;

4. to plan a bigger study of genetics and lifestyle across ethnicity.


IMMIDIAB

Genetic susceptibility for Type 2 diabetes and obesity among immigrants in Europe:Prevention and treatment

DIABETES


Expected resultsReports and review articles from the workshops will be made.Twotraining courses for new researchers will be arranged.At the end ofthe period, an international conference will be held.

Three workshops will address different aspects of the mentionedconditions. Reports and review articles will be made in order toprovide new information and to identify needs and develop protocolsaccordingly for future research.

The current project will contribute to better identifications ofdifferent subtypes, first, by summing up present knowledge, andsecond, by planning and making concerted research on genetics,epidemiology and clinical conditions together with obesity.

Potential applicationsThe overall aim is to provide qualified suggestions to policymakersand to different interest groups for the development of preventionand treatment strategies for people at risk across differentgenotypes, clinical diagnoses, lifestyles and cultures. The ultimateobjective for the network is to plan a bigger study of genetics andlifestyle across ethnicity in Europe. In order to implement the planwe must be able to bridge the fragmented research and form acohesive approach.


DIABETES

Coordinator Prof. Claussen, Bjørgulf

University of Oslo

Pb. 1130-Blindern

0318 Oslo, Norway

Phone +47 2 285 0614

Fax: +47 2 285 0610


Project web-site:www.med.uio.no/iasam/arbeidstrygd/immidiab

Key words: Type 2 diabetes, obesity, genetics, lifestyle

PartnersUniversity of Rome TorVergata, Italy

kBioscience Ltd, Cambridge, United Kingdom

The European Association for the Study of Diabetes,Dusseldorf, Germany

Diabetic Association of Bangladesh

Diabetic Association of Pakistan

University of Malmo, Sweden

London University, United Kingdom

University of Helsinki, Finland

WHO collaborating Centre on Diabetes in India

University of Geneva, Switzerland

Acronym: IMMIDIABProject number: LSHM-CT-2004-504839EC contribution: €200 000Instrument: Specific Support ActionDuration: 18 monthsStarting date: 01/03/2004


• Eumitocombat 44

• Euroglycanet 47

• GENESKIN 49

• EuroWilson 52

• PWS 56

• EUGINDAT 58

• EURAPS 60

• AUTOROME 62

• Orphanplatform 64

Rare diseases


RARE DISEASES Eumitocombat


SummaryDefects in the mitochondrial oxidative phosphorylation (OXPHOS)

system,the principal circuit for cellular energy production,lead to often

fatal, multi-system disorders affecting organs and tissues with a high-

energy demand. The Eumitocombat consortium, consisting of 12

partners and encompassing 21 scientific groups from nine different

countries, aims to integrate and extend knowledge on basic aspects of

OXPHOS biology and the patho-biological cascades underlying

OXPHOS disease manifestation in humans.All of the major European

groups active in the forefront of OXPHOS research will participate in

the project, including the Nobel Prize laureate, Sir John Walker.The

Eumitocombat project will reinforce Europe as the international leader

in the development of treatments capable of combating these disorders.

To this end we will:

• integrate clinical and model-system expertise

• characterise important genes and proteins involved in the formation

and regulation of the OXPHOS-system

• study the network of components involved in cellular energy

metabolism by functional genomics

• develop more efficient genetic and protein (mutation) screening

methods

• evaluate the cellular alterations/adaptations of these defects in

specified cells, tissues, models and humans

• develop methods to target and test therapeutic agents to specific

(sub)cellular locations.

ProblemMitochondrial DNA (mtDNA),and the machinery that maintains andexpresses it, constitute a partially autonomous genetic system withineukaryotic cells.Present in hundreds or even thousands of copies percell, with the possibility of heteroplasmy (mixtures of mtDNA ofdifferent genotypes), maternal inheritance, and dependence uponhundreds of diverse nuclear genes for its function, mtDNA is alsosubject to unique rules.

Moreover,the functions that it encodes -13 key subunits of the OXPHOScomplexes,plus the translational RNAs needed to synthesise them - areessential for life,being at the core of energy metabolism.Therefore, it isnot surprising that the genetic fitness of mtDNA is crucial for health.

The contribution of mtDNA mutations to human disease was alreadyrecognised in the late 1980s,when maternally inherited point mutations,as well as clonally inherited mtDNA deletions arising spontaneouslyduring development,were found to be associated with rare neurologicalsyndromes.Since then,three further advances in our understanding havegreatly expanded the field of mitochondrial OXPHOS disorders:

• The mtDNA genotype has been found to be a significant contributorto a range of relatively common,complex or heterogeneous disorders,including diabetes, sensorineural deafness and cardiomyopathy.

• Many nuclear genes that play roles in mtDNA maintenance orexpression have also been found to be involved in disease, includingsome disorders whose ‘mitochondrial basis’ was not previouslyrecognised.

• More controversially, the demonstrable alterations to mtDNAduring aging have given rise to the idea that somatic mutation ofmtDNA as a result of oxidative damage may play a functionallysignificant role in the degenerative processes of aging itself.

Despite a relative explosion of knowledge in the past decade,mitochondrial OXPHOS disease remains essentially intractable.Furthermore, it is also devastating in its impact on patients and theirfamilies.

For all these reasons, new knowledge about mtDNA, about theOXPHOS system and its biogenesis, and about the cellular,developmental and physiological consequences of OXPHOSdysfunction, is urgently needed, in order to establish a feasibletherapeutic strategy to treat these debilitating disorders.

Rational treatment strategies combating mitochondrial oxidative phosphorylation disorders

Model of human complex I, with the various subunits


AimThe project’s main goals are to obtain a detailed understanding of theclinical and pathobiological consequences of OXPHOS disease inorder to develop new treatment strategies.Efforts will be focused oncomplex I, complex IV, mitochondrial DNA maintenance andmitochondrial protein synthesis disturbances.The major objectives,around which the scientific and technological work is structured,applyto each of these disease categories:

1. to understand properly the natural history of the disease, its clinicalmanifestations and their time-course,and the relationship betweengenotype and phenotype. The eventual goal will be to provideroutine and rapid diagnosis, which will form the rational basis forfuture therapy

2. to elucidate the pathophysiology of the disease by the analysis ofbiological models, thus revealing potential new therapeuticstrategies or targets

3. to characterise in detail the cellular machinery primarily affectedby the disease process (i.e. complexes I and IV, the componentsinvolved in their assembly, and the machinery of mtDNAmaintenance and expression). A complete understanding of basicbiological processes underlying OXPHOS will lead to thediscovery of novel drug targets

4. to apply the knowledge gathered from such approaches to therational design and testing of therapeutic agents and manipulationsto ameliorate the manifestations of OXPHOS disease.

Expected resultsArising from the work on the natural history of OXPHOS disease, aseries of workshops will be organised, leading finally to the elaborationof guidelines for clinical management of OXPHOS patients and theevidence-based nosological reassessment of the entire field ofOXPHOS disease. News about progress towards the objectives willbe published and updated annually. Dissemination will be via existingclinical and patient organisation networks in the format of annualelectronic newsletters.

Major achievements of the project will be pre-published on theEumitocombat website. All scientific results will be submitted forpublication in high quality, peer-reviewed journals.

During the lifetime of the project it is expected to elucidate novelgene defects causing OXPHOS disease, using linkage analysis. Newtools for diagnosis of OXPHOS disease will be developed, based onretrovirus- and baculovirus-mediated complementation.New animalmodels are expected to be generated during the project.Proceduresand tools for analysing the mtDNA maintenance machinery will bedeveloped, including an improved procedure for the isolation ofmitochondrial nucleoids. Each of the new treatment compounds tobe developed will be characterised and tested in vitro. In the finalconference/workshop organised by Eumitocombat the state ofmitochondrial research will be evaluated, focusing on the evaluationof new treatment strategies at the patient level, arising from theoutcomes of the project.

Potential applicationsThe project sets out an ambitious, integrated research programmeto build on the achievements described in the preceding section.Using many of the same tools and models, innovative, functionalgenomic technologies will be applied to define the cellular andorganismal consequences of OXPHOS dysfunction and revealpathways and molecules of potential value as drug targets. Adefinitive classification of OXPHOS disorders will be elaborated,using systematic clinical criteria and a rigorous application ofgenetics. Novel techniques will be developed for rapid diagnosis ofmitochondrial disease based on functional complementation.The fullpanoply of genomic tools to identify the remaining key loci involvedin OXPHOS disease will be applied.The consortium will combinetheir existing OXPHOS disease models and promisingpharmacological agents to test out therapeutic strategies, incollaboration with SME partners.

The aim for the four years of the project is to provide a platform forthe development of effective treatments for OXPHOS disease thatcan have a real and sustained impact on the lives of patients and theirfamilies.

RARE DISEASES


Calcium signal following loading with Rhod-2 and the hormonebradykinine in a control human fibroblast cell line


RARE DISEASES


Acronym: EumitocombatProject number: LSHM-CT-2004-503116EC contribution: €8 196 135Instrument: Integrated ProjectDuration: 48 monthsStarting date: 01/07/2004

Coordinator Prof. Smeitink, Jan

Stichting Katholieke Universiteit

University Medical Centre Nijmegen

Nijmegen Center for Mitochondrial Disorders

Department of Paediatrics

Geert Grooteplein 10

P.O. Box 9101

6500 HB Nijmegen,The Netherlands

Phone: +31 24 361 4430

Fax: +31 24 361 6428

Project web-site: http://www.eumitocombat.org

Key words: rare diseases, inborn errors of energymetabolism, orphan diseases

PartnersDr. Peer Bork

European Molecular Biology Laboratory, Structural andComputational biology, Heidelberg, Germany

Dr. José A. Enriquez

University of Zaragoza, Department of Biochemistry and Molecular Cell Biology, Spain

Dr. Nib-Göran Larsson, Dr. Claes Gustafsson

Karolinska Institute, Sweden

Prof. Sir John Walker, Dr. Ian Holt,Dr. Michael Murphy

Medical Research Council, Department MRC-DunnHuman Nutrition Unit, Cambridge, United Kingdom

Dr. Josef Hous μte μk

Institute of Physiology,Academy of Sciences of the CzechRepublic

Prof. Jiri Zeman

Charles University, 1st Faculty of Medicine, Prague,Czech Republic

Prof. Howard Jacobs

University of Tampere, Institute of Medical Technology,Finland

Prof. Robert Lightowlers, Dr. Douglas Turnbull

University of Newcastle Upon Tyne, Department ofNeurology, Newcastle upon Tyne, United Kingdom

Prof. Ferdinando Palmieri, Prof. Luigi Palmieri

University of Bari, Department of Pharmaco-Biology,Bari, Italy

Dr.Agnès Rötig, Dr. Pierre Rustin

Institut National de la Santé et de la Recherche Médicale,Paris, France

Dr. Massimo Zeviani

Istituto Nazionale Neurologico “C. Besta”, Milano, Italy


RARE DISEASES


SummaryThe congenital disorders of glycosylation (CDG) are an emerging

group of inborn errors of metabolism. CDG are typically multi-

system diseases,with a broad spectrum including mental retardation

and severe developmental delay, structural abnormalities of the

central nervous system and cardiac defects, malformations,

hormonal deregulation and coagulation problems, peripheral

neuropathies, etc. There is a high morbidity and a significant

mortality.

Euroglycanet will promote early diagnosis by offering the diagnostic

tools for screening as well as for expert analysis and by raising

awareness. It will integrate research activities in the field, and work

towards the development of therapies for CDG and related

disorders.

To fulfil these aims, Euroglycanet will 1) develop and share effective

tools for early and expert diagnosis; 2) manage a sample flow

through the different laboratories involved in this activity and 3)

maintain a database, accessible through Internet and a public

website.

Euroglycanet will also raise awareness by 4) providing information

to the public and to physicians and other professionals, and by 5)

offering training to expert clinicians and researchers in the field.

To foster research it will select interesting cases for research and 6)

establish an international research forum, including one international

congress,where clinical and basic scientists will meet.The coordinated

diagnostic and research activities include a.o. applications of DNA-

arrays, 2-D gels, mass spectrometry and capillary electrophoresis for

the study of glycoprotein synthesis and defects. 7) The network will

promote collaborations with companies for the development of

therapeutics. The integration of clinical and basic research groups

within the network is a strong advantage in this respect.

Euroglycanet will also 8) increase quality and standardisation by

offering QA schemes and 9) spread and promote access to

diagnostic services by installing additional referral centres in

different European countries, including the new member states.

ProblemGlycosylation is the most complex type of biomolecule modificationoccurring in living organisms. Given this complexity and the largenumber of enzymatic steps involved in protein glycosylation, it isanticipated that many disorders are still unrecognised. Also, it is a raredisease, for which the diagnostic, clinical and research expertise islimited to a few centres in Europe.

Most patients with CDG can be diagnosed by relatively simplelaboratory tests that detect abnormal glycosylation in serum proteins.In contrast, the identification of the underlying defect often requiresexpert enzymatic,biochemical or molecular investigations. It is at thisstage that the expert diagnostic services, offered by the differentlaboratories involved in the network, are playing an important role inthe diagnosis of CDG.

AimEuroglycanet will bring together all the leading European groupswith an interest and expertise in CDG and related syndromes.Theaim is to co-ordinate research and expert diagnostic activities, andto promote awareness and knowledge of this group of diseases.The project also aims at providing the basic diagnostic tools forphysicians by establishing referral laboratories in the Europeancenters that collaborate with Euroglycanet.

It will integrate research activities in the field, and work towardsthe development of therapies for CDG and related disorders.These research activities are grafted onto a central database andpatient sample repository.The samples circulate along the differentexpert laboratories – a principle which was coined ‘carouseltesting’.

Euroglycanet

Congenital disorders of glycosylation: a European network for theadvancement of research, diagnosis and treatment of a growing group of rare disorders

Distribution ofPartners of the

Euroglycanet projectaccross Europe


Expected results1.unite the leading European groups into a multidisciplinary network

2. exploit novel diagnostic and scientific tools

3. continue the patient database and specific mutation databases

4. coordinate and expand a network of specialised centres thatprovide early and accurate diagnosis

5. develop new therapeutic strategies

6. raise awareness

7. training of young, expert clinicians and scientist and education ofother specialists

8. quality assurance, quality assessment and standardisation

Potential applicationsEuroglycanet has identified national referral laboratories that willassume a role of ‘satellites’ or ‘outstations’ for the first-line analysisand dispatch of samples.All satellite laboratories from the networkwill be provided with the same technical equipment and standard testprotocols.

The network will provide access to (early) diagnostics at a pan-European scale; it is committed to training and education, directlycoupled to clinical and basic research. These activities will affectquality of life of the patients with CDG, and their families. Adefinitive diagnosis is one of the most important things for familieswith an affected child.

The network will try to consolidate the European lead on clinicaland fundamental research into this group of rare diseases. Theclose interaction between expert clinicians and specialisedresearchers, together with the centrally monitored ‘carousel’testing, could become a model for the organisation and integrationof clinical and basic research for other rare diseases, in and beyondthe metabolic field.

RARE DISEASES


Acronym: EuroglycanetProject number: LSHM-CT-2005-512131EC contribution: €1 200 000Instrument: Coordination ActionDuration: 48 monthsStarting date: 01/02/05

Coordinator Prof. Matthijs, Gert

Centre for Human Genetics, University of Leuven,

Gasthuisberg, Herestraat 49

3000 Leuven, Belgium

Phone: +32 16 34 60 70

Fax: + 32 16 34 60 60


Project web-site: www.euroglycanet.org

Key words: early diagnosis, patient database, awareness,training and education

PartnersAssistance Publique-Hôpitaux de Paris, France

University of Nijmegen, the Netherlands

University of Zurich, Switzerland

Hospital Sant Joan de Déu / IBC, Spain

Institute of Child Health, London, United Kingdom

University of Göttingen, Biochemie 2, Germany

Eidgenössische Hochschule, Zurich, Switzerland

Christian de Duve Institute of Cellular Pathology, Belgium

INSERM U504,Villejuif, France

Institute of Child Health,Athens, Greece

University of Catania, Italy

University of Porto, Portugal

Children’s Memorial Health Institute,Warsaw, Poland

University Hospital of Copenhagen, Denmark

Charles University, Prague, Czech Republic

Higher Medical School, Sofia, Bulgaria

Universidad Autonoma de Madrid, Spain

Hadassah and Shaare Zedek MC, Jerusalem, Israel

Rambam Medical Center, Haifa, Israel

Department of Paediatrics, Zagreb, Croatia

Institute of Chemistry and Technology of Polymers,Catania, Italy

Orphan Europe, Paris, France

CLIMB, Crewe, United Kingdom

Universitätskinderklinik, Heidelberg, Germany


SummaryGenetic skin diseases comprise almost 300 rare but often severe

and even life-threatening diseases and syndromes. Despite recent

identification of causative genes in a number of these disorders,

the molecular bases of several others are still unknown, and often

the function of the identified disease-gene products remains an

unsolved mystery. In addition, disease number and rarity impair

proper management, and no curative therapy is available. By

bringing together clinicians, researchers and patient associations,

GENESKIN aims to generate accessible knowledge and improve

health care service structures for affected people.The focus is on

five major disease categories: epithelial adhesion disorders,

keratinisation disorders, ectodermal dysplasias, connective tissue

diseases, DNA repair disorders. For each group, a clinical and

laboratory network will generate and disseminate: 1) a list of

reference centres with services offered, 2) diagnostic question-

naires/protocols, 3) gene cards, mutation database, diagnostic

reagent lists, and ongoing clinical trial list.The research topics to

be co-ordinated in GENESKIN deal with: i) improved early post-

natal and pre-natal diagnosis by novel immunohistochemical/

biochemical and molecular tests, ii) identification of new

genes involved in genetic skin diseases by collecting a

sizeable number of biological samples, iii) definition of

genotype-phenotype correlation and characterisation of

newly identified gene product functions by creation of

a sample databank. Knowledge dissemination and

improved management will also be ensured through the

organisation of involved personnel training. Finally, pan-

European communication among patients’ organisations,

ethics committees, physicians and scientists will be

promoted.The information regarding clinical/diagnostic

protocols/lists, diagnostic and research tools and

communication among different groups will be

integrated and disseminated through a dedicated

website.

ProblemGenetic skin disorders encompass almost 300 different diseases andsyndromes, most of which are severely disabling or life threateningand have a major impact on health care services and personnel.Thenumber and rarity of these disorders (prevalence between 1:6 000and <1:500 000 for each condition) hamper single-centre (or country)studies aimed at their characterisation and cure. Despite the greatprogress of the last decade, the molecular basis of several of thesediseases is still unknown,and in many cases the function of the knowndisease-gene products remains an unsolved mystery.Furthermore,nocurative therapy is at present available for any form of genetic skindisease and pharmaceutical companies have limited or no interest indeveloping diagnostic and therapeutic strategies for these orphandiseases.A significant logistical problem is that only a few centres inEurope are in a position to try to deal with groups of these diseasesand even then their expertise is limited to just a few specificconditions. Thus, expert knowledge for clinical and moleculardiagnosis, for management and innovative therapy is isolated andscattered in an often uncoordinated way throughout Europe. As aresult patients experience significant difficulties in finding experts andmultidisciplinary healthcare teams specialised in clinical andmolecular diagnosis, able to offer high quality disease management.This situation can only be overcome by a European mobilisation ofactivities and resources, most effectively through a Europeanconsortium that will facilitate development of substantially improvedand cost-effective health care services.

RARE DISEASES


GENESKIN

Rare genetic skin diseases: advancing diagnosis,management and awareness through a European network

Schematic representation of the GENESKIN project


RARE DISEASES


AimThe present project arises as a joint effort of European scientists andclinicians, with the direct involvement of patients’ associations, toestablish a consortium of groups engaged in providing a critical massof patients and research tools in the fields of inherited skin diseases,including diseases predisposing to skin cancer. To this regard, theproject’s main objectives are:

• to create a European clinical and diagnostic network for five majorgroups of genetic skin diseases,namely epithelial adhesion disorders,keratinisation disorders, ectodermal dysplasias, connective tissuediseases, and DNA repair diseases

• to integrate, test and validate diagnostic and research tools for theabove-mentioned disease groups

• to promote training on clinical, diagnostic and management aspectsof specific disease groups

• to promote pan-European communication pathways among patients’organisations, ethics committees, physicians and scientists.

Expected results • a web-based informatics platform that, for each of the five

categories of diseases listed above, will contain:

1) a list of reference centres with clinical/diagnostic services offered;

2) diagnostic questionnaires/protocols/check-lists;

3) gene cards and mutation database;

4) lists of available diagnostic reagents;

5) disease-related web-sites and ongoing clinical trials;

6) recent updates in the proper field.

• for selected diseases:

1) standardised immunohistochemical/ biochemical screeningtests, preliminary to molecular diagnosis;

2) standardised prenatal and postnatal molecular diagnostic testsand a prototype assay based on microchip technology;

3) a ‘virtual’ biological sample databank.

• dissemination of knowledge about clinical features, diagnosticprocedures and management of specific disease groups at aEuropean scale

• close alliance of patients’ organisations and ethics experts withphysicians and scientists.

Potential applicationsThe achievement of the proposed objectives will greatly contribute tothe implementation of the Community Policy Objective aimed atcombating rare diseases. In fact, bypassing the problems related to therarity of inherited skin diseases, the clinical and research network willprovide a rapid translation of emerging gene discovery and gene

function findings into clinical applications that are relevant to accurate,rapid and early diagnosis,molecular and prenatal testing,and to fosterimplementation of clinical trials. In particular, the multidisciplinarysynergistic efforts of investigators and clinicians, in close collaborationwith patient associations, will allow:

• the establishment of a European task force for the study of theserare disorders at fundamental and clinical levels;

• the rapid translation of the novel knowledge and diagnostic toolsfrom the bench to the bedside, resulting in an improved diagnosisand management of these disorders at European and national scale;

• the augmentation of an early and accurate pre- and post-nataldiagnosis, which is crucial for prognosis definition and propermanagement, and is beneficial for the psychological well-being ofpatients and families who do not feel well living in diagnosticuncertainty and insecurity;

• easier access for patients to clinical trials and in general earlier andproper management leading to an increase of the quality of life ofthe patients, and improvement of the clinical course of the disease.This will reflect positively over the duration of life expectancy andmedical costs.

In addition,close co-operation of physicians and scientists with publicnon-medical groups, i.e.patients’ organisations and ethics committeeswill contribute to:

• developing and maintaining an equal dialogue among these differentparts;

• patient-specific needs being continuously part of medical and/orscientific decisions, in agreement with ethical values;

• further raising public awareness about rare diseases, fulfilling societalgoals.


RARE DISEASES


Centre National de la Recherche Scientifique, Laboratoryof Genetic Instability and Cancer – UPR 2169-CNRSInstitut Gustave Roussy,Villejuif, France

Hopital Necker Enfants Malades, Service deDermatologie, Paris, France

Consortium National de Recherche en Genomique,Centre National de Genotypage - Department ofDermatological Diseases,Evry, France

Assistance Publique - Hôpitaux de Paris Hospices Cantonaux - Centre Hospitalier UniversitaireVaudois, Service de Dermatologie des Hospices,Lausanne, Switzerland

Universiteit Gent, Department of Medical Genetics,Ghent University Hospital, Belgium

Erasmus Medical Center Rotterdam, Medical GeneticCluster - Department of Cell Biology & Genetics,The Netherlands

Academisch Ziekenhuis Gronigen, Department ofDermatology,The Netherlands

Asociacion de Epidermolisis Bullosa de Espana, ConsejoSuperior de Investigaciones Cientificas, Centro Nacionalde Biotecnologia,

Departamento de Immunologia y Oncologia,Madrid, Spain

Federal Academic Hospital of Feldkirch, Department ofDermatology,Austria

Gemeinnutzige Salzburger LandesklinikenBetriebsgesellschaft mbH, Dermatology - Laboratories,Salzburg,Austria

Department of Dermato-Venereology – SemmelweisUniversity, Budapest, Hungary

Department of Medical Sciences /Dermatology andVenereology, University Hospital,Uppsala, Sweden

Uppsala Universitet, Department of Medical SciencesDermatology and VeneralogyUppsala, Sweden

Acronym: GENESKINProject number: LSHM-CT-2005-512117EC contribution: €1 238 199Instrument: Coordination ActionDuration: 36 monthsStarting date: 01/07/2005

Coordinator Zambruno, Giovanna

Provincia Italiana della Congregazione dei Figlidell’Immacolata Concezione-I.D.I-I.R.C.C.S.

Laboratory of Molecular and Cell Biology

Via dei Monti di Creta 104

00167 Rome, Italy

Phone: + 39 0666 464738

Fax: + 39 0666 464705


Project web-site: to be developed.

Key words: rare genetic diseases, skin, dermatology,diagnosis

PartnersConsiglio Nazionale delle Ricerche, Rome, Italy

Department of Biomedical Sciences, Università diModena e Reggio Emilia, Modena, Italy

Department of Dermatology, University Hospital,Freiburg, Germany

Department of Dermatology, University of Munster,Germany

Centre for Functional Genomics, University of Cologne,University Hospital, Cologne, Germany

Philipps-Universitaet Marburg, Institut fuer AllgemeineHumangenetik, Marburg, Germany

Genetic Skin Disease Group, King's College, London,United Kingdom

Centre for Cutaneous Research, Queen Mary &Westfield College, University of London, United Kingdom

Genome Damage and Stability Centre, University ofSussex, Brighton, United Kingdom

Cancer Sciences and Molecular Pathology, University ofGlasgow, United Kingdom

DebRA Europe, Crowthorne, United Kingdom

Our Lady’s Hospital for Sick Children, Department ofPaediatric Dermatology, Dublin, Ireland

Institut National de la Santé et de la Recherche Médicale,INSERM Unités 634, 563 and 217,Nice, France

Centre Hospitalier Universitaire de Nice, Service deDermatologie, Nice, France


The trans-Golgi P-type ATPase, with its 8 transmembrane sections

RARE DISEASES EuroWilson


SummaryWilson Disease is genetic disorder in which deficiency of a copper-

transporting P-type ATPase leads to intracellular retention of

copper in the liver, brain, and kidney. Incidence estimates vary from

1/30 000 to 1/100 000. There is controversy as to treatment,

because of a lack of randomised trials comparing copper-chelators

such as penicillamine or trientine with zinc. In preparation for the

planning of such trials, a European Clinical Database is to be

established.This will inform us as to the incidence of the disease,

its geographical variation, and the frequency of its differing clinical

presentations.

ProblemIt is almost exactly 100 years since Wilson described the neurologicaland liver disorder which bears his name. It was recognised to beautosomal recessive in inheritance in 1921, and to be associated withcopper storage in 1945.The discovery of penicillamine (1953), zinc

sulfate (1961),and trientine (1969) were major therapeutic advances.We now know it to be a disorder of a P-type ATPase situated in thetrans-golgi,ATP7B, which is a copper transporter. Its deficiency leadsto impaired biliary excretion of copper, impaired caeruloplasminsynthesis, and copper accumulation in the liver, the basal ganglia ofthe brain, and proximal renal tubules.The clinical manifestations arediverse. Liver disease is the most frequent presentation in children,and may be of different types and severity. Some present with acuteliver failure with encephalopathy, requiring urgent transplantation.Some have a more gradual onset resembling a chronic hepatitis,whileother may be discovered to have cirrhosis with few symptoms.Haemolysis is frequently also found. By contrast, older patients tendto present with neurological difficulties. Abnormalities of speech,coordination and fine motor performance progress to severe tremor,movement disorder and disability. Other organs are affected to avariable degree,resulting in joint symptoms,renal disease,and anaemia.Pre-symptomatic patients are detected through family studies.

Older patients with neurological disease tend to have the commonH1069Q mutation. However, there is great phenotypic variabilityamongst patients with the same genotype, and the reasons for thisare not known.

Wilson Disease: Creating a European clinical database anddesigning multicentre randomised controlled clinical trials


There is a need to determine an optimum treatment regime. ACochrane style evaluation of the current literature on Wilson Diseaseand treatment yielded over 1000 hits.Over 500 articles were ‘expert’opinions in favour of either zinc treatment or the use of copperchelators. No randomised clinical trial could be found, and less than

20 articles described the results of a particular treatment in a seriesof patients. In only one article, describing 58 patients, both treatmentoptions (zinc and D-penicillamine) were evaluated in a non-randomised way. As no strict end points were defined no firmconclusions could be drawn.

RARE DISEASES


Members of the consortium at a meeting in September 2004


RARE DISEASES


AimThe principal aim of this project is to establish a European ClinicalDatabase of newly presenting patients with Wilson Disease.

Expected resultsWe will determine:

1. the overall incidence of Wilson Disease, and its variation indifferent countries.There is an impression of increased incidencein, for example, Sardinia, but this may be because of betterascertainment;

2. the numbers of patients in different clinical categories;

3. the treatment regimes currently being used and their short-termoutcomes;

4. the genotype of newly presenting patients.

From this data, the feasibility of a randomised trial will be assessed.Phenotypic heterogeneity implies that this will either be a stratifiedtrial, or a series of trials of homogeneous subsets.

Additional benefits1.The project will bring a profile to a rare disease, provide patient

and physician information, and stimulate related research.

2.A quality assurance scheme will be established amongst theparticipating molecular diagnostic laboratories.

3.The discussions between clinicians about database items are yieldinga valuable consensus about physical sign assessment in Wilsondisease, and potentially other disorders.

4. Continuation of the database will provide a long-term researchresource.

5.The data collection system will be useful for other multicentrestudies.

The Kayser-Fleischer(KF)ring,

copper deposit in Descemet’s membrane in

the eye.


RARE DISEASES


Dr Loudianos, Georgios

Dipartimento di Scienze Biomediche e Biotecnologie

Cagliari, Italy

Dr Schmidt, Hartmut

Med Klinik m.S. Gastroenterologie, Hepatologie, Charite– Universitatsmedizin BerlinBerlin, Germany

Dr Melter, Michael

Pediatric Gastroenterology, Hepatology and LiverTransplanatation

Hannover Medical School

Hanover, Germany

Dr Houwen, Roderick

Department of Pediatric Gastroentrology

Utrecht,The Netherlands

Prof. Cohen, Olivier

HC Forum, Equipe Genome

Laboratoire TIMC

Medical School of Grenoble

La Tronche, France

Mrs Parker, Samantha

Medical and Marketing Department

Orphan Europe Sarl

Paris-La Defense, France

Prof. Sarles, Jacques

Service de Pediatrie Multidisciplinarire

Hopital d’enfants de la Timone

Marseille, France

Dr Dhawan,Anil

Division of Hepatology and Transplantation

Institute of Liver Studies

King’s College London

London, United Kingdom

Acronym: EuroWilsonProject number: LSHM-CT-2004-503430EC contribution: €799 645Instrument: Coordination ActionDuration: 48 monthsStarting date: 01/06/04

Coordinator Prof.Tanner, Stuart

Academic Unit of Child Health

University of Sheffield

Children’s Hospital Western Bank

S10 2TH Sheffield, United Kingdom

Phone: +44 114 271 7303

Fax: +44 114 275 5364


Project web-site: www.eurowilson.com

Key words: copper, liver, cirrhosis, movement disorder,database, randomised trial

PartnersProf. Czlonkowska,Anna

2nd Department of Neurology

Institute of Psychiatry & Neurology

Warsaw, Poland

Dr Socha, Piotr

Dept. of Gastroentology, Hepatology

The Children’s Memorial Health Institute

Centrum Zdrowia Dziecka,

Warsaw, Poland

Dr Szonyi, Laszlo

1st Department of Paediatrics,

Semmelweis University

Budapest, Hungary

Prof Ferenci, Peter

Dept. Of Internal Medicine

Medizinische Universitat Wien

AKH Wien,Vienna,Austria

Prof. Deutsch, Johann

Medizinishe Universitat Graz

Univ Klinik fur Kinder and Jugendheilkunde

Graz,Austria

Prof.Vegnente,Angela

Department of Paediatrics, University "Federico II"Naples

Naples, Italy


RARE DISEASES PWS


SummaryPrader-Willi syndrome is a rare neurodevelopmental disorder with

a characteristic physical and behavioural phenotype that results

from the absence of expression of as yet unidentified maternally-

imprinted/ paternally-expressed gene(s) at 15q11-13. Seven

maternally-imprinted genes have been located in the PWS critical

chromosomal region and in the mouse homologues. HBII-52 and

HBII-85 in humans, Magel 2, and Necdin are four candidates that

will be the focus for developing mouse models in order that

genotype/phenotype relationships and signalling pathways can be

studied.Hypothalamic tissue obtained at post-mortem from people

with PWS will also be used to investigate hypothalamic pathways

known to be important in the control of eating behaviour.The basis

for a European-wide clinical study of developmental outcomes in

PWS will be established through the development of a clinical

database and its evaluation in specific EU countries.

ProblemPrader-Willi syndrome is a complex neurodevelopmental disorderresulting from absent expression of maternallyimprinted/paternally-expressed, but as yet unidentified, gene(s) atthe locus 15q11-13.The two most common genetic sub-types arechromosomal deletions at 15q11-13 involving chromosome 15 ofpaternal origin and chromosome 15 uniparental maternal disomies.Two other rare genetic abnormalities are also described.The PWSphenotype in infancy is characterised by extreme hypotonia, failureto thrive, hypogonadism, and the need for augmented feeding. Fromapproximately two years of age,excessive eating becomes apparent,remaining throughout life and if left unchecked, leads to severeobesity and early death. Other diagnostic characteristics includedevelopmental delay, mild intellectual disabilities, short stature,small hands and feet, and delayed sexual development, together witha propensity to other maladaptive behaviours. This over-eatingbehaviour is due to an abnormal satiety response to food intake.In adult life those with PWS due to chromosome 15 maternaldisomy invariably develop severe affective psychotic illness. Studieson post-mortem-obtained hypothalamic tissue have shown areduction in oxytocin expressing neurones of the hypothalamus.So far the function of only two of the hypothalamic peptidesimportant in the regulation of appetite have been investigated andin these two cases no abnormalities have been found (NPY andagouti-related peptide).

The mouse 7C chromosomal region has conserved synteny with thehuman 15q11-q13 region. Four potential mouse models with a globaldeficiency of paternal gene expression in the 7C chromosomal region,and therefore potential models for PWS, have been described. Theobserved phenotype is consistent with the feeding difficulties andfailure to thrive that is characteristic of PWS infants.Thus, complexmouse models provide the means for investigating protein interactionsand signalling pathways linking gene expression to observedbehaviours.

The power of clinical studies of PWS at national levels are limitedbecause of the relative rarity of the syndrome. Clinical studies thatinclude sufficient numbers of people with PWS of different geneticsub-types of both genders across all ages are required to determineinfluences on developmental outcomes.

Aim1.To establish specific mouse models of PWS in order to investigate

genotype/phenotype relationships and signalling pathways;

2. to investigate hypothalamic feeding pathways using post-mortemtissue from people with PWS;

3.to establish the basis for a European-wide clinical study investigatinginfluences on developmental outcomes for people with PWS.

Expected results1.The development of a complex mouse model and four specific

knockout mouse models of PWS.

2. Full investigation of genotype/phenotype relationships in thespecific mouse models and of the biological functions of the genesand the associated protein interaction networks and signallingpathways.

3. Investigation of specific hypothalamic feeding pathways in humanhypothalamic tissue obtained at post-mortem from people withPWS.

4.The establishment of a clinical database compatible with ethical andclinical practice throughout the EU for the collection of clinical andresearch data on people of all ages with PWS.

5.The assessment of the database in different European settings.

6.The integration of data from mouse, human hypothalamicinvestigations and existing clinical studies in PWS to inform obesityand behavioural research more generally.

Prader-Willi Syndrome:A model linking gene expression,obesity and mental health


Potential applicationsFor people with PWS and their families it is this extreme propensityto over-eating and other associated behavioural and psychiatricproblems that has the most significant detrimental effect on theirquality of life and on life expectancy.Understanding the mechanismsin PWS that link genotype to phenotype has the potential to resultin new treatments and will provide models for obesity andpsychiatric research more generally.The main focus of this projectis on basic science research but results from subsequent clinicalstudies on developmental outcomes will make possible theintegration of basic science and clinical data leading to thedevelopment of more sophisticated models linking the abnormalexpression of imprinted gene(s) to developmental processes andspecific behavioural and physical outcomes.

RARE DISEASES


CoordinatorProf. Holland,Tony

Section of Developmental Psychiatry

Department of Psychiatry

University of Cambridge

18b Trumpington Road

Cambridge, CB2 2AH, United Kingdom

Phone: + 44 1223 746112

Fax: + 44 1223 746122


Project web-site: to be developped

Key words: Prader-Willi Syndrome, genomic imprinting,hypothalamus, obesity

PartnersCNRS/Institut de Biologie du Developpement deMarseille-Luminy/UMR 6256, Marseille, France

Katholieke Universiteit Leuven, Leuven, Belgium

Section of Biological Developmental Psychology,University of Maastricht,The Netherlands

Institut fur Humangenetik, Universitat Duisburg-Essen,Essen, Germany

Netherlands Institute for Brain Research,Amsterdam,The Netherlands

Department of Women’s and Child Health, KarolinskaInstitute, Stockholm, Sweden

Department for Functional Genomics, University ofInnsbruck,Austria

Weizmann Institute of Science, Rehovot, Israel

HC Forum, Grenoble, France

Centre Européen de la Recherche en Biologie et enMédecine

Acronym: PWSProject number: LSHM-CT-2005-512136EC contribution: €1 655 342Instrument: Specific Targeted Research Project Duration: 36 monthsStarting date: 01/12/2005


SummaryThe project EUGINDAT is an integrated approach that links genetics,

biochemistry, physiology, genomics, proteomics, structural biology,drug

development and clinical studies in an attempt to improve understanding

and treatment of Primary Inherited Aminoacidurias (PIA). PIA are rare

diseases involving defects in renal reabsorption of amino acids that also

affect other organs.The project applies three main technological avenues

to the study of PIA: I) clinical and genetic characterisation of PIA; II)

functional genomics of renal reabsorption of amino acids; III) structural

biology of PIA-associated amino acid transporters.Moreover,the present

developments in the clinics and the molecular bases of two of these

diseases (Cystinuria and Lysinuric protein intolerance [LPI]) allows the

application of this knowledge to unravel the pathophysiological

mechanisms of these diseases and to test new therapeutic strategies.

ProblemPIA are rare disorders of amino acid transporters expressed in theplasma membrane of renal epithelial cells that impair tubular andintestinal absorption of amino acids,and that may also affect other organsand produce severe clinical consequences.These are rare or orphandiseases.The orchestrated way in which the various amino acid andpeptide transporters in renal apical and basolateral membranes allowefficient renal reabsorption of filtered amino acids and provide aminoacids for the needs of the cells is far from being completely understood.

AimThe EUGINDAT project has two main goals: the first is, to improveour understanding of the genetic,molecular,cellular and physiologicalbasis of PIA.

The key goal of the basic science part of EUGINDAT is the mostcomprehensive understanding of the inherited aminoacidurias byanalysis of the patho-physiological processes down to individualproteins and genes followed by a systematic reintegration of theknowledge gathered to the most complex level of the organisms.

The second goal is to explore new strategies for the diagnosis andtherapy of these diseases, including improved patient care based onthe knowledge generated in the project.

Expected results1. to complete a clinical and molecular-genetic description of PIA

with the generation of a European PIA-DATABASE including:Cystinuria, Lysinuric Protein Intolerance (LPI), DicarboxylicAminoaciduria (DA), Hartnup Disorder (HDis), Iminoglycinuria

(IG) and ‘unlabeled aminoacidurias’.The proposal aims to studynew candidate genes for cystinuria, DA, HDis and IG.

2. to gain a thorough knowledge of the molecular structure of re-levant transporters using 2D crystals of prokaryotic, and event-ually eukaryotic homologues and 3D crystals of water-solubleextracellular domains.

3. to complete a functional genomic study of relevant transportersunderlying PIA and renal reabsorption of amino acids at three levels:i) identification of transporters with a role in the transepithelialtransport of amino acids in the proximal tubule OK cell model, ii)generation of KO mice,and iii) identification of polymorphisms (SNPs)in renal transporters that show association with renal reabsorptionof amino acids in genetically isolated human populations.

4. to identify genes and/or loci that affect cystinuria lithiasis, and mayeventually explain gender-related and individual variability in stone-forming activity in patients with cystinuria.

5. to develop new therapeutic strategies for cystinuria lithiasis.

6. to identify the mechanisms contributing to the pathology of LPIwhich explain the hepatic phenotype (hyperammonemia) and theimmune system-compromising symptoms.

7. to test new therapeutic approaches for the life-threateningcomplications of LPI.

Potential applicationsThe integrated knowledge to be acquired on PIA within EUGINDATwill result in: a) deep clinical and genetic description of PIA, includingvery rare forms of these diseases (PIA-DATABASE); b) generation of anew picture of the physiology and pathophysiology of the cellularhandling of amino acids in the mammalian kidney. Moreover, with thecapability of crossing animals with defects in individual genes to obtainmultiple knock-out lines a unique European competence area on renalamino acid transport processes is created. c) EUGINDAT also takes its

Chimeras used to generate the LAT-2 knock-out mouse model

European genomics initiative on disorders of plasmamembrane amino acid transporters

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world-recognised expert knowledge and its technological capabilities towork on the carrier protein structures,which represents an added valueas this area has traditionally been solely in the hands of biochemists,physicist or chemists. The 3D structure of amino acid and peptidetransporters related to PIA and nutrition will provide the basis for theunderstanding of the malfunctions of the proteins based on sequence-dependent conformational alterations in substrate binding and transportcapability and protein stability. d) Finally, information gained on PIAdiseases is being transferred into development of new drug andtherapeutic approaches for Cystinuria and Lysinuric protein intolerance.

Coordinator Dr Palacín, Manuel Universitat de BarcelonaFacultat de BiologiaDepartment de Bioquímica y Biologia MolecularAvgda. Diagonal, 645. Edifici Nou.Planta –1 08028 Barcelona, SpainPhone: +34 93 403 4617- Fax: +34 93 402 1559Email: [email protected] web-site: http://www.ub.edu/eugindatKey words: amino acids, transporters, primary inherited

aminoacidurias, Cystinuria, Lysinuric proteinintolerance, Dicarboxylic aminoaciduria,Hartnup disorder, Iminoglycinuria, genomics,structural studies, knock-out models.

PartnersDr Orozco, ModestoUniversitat de BarcelonaFacultat de Química Dept Bioquímica y Biologia Molecular (Biologia)Barcelona, SpainProf. Daniel, Hannelore TU MünchenWissenschaftszentrum WeihenstephanInstitut für ErnährungsphysiologieFreising-Weihenstephan, GermanyDr Nunes,VirginiaCentro de Genética Médica y MolecularInstitut de Recerca Oncologica (IRO)Hospital Duran i ReynalsSpainDr Gasparini, Paolo Fondazione TelethonRome. ItalyProf. Sebastio, Gianfranco Professore Associato di Pediatria, Università Federico IINaples, Italy

Dr Fotiadis, Dimitrios Maurice E. Müller Institute at the Biozentrum,University of BaselBasel, SwitzerlandDr. Kanner, Baruch The Hebrew University of JerusalemJerusalem, IsraelHuoponen, Kirsi University of Turku, Department of Medical GeneticsTurku, FinlandDr. Simell, Olli University of Turku, Department of PediatricsTurku, FinlandDr Wagner, Carsten Institute of Physiology, University of ZurichZurich, SwitzerlandProf.Verrey, François Institute of Physiology, University of ZurichZurich, SwitzerlandProf. Borsani, Giuseppe University of Brescia, School of MedicineDepartment of Biomedical Sciences and BiotechnologiesBrescia, ItalyProf. Lang, Florian Department for Physiology, University of TubingenTubingen, GermanyDr Della Strogalo, LucaHead Dpt. Of Nephrology and UrologyChildren’s Hospital and Research Institute Bambino GesùRome, ItalyDr Bisceglia, Luigi IRCCS Casa Sollievo della Sofferenza, Servizio di GeneticaMedicaSan Giovanni Rotondo (FG), ItalyDr Pras, Elon Institute of Human GeneticsSheba Medical Center, IsraelDr Rubio, GuillermoLaboratorios Rubió, S.ACastellbisbal, SpainDr Grosse, Johannes Ingenium Pharmaceuticals AGDirector Bussines Development, Program PartneringMartinsried, Germany

Acronym: EUGINDATProject number: LSHM-CT-2003-502852EC contribution: €3 050 000Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/03/2004


SummaryAutoimmune polyendocrine syndrome type I (APS I; OMIM 240300),

a rare genetic disorder of childhood with autoimmune reactions against

a range of different tissues, has been shown to be an invaluable tool in

understanding autoimmune reactions. APS I is characterised by

autoantibodies against several defined autoantigens often identical to

those found in common autoimmune disorders such as type 1 diabetes

mellitus.The cellular and molecular mechanisms leading to this complex

syndrome remain, however, incompletely understood. Studies on

recently generated animal models for the disease, as well as genomic-

wide approaches to identify immune-modulating genes, will provide

novel information of importance not only to the patients affected with

this rare disorder, but will also increase our understanding of the

pathogenesis of autoimmune diseases in general.

ProblemAPS I (OMIM 240300), also known as APECED (autoimmunepolyendocrinopathy-candidiasis-ectodermal dystrophy) is an autosomalrecessive disorder caused by mutations in the AIRE gene onchromosome 21. Patients develop the first symptoms of the disease at

an early age with both endocrine and non-endocrine tissues affected,and in addition, mucocutaneous candidiasis that is often a hallmark ofthe disease. APS I is more common in certain areas, such as Finland(prevalence 1/25 000) and Sardinia.A number of autoantigens have beenidentified in APS I.These discoveries have provided diagnostic tools andpredictive markers for the appearance of various clinical componentsof the disease. Furthermore, some of the autoantigens identified in APSI have later been shown to be of importance in more commonautoimmune disorders. The AIRE gene product is most prominentlyexpressed in the medullary epithelial cells of the thymus. Thymicmedullary epithelial cells are involved in the negative selection oflymphocytes during the lymphocyte maturation process in the thymus.An analysis of the cellular and functional consequences of differentmissense mutations of the AIRE gene product has allowed a detailedmapping of the various functional domains of the protein. Several linesof Aire -/- mice have been generated providing an excellent animal modelfor the disease.Despite these recent advances,the physiological functionof AIRE or the mechanisms responsible for autoimmunity when AIRE isdefective are not yet fully understood. The reason for themucocutaneous candidiasis infection occurring in almost all patientsremains completely obscure.

AimThe first objective is to use this disorder as a model to understandthe immunological mechanisms at a molecular level that predisposeto autoimmunity and to the propensity to develop fungal infections.The second objective is to provide better care of patients with APSI by developing new diagnostic tests, revising the diagnostic criteria,and improving the understanding of the clinical course and the long-term complications.

Expected results1. Establishment of a pan-European database and biobank for APS I

patients.

2. Increased awareness of the disease among physicians and dis-semination of knowledge about recommended follow-up proceduresand diagnostic and therapeutic options.

3. Define the function of the AIRE gene product in thymic T celldevelopment and in the establishment of tolerance.

4. Identification T cell and B cell epitopes of defined autoantigens.

5. Discovery of genes that modify the intensity and/or course of APS I.

6.A collection of expression profile data from cells and tissues with anormal or defective AIRE to identify targets regulated by AIRE.

7. Elucidation of the mechanisms underlying the propensity to developmucocutaneous candidiasis.

Embryonic thymusday 13 of gestation.Cortical epithelialcells are stained ingreen for Keratin 8,medullary epithelial

cells to be arestained in pink forcytokeratin 5 and

MTS10 cell antigen

Autoimmune polyendocrine syndrome type I – a raredisorder of childhood as a model for autoimmunity

EURAPS

Staining of Paneth cells(producing defensins andenzymes important to

the host defence againstbacterial, fungal and viralinfections) in the smallintestine using a serum

from a patient withautoimmune polyen-

docrine syndrome type 1.

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Potential applicationsIdentification of modulating genes for the disease, of factors in the up-stream regulation of AIRE gene expression and of proteins down-streamregulated by the AIRE gene product,will all undoubtedly help in identifyingimportant drug targets for the modulation of various immune reactions.Also,the discovery of novel autoantigens will improve the clinical follow-up of APS I patients and may be of value in the diagnosis of otherautoimmune disorders not associated with APS I.Moreover,clarificationof the mechanisms underlying the propensity to develop mucocutaneouscandidiasis can lead to novel therapeutic possibilities.

Coordinator Prof. Kämpe, OlleUppsala UniversityDepartment of Medical SciencesUniversity Hospital75185 Uppsala, SwedenPhone: + 46 186 112 978Fax: + 46 185 25795E-mail: [email protected] web-site:http://www.molecularmedicine.se/EURAPSKey words: rare disorders, autoimmunity,

polyendocrinopathies; thymus, disease mod-els,

PartnersProf. Betterle, CorradoUniversity of PaduaDepartment of Medical and Surgical Sciences,Endocrine UnitPadua, ItalyProf. Cahill, DoloresRoyal College of Surgeons in IrelandDublin, IrelandProf. Cerundolo,VincenzoUniversity of Oxford, Department of Medicine,TumourImmunology UnitThe Weatherall Institute of Molecular MedicineOxford, United KingdomProf. Goodnow, Christopher C.The Australian National UniversityMedical Genome Centre, John Curtin School of MedicalResearch, Canberra,Australia Prof. Holländer, GeorgesUniversity of Basel, Pediatric ImmunologyDepartment of Clinical-Biological SciencesBasel, SwitzerlandProf. Holmdahl, RikardLund University, Department of Cell and MolecularBiology

Lund, SwedenProf. Husebye, Eystein S.University of BergenEndocrinology unit, Institute of MedicineBergen, NorwayProf. Manns, Michael P.Medizinische Hochschule HannoverDepartment of Gastroenterology, Hepatology andEndocrinologyHanover, GermanyProf. Palmer, EdUniversity Hospital BaselBasel, SwitzerlandProf. Peltonen, LeenaNational Public Health InstituteDepartment of Molecular MedicineHelsinki, FinlandProf. Peterson, PärtUniversity of Tartu, Institute of General and MolecularPathologyTartu, EstoniaProf. Romani, LuiginiaUniversity of Perugia, Department of ExperimentalMedicine and Biochemical SciencesPerugia, ItalyProf. Samaranayake, Lakshamn P.University of Hong KongDepartment of Oral Microbiology, Faculty of DentistryHong Kong, ChinaProf.Weetman,Anthony P.University of Sheffield, Division of Clinical SciencesClinical Sciences Centre, Northern General HospitalSheffield, United KingdomProf. De Virgiliis, StefanoUniversity of Cagliari, Dipartimento di ScienzeBiomediche e BiotecnologieLaboratorio di immunologia e genetica molecolare,Clinica PediatricaCagliari, ItalyProf. Scott, Hamish S.Walter and Eliza Hall InstituteGenetics and Bioinformatics DivisionParkville, Australia

Acronym: EURAPSProject number: LSHM-CT-2005-005223EC contribution: €3 000 000 Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/05/2005


AUTOROME

SummaryRare autoimmune diseases are chronic inflammatory diseases affecting

a large number of the European population. Chronic inflammation

leading to destruction of target organs results in disability and enormous

human suffering and to large socio-economic costs. Therefore,

understanding its pathogenesis constitutes an R&D area of strategic

importance, both, scientifically and also socio-economically. This

proposal integrates leading groups with state-of-the-art resources and

projects from academia and SMEs by creating a critical mass sufficient

to promote R&D interactions between basic and applied science.The

work will lead to a better understanding of mechanisms that contribute

to rare autoimmune diseases and provide us with leads for improved

diagnostics and therapeutics.

ObjectivesRare autoimmune diseases e.g. various subtypes of systemic vasculitis,are associated with substantial morbidity and even accelerated mortalityin affected persons (children and elderly). In many cases these diseasesare systemic,inflammatory,progressive,chronic and destructive diseasesaffecting numerous organs and tissue types.These diseases are associatedwith pain, and various organ manifestations (entitledsyndromes) leading to organ failures and final death. Oneof the hallmarks of rare systemic autoimmune diseases isthe formation of autoantibodies driving the pathology ofthe disease.These autoantibodies are directed e.g. againstnegatively charged phospholipids as in the anti phospholipidsyndrome (APS), against components of the nucleus suchas DNA, RNA, histones, nuclear proteins and protein-nucleic acid complexes as in SLE and against nuclearcomponents like centromer antigens or topoisomerase Ias in systemic scleroderma (SSC).As of yet it is not clearhow the different autoantibodies contribute to the organspecific pathologies of the various diseases.Neither clear-cut diagnostics and prognostics nor specific therapeuticsultimately leading to a cure of the disease are available.

Work packagesAUTOROME is dedicated to improve the current state-of-the-art methodology in the understanding ofaetiology, pathophysiology, progress and therapy of rareautoimmune diseases by conducting the following workpackages:

• by profiling autoantigens and autoantibodies and determine themajor autoreactive epitopes

• by addressing mechanisms that determine the initiation,progressionand chronicity of the humoral immune response on the cellular level(T-cells,APC cells, B-cells, epithelial cells)

• by characterising cellular differentiation, maturation and migrationprocesses with a strong focus on B cell development,making use ofanimal models

• by developing therapeutic approaches to eliminate autoantibody-producing cells.

Novel human and murine autoantigens will be characterised andepitope and paratope mapping will be performed. Peptide andautoantigen filters/chips will be validated in concert with clinicalpartners leading to diagnostic kits. Anti-idiotypic antibodies will beanalysed from intravenous immunogloblulin fractions (IVIG). Idiotypicpeptides and therapeutic antibodies are generated and validated infunctional assays as well as in animal models. Cell types anddifferentiation steps of the cellular immune system are studied indifferent mouse models.This analysis is complemented by FACS sortedcellular blood components derived from diseased patients to bestudied in depth on the transcriptome and proteome level in orderto functionally analyse molecular parameters found in rareautoimmune diseases under study.

Project overview

From immune responses in rare autoimmune diseases to novel therapeutic intervention strategies - a personalised medicine approach

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Expected results Comprehensive technology platforms (including protein chips, massspectrometry, phage libraries, immunoscoping) will be employed toidentify autoantibodies, autoantigens and epitopes contributing todisease initiation, progression and chronicity.The rationale of noveltherapeutic strategies depending on the generation of anti-idiotypicpeptides and therapeutic antibodies as well as siRNA constructs willbe evaluated. In a personalised manner pathogenic B cells and plasmacells will be targeted related to the disease parameters found inindividual patients determined by spectratyping and massspectrometric autoantibody characterisation.Expected achievementsand deliverables of this proposal are likely to also help to elucidatemolecular mechanisms in immune processes and autoimmune diseasesin general and will,therefore,be of broad scientific and socio-economicvalue. Specific expected results are:

• identification of novel autoantigens and immuno-dominant epitopesin rare autoimmune diseases

• identification of immune cell subsets associated with rareautoimmune diseases

• description of autoantibody profiles specific for individual patients,specific diseases and in animal models

• identification of novel target genes in rare autoimmune diseases

• elucidation of synthetic autoreactive peptides and siRNAs for thedevelopment of specific modulators of the pathogenic humoralimmune response

• development of diagnostic tools to assess disease severity and topredict disease onset

• detailed characterisation of human B cell development and selection

• elucidation of autoimmune pathways and therapeutic approachesusing mouse models

• improved understanding of the immunopathology of autoimmunediseases

Finally, prognostic markers and diagnostic tools should lead toindividualised therapeutic approaches using idiotypic peptides as wellas therapeutic antibodies and siRNA. Synthetic peptides will begenerated and applied for the following aims: 1) to develop an ELISAkit for detection of autoAbs specific for thrombosis-associatedpathogenic epitopes in order to predict thrombotic risk or recurrentfetal loss in patients having these specific autoAbs; 2) to neutralizethe biological activity of the studied autoAbs, in vivo and in vitro; 3)to induce specific B cells apoptosis of the pathogenic autoAbssecreting cells.

Potential applicationsDiagnostic tools assessing the relevance and distribution of pathogenicantibodies in individual patients are one essential milestone ingenerating and selecting appropriate therapeutic interventionsstrategies.The generation and administration of anti-idiotypic peptidesinterfering with pathogenic antigen-antibody interactions is one wayto help patient suffering from severe autoantibody-mediatedautoimmunities.The analysis of autoimmune diseases might becomea leading force on the way to more personalised therapeutic strategiesand prevention. Reducing the incidence, prevalence and severity ofautoimmune diseases consequently relieves the economic and socialimpact on health-care costs for any society.

Coordinator Prof.Thiesen, Hans-Jürgen

Institute of Immunology

University of Rostock

Schillingallee 70

18055 Rostock, Germany

Phone: +49 381 494 5870

Fax: +49 381 494 5882


Project web-site: http://www.autorome.de

Key words: anti-idiotypic; anti-phospholipid syndrome(APS); autoimmune lymphoproliferativesyndrome (ALPS); autoimmunity; autoanti-gen; autoantibody; systemic lupus erythe-matosus (SLE); systemic scleroderma; sys-temic vasculitis

Partners2 France

3 Denmark

3 Switzerland

1 Ireland

1 Israel

1 The Netherlands

Acronym: AUTOROMEProject number: LSHM-CT-2004-005264EC contribution: €2 700 000Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/11/2004


SummaryThe project aims at developing information tools to address in a

comprehensive and integrated approach the set of factors that

currently affects research on rare diseases and its coordination.The

specific objectives are: (1) to develop an information service, freely

accessible on the Internet,dedicated to research activities in the field

of rare diseases and orphan medicinal products, including a database

of research projects, funded at MS level and at the EU level, and a

database of collections and research networks;(2) to develop services

aiming at speeding up the enrolment of patients in clinical research;

(3) to develop a database of research projects with development

potential, to help scientists and industry establish the necessary

partnerships; (4) to organise a workshop with all stakeholders to

discuss identified bottlenecks and find solutions.This project is based

on input from the following (1) an EU-funded information service on

rare diseases:Orphanet (www.orpha.net); (2) a European platform of

patients’ organisation, science and industry (EPPOSI) which actively

supports partnering activities; (3) an umbrella organisation of patient

support groups (Eurordis) involved in supporting research and

regulatory activities.The project aims at establishing the platform of

services in 11 European countries in the pilot phase in order to

propose an extension to the 25 European countries within two years.

Ultimately, the goal is to convert scientific developments into

diagnostic tools and therapies as quickly as possible.

ProblemOver 20 million Europeans are affected with rare diseases.Almost allthese rare diseases are life-threatening or chronically debilitatingdisorders and most of them are genetic.To date, 5000 to 8000 phe-notypes have been described among which 2000 are already assignedto one or several genes. Rare diseases are of the utmost importancein terms of both public health and scientific challenge as they are dueto the failure of unique physiological pathways.Moreover,rare diseasesrepresent an experimental model of normal cellular and tissularfunction of cells and contribute to a better understanding of morecommon diseases as well as paediatric diseases.

Patients suffering from such conditions should benefit from the samequality of treatment as other patients.Treatment of the very smallnumber of patients affected by a specific rare disease results infragmentation of research efforts and limited potential forcommercial development of medicinal products. Therefore it isessential to act at a European level.

The Fifth Framework Programmes for Research and TechnologicalDevelopment has supported research on rare diseases, to promotethe establishment of cross-national cooperation.The EU gives priorityto rare diseases within the new EU public health framework.The EURegulation on Orphan Medicinal Products (OMP) was adopted inorder to stimulate prevention and development of new diagnostictools, and therapies for rare diseases. It is highly effective.

Several Member States have taken initiatives to support research inthe field of rare diseases. France,Germany, Ireland and Spain have setup specific programmes to support networking activities. France,Germany,Spain,Italy and the Netherlands have established committeesto review research activities and advise on research issues at thegovernmental level.Several charity organisations are strongly involvedin the field, especially the French and Italian Telethons.

The Orphanplatform website

A European platform of integrated information services for the coordination of rare disease research in Europe,with various stakeholders from research, SMEs and patient organisations and the coordination of early clinical trials

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AimThe project aims to develop information tools in order to address ina comprehensive and integrated approach the set of factors thatcurrently affects research on rare diseases and their validation atEuropean level. Ultimately, the goal is to convert scientificdevelopments into therapies as quickly as possible and to ensuretimely access to innovative practices, tools and medicines.

Expected results1) Availability of a European Internet-based information system able

to provide the rare disease research community with accurate,reliable and comprehensive European data on existing researchprojects and networks, registries of cases, directories of patients,cohorts of patients, networks of banks and available biologicalresources. This information is expected to facilitate exchangesbetween various stakeholders and to stimulate cooperationbetween research groups.

2) Availability of an on-line service to speed up the enrolment ofpatients in clinical research projects.This service is expected tofacilitate and to accelerate enrolment of patients in clinical researchstudies, leading to money savings and to a higher chance to finalisethe projects.

3) Availability of OrphanXchange, a marketplace of research projectsof potential interest for biotech and pharma industry.This serviceis expected to contribute significantly to the transfer to the marketof innovative therapeutics, devices and new diagnostic tools.

4) Organisation of a partnering workshop which will bring togetherpatient representatives, scientists, clinicians, industryrepresentatives and capital providers. Its objectives are to findmeans of facilitating mutual understanding between the partiesinvolved; to identify roadblocks in the development of therapiesfor rare conditions and to examine possible means around theseroadblocks; to support partnerships; to disseminate expertknowledge to all participants, researchers, patient organisations,industry and regulators.

The project also addresses the needs of diseases’ specific researchnetworks.Through bridging the upstream needs for data availabilitywith the downstream issues faced by clinical researchers, the projectaims at building synergies with, and acting as a facilitator for otherimportant research and development projects in the fields of raredisorders, genomics and post-genomics, gene and cell therapies.

The project addresses the needs of EMEA and industry.The projectis of course directly relevant to the activities of the Committee forOrphan Medicinal Products and of the Committee for MedicinalProducts for Human Use, including its Scientific Review Group toprovide protocol assistance and its safety,efficacy and quality workingparties. The project is also expected to have direct benefits forEuropean industry and particularly for small and medium enterprises(SMEs), which account for 80% of OMP applications submitted toEMEA. The platform of services at the centre of the project willprovide these industry partners with cost-effective services andsolutions that are not yet available. The platform will also steerinnovation capacity for new therapies and will reduce the currentcompetitiveness gap of EU industry versus US.

The project will benefit paediatric drugs and cancer treatmentsdevelopment.This represents another major public health objectivefor the EU on which the European Commission envisages specificregulatory and research initiatives. 80% of rare diseases appear at anearly age and are directly responsible for 25% of the mortality inchildhood.

The project is an archetype of the need for action at European level.The specificity of the small number of patients, scarce professionalcompetences and fragmented resources are defining the relevance ofthis structuring project at EU level.

Orphanet, the European database on rare diseases and orphan drugs


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Coordinator Dr Aymé, Ségolène

INSERM

SC11

Hôpital Broussais, 102 rue Didot

75014 Paris, France

Phone: +33 1 56 53 81 37

Fax: +33 1 56 53 81 38


Project web-site: http://www.orphanplatform.org,http://www.orphanxchange.org, http://www.orpha.net.

Key words: rare diseases, genetic diseases, orphandrugs, information systems, database, technology transfer,clinical research, clinical trials

PartnersDr Buckley, Brendan

European Centre for Clinical Trials in Rare Diseases

Cork Airport, Ireland

Prof. Dallapiccola, Bruno

IRCCS

Rome, Italy

Dr Del Campo, Miguel

Universitat Pompeu Fabra

Department Cieucies Experimentals

Barcelona, Spain

Prof. Donnai, Dian

The Victoria University of Manchester

Academic Unit of Medical Genetics

Manchester, United Kingdom

Prof. Fryns, Jean-Pierre

Katholieke Universiteit Leuven

Center of Human Genetics

Leuven, Belgium

Mrs Greene, Lesley

EURORDIS

Crewe, United Kingdom

Prof. Hennekam, Raoul

Universiteit van Amsterdam

Dept of Pediatrics and Clinical Genetics

Amsterdam,The Netherlands

Prof. Kääriäinen, Helena

University Turku

Department of Medical Genetics

Turku, Finland

Dr Lassale, Catherine

Les Entreprises du Médicament

Paris, France

Dr Oosterwijk, Cor

Vereniging Samenwerkende Ouder- enPatientenorganisaties

Soestdijk,The Netherlands

Mr. Poortman,Ysbrand

EPPOSI

Soestdijk,The Netherlands

Ms Jürgen Reden

EBE – EFPIA

Brussels, Belgium

Dr Reis Lima, Margarida

Instituo de Genética Médica Jacinto Magalhães

Porto, Portugal

Prof. Schmidtke, Joerg

Medizinisch Hochschule HannoverInstitut für Humangenetik

Hanover, Germany

Dr Squiban, Patrick

Europabio

Strasbourg, France

Dr.Voigtlander,Till

Medical University of Vienna

Institute of Neurology

Vienna, Austria

Acronym: OrphanplatformProject number: LSSM-CT-2004-503246EC contribution: €400 000Instrument: Specific Support ActionDuration: 24 monthsStarting date: 01/04/2004


• EUR-INTAFAR 68• ActinoGEN 70• VIRGIL 73• PNEUMOPEP 75• AMIS 77• PREVIS 79• COBRA 82• micro-MATRIX 85

Anti-MicrobialDrug Resistance


SummaryPeptidoglycan biosynthesis and bacterial cell morphogenesis are related

phenomena and are totally specific to bacterial cells without even

remotely equivalent systems in eukaryotic cells. The enzymes and

proteins involved in these processes are thus potential targets for the

design of new antibiotics. Interfering with the activities of the

participating enzymes or with the protein-protein interactions which

take place along these metabolic pathways should result in the

perturbation of the bacterial cell cycle and, hopefully, supply new

weapons in the fight against dangerous pathogenic organisms such as

the methicillin-resistant Staphylococcus aureus (MRSA).

ProblemAlthough antibiotics have drastically reduced illness and death frominfectious diseases, bacteria have exhibited a remarkable capacity toquickly become resistant to one or several classes of antibiotics. Forexample, in the US, until 2000, Streptococcus pneumoniae infectionscaused,each year,100 000 to 135 000 hospitalisations for pneumonia,6 million cases of otitis media and 60 000 cases of invasive diseasesincluding 3 300 cases of meningitis. Up to 40% of the infections werecaused by bacteria resistant to at least one and 15% to three or moreantibiotics. The percentage of S. pneumoniae strains resistant topenicillin varies from 3.2 in The Netherlands to 53 in France.Valuesas high as 60 and 78% are observed in Hong Kong and Saudi Arabia,respectively.Resistance to ß-lactams is often associated to resistanceto macrolides.

In 1996, two million cases of nosocomial infections were countedannually in US hospitals. Their global cost ranged from $600 for aurinary infection to $40 000 for a septicemia. Extrapolations made in1996 in a French study showed that due to nosocomial infections, thestays in hospital were three to seven days longer and the expensesper patient were €750 to €1500 higher.These annual extra costsrepresented about 2% of the total hospital expenses.

Strains isolated from farm animals present even higher levels ofresistance. In a recent study performed in Belgium, 95% of theEscherichia. coli strains isolated from poultry, 44% of the strains ofbovine origin and 90% strains of porcine origin were resistant totetracyclines. In all of these cases, resistance to aminoglycosides(streptomycin),chloramphenicol and amoxycillin or ampicillin was alsowidespread.

The increase in antibiotic resistance is thus a global problem,both fornosocomial as well as community-acquired infections.A return to thepre-antibiotic era has even been forecasted. Hence the problem ofresistance can only be solved by a multidisciplinary and internationalapproach,which will require a better understanding of the fundamentalaspects of bacterial physiology,growth and multiplication mechanisms,

areas which have been relatively neglected in the recent past whencompared to eukaryotic systems.

AimThe aim of this network is to find new potential targets for antibioticsand to use the knowledge accumulated on the antibiotic-resistantforms of some ‘old’ targets for the design of more efficient molecules.

To do so, the fundamental aspects of peptidoglycan biosynthesis andbacterial cell morphogenesis will be investigated. The phenomenawhich take place at the level of the cytoplasmic membrane and arestill very poorly understood will receive special attention.

Expected results1.The design, synthesis and evaluation of inhibitors or inactivators

of the penicillin-resistant DD-transpeptidases. In sensitivebacteria, these enzymes, often referred to as PBPs (for PenicillinBinding Proteins) and which catalyse the final step ofpeptidoglycan biosynthesis are the targets of penicillins andrelated compounds.

2.The development of inhibitors of the glycosyltransferase domainof class a PBPs.The reaction catalysed by this enzyme immediatelyprecedes the transpeptidation reaction. No clinically usefulinhibitor of this activity is known.

3. Characterisation of the membrane steps involved in the synthesisof the immediate precursor of the transglycosylation reaction(the lipid II) and of the mechanism responsible for thetranslocation of the disaccharide peptide moiety of lipid II acrossthe membrane and design of inhibitors of these processes.

Structure of the Mur D ligase of Escherichia coli (Bertrand et al., J. Mol. Biol., 289, 579-590, 1990)

Inhibition of new targets for fighting antibiotic resistance


AMDR EUR-INTAFAR


4.The development of inhibitors targeting the intracellular stepsof soluble precursor synthesis which will rest in part on thedifferences in the structures of the peptide moieties in severalGram positive pathogens such as Staphylococcus aureus,Streptococcus pneumoniae and Enterococci.Elucidation of the roleof the Mur synthetases in Chlamidiae, bacteria which lackdetectable peptidoglycan.

5. Understanding the integration of the peptidoglycan manufacturingmachineries in the cell morphogenesis and regulation apparatus.A number of proteins which regulate processes such as cellelongation and division are known but their exact modes of actionremain to be clarified. Compounds which can interfere with theprotein-protein interactions involved in these machineries arepotential antibacterial compounds.

Potential applicationsNew antibiotics are needed to fight the multi-resistant pathogens.Large pharmaceutical companies have been leaving the field ofantibacterial research for a number of years.Although the potentialantibiotic market remains huge,up to 90% of infections can be treatedwith the presently available compounds. The design of specificantibacterial agents directed towards specific species or strains is asensible strategy from a public health point of view. It is much lessinteresting commercially. Indeed, a good antibiotic is expected to betaken by the patient over a short period of 1-2 weeks. In consequence,if public authorities do not take charge of the problem, it will remainunsolved at a large cost for society.

This project is of prime importance as a springboard to re-activatethe utmost important area of antibiotic drugs.

A better understanding of the physiology and biochemistry of bacterialcell morphogenesis and peptidoglycan biosynthesis will create newavenues for the design and synthesis of efficient antimicrobials.Thiswill make new opportunities available for companies of different sizesto develop these compounds until they reach the clinical level.


AMDR

Coordinator Jean-Marie Frère

Centre for Protein Engineering, Institut de Chimie B6a,University of Liège

4000 Liège, Belgium

Phone: +32 43 663398

Fax: +32 43 663364

Project web-site:(in creation) http://www.ulg.ac.be/cingprot/intafar.htm

Key words: antibiotics, peptidoglycan, bacterial cellmorphogenesis, transpeptidase, transgly-cosylase, Lipid II, Mur proteins, Fem proteins

PartnersMolecular Cytology, Swammerdam Institute for LifeSciences, University of Amsterdam,The Netherlands

UMR 8619 CNRS, Institut de Biochimie, Université deParis-Sud, France

Department of Biochemistry of Membranes, UtrechtUniversity,The Netherlands

LCM, Institut de Biologie Structurale, Grenoble, France

Mikrobielle Genetik, Universität Tübingen, Germany

Department of Microbiology, University of Kaiserslautern,Germany

L.R.M.A./E0004, Université Paris VI, France

Division of Microbiology, School of Biochemistry andMolecular Biology, University of Leeds, United Kingdom

LCM, Institut de Biologie Structurale, Grenoble, France

Centre de Recherches du Cyclotron B30, University ofLiège, Belgium

Oxford Centre for Molecular Sciences and Dyson PerrinsLaboratory, United Kingdom

Laboratoire de Chimie et Biochimie, Université RenéDescartes, France

Faculty of Pharmacy, University of Ljubljana, Slovenia

Lek, d.d. Pharmaceutical and Chemical Company,Ljubljana, Slovenia

ProtNeteomix, Université de Nantes, France

Acronym: EUR-INTAFARProject number: LSHM-CT-2004-512138EC contribution: €11 300 000 Instrument: Integrated ProjectDuration: 60 monthsStarting date: 01/01/2005


SummaryActinoGEN is an Integrated Project aimed at developing novel

genomics-based approaches to exploit hitherto overlooked genetic

resources for new antibiotics.Drug discovery will focus on (1) accessing

new antibiotic biosynthetic pathways from diverse actinomycetes that

have yet to be cultured; (2) activating cryptic pathways from well-

characterised actinomycetes;and (3) engineering novel hybrid antibiotics

by combinatorial biosynthesis.To greatly accelerate the drug discovery

process, a parallel strategy will be to engineer generic hosts optimised

to produce high antibiotic yields.With the complete genome sequence

of the model actinomycete, Streptomyces coelicolor, and mobilisation of

a pan-European effort to apply newly developed multidisciplinary post-

genomic technologies, a holistic understanding of the physiology and

regulation of antibiotic biosynthesis will be achievable for the first time.

This will, in turn,permit rational intervention to engineer generic hosts

for high-yield antibiotic production.This synergy of discovery linked to

overproduction will place the European biotechnology sector at the

forefront of developing much-needed new antibiotics

to combat multi drug-resistant pathogens.

ProblemMultiple drug-resistant bacteria are a major threat tohuman health and a significant burden on alreadystretched medical budgets.This threat is predicted toincrease in severity, and remedial actions of reducingantibiotic use in animal husbandry and limiting currentprescribing activities for non-lethal human disease areboth unlikely to reduce the danger in the short term.Of major concern are antibiotic-resistant nosocomialinfections.The economic and societal costs of thesehospital-acquired infections are enormous: the UKNational Health Service has estimated an annual costof €1.5 billion for extra patient care and that 5000deaths result each year. In addition, the incidence ofinfection by multiple drug-resistant strains ofMycobacterium tuberculosis, the causative agent of thetuberculosis, is rapidly increasing, particularly amongthe disadvantaged in society. Investment in R&D intoantibiotic discovery by the major pharmaceuticalcompanies has declined dramatically in the last 15 yearsas a perception has taken hold that easily obtainednatural products may have been fully exploited.Henceconventional screening of natural products for new

drugs is no longer considered to be economically worthwhile.Unfortunately, the downturn in drug discovery has coincided with adramatic worldwide increase in the incidence of resistance to all theantibiotics currently used in medicine.

AimThe aim of this project is to combine new functional genomictechnologies with chemical analysis in an integrated multidisciplinaryapproach,both to exploit hitherto overlooked genetic resources fornew antibiotics and, secondly, develop generic ‘superhosts’ toproduce these new antibiotics in high yields.ActinoGEN proposesthree parallel objectives to discover and develop new antibioticsbased on exploiting the genetic resources of actinomycetes,hithertothe major source of existing antimicrobials.The first of these is toactivate cryptic antibiotic biosynthetic pathways. Recent genomesequencing projects have revealed a genetic potential foractinomycetes to produce many more antibiotics than previouslyrecognised. ActinoGEN will explore how different cryptic pathwayscan be activated and then determine the structures and activitiesof the resulting new antimicrobials.The second approach will relyon the discovery of new antibiotic biosynthetic pathways fromdiverse actinomycetes. The number of actinomycete species that

Genetic engineering ofcosmid clones for het-erologous expression ofnew antibiotics (provid-ed by Bertolt Gust and

Lutz Heide).

Integrating genomics-based applications to exploit actinomycetes as a resource for new antibiotics


AMDR ActinoGEN


have been isolated to date represents a small fraction of the totalin the environment. ActinoGEN will exploit the untapped geneticresource of as yet uncultured species to obtain antibioticbiosynthetic gene clusters that can direct synthesis of newantimicrobials. A third route to new antimicrobials is bycombinatorial biosynthesis. Biosynthetic genes from both new andexisting pathways will be combined to direct synthesis of newantibiotics with predicted structures. The design of new hybridmolecules will be related to improving antimicrobial activity. A fourthmajor aim, underpinning the Drug Discovery objectives, is theengineering of generic superhosts for antibiotic production. A rate-limiting step to developing a new antibiotic is yield improvement.Post-genomic analysis permits, for the first time, a concerted andholistic approach to engineering generic superhosts for use in theproduction of high yields of a wide variety of antibiotics. As part ofActinoGEN,this complementary activity is vital to greatly acceleratethe discovery and development of new drugs.

Expected results1.The establishment of generic procedures for the activation of

cryptic antibiotic biosynthetic pathways.

2. Expression of a variety of heterologous cryptic pathways after theirtransfer to defined superhost antibiotic production strains.

3. Optimised expression of new antimicrobials, and engineeredvariants thereof, derived from activation of cryptic pathways,together with structural analysis and antimicrobial spectra.

4.The establishment of refined genomic-based procedures for analysisof metagenomes to identify new antibiotic biosynthetic pathways.

5. Expression of a variety of metagenomic pathways after their transferto defined superhost antibiotic production strains.

6. Optimised expression of new antimicrobials, and engineeredvariants thereof,derived from metagenomic pathways,together withstructural analysis and antimicrobial spectra.

7. Optimised expression of new combinatorial antibiotics, togetherwith structural analysis and antimicrobial spectra.

8. Generic antibiotic production superhosts derived by rationalgenomics-driven manipulation of Streptomyces coelicolor.

9. Refined superhosts strains optimised for production of key newantimicrobials.


AMDR

Secreted droplet of antibiotic on the surface of the model actino-mycete Streptomyces coelicolor: the shape of the droplet is a con-sequence of hydrophobicity of the colony surface due to surface-active

chaplin proteins (provided by Lubbert Dijkhuizen).

Genetic and environmental influences on antibiotic production:(A) actinomycetes such as S. coelicolor produce antibiotics late

in their development, influenced by growth conditions, (B) acrgA mutant exhibits precocious pigmented antibiotic produc-

tion, (C) the crgA mutant complemented with a functional copyof crgA introduced on a plasmid vector is delayed in antibiotic

biosynthesis, (D) the crgA mutant containing the plasmid vectorwithout the gene, again exhibiting precocious antibiotic produc-

tion (provided by Ricardo Del Sol and Paul Dyson).


Potential applicationsThe development of new technologies for antibiotic discovery andproduction will benefit European SMEs in the biotechnology sectorwhose remit is to provide new antibiotics.Application of these newgenomics-based procedures and technologies for discovery andexploitation of natural products can provide a platform for arenaissance in drug discovery after 15 years of stagnation in this area.The pharmaceutical world market is estimated to amount to €506billion in 2004. Antibiotics represent one of the principal andindispensable groups of pharmaceuticals.Hence the project can helpto stimulate significant growth of European biotechnology SMEs. Inaddition, new antimicrobials discovered in the course of the projectcan potentially help alleviate the current crisis in the treatment ofmultiple drug-resistant pathogens. New antibiotics can providetreatments of last resort for life-threatening diseases such astuberculosis and nosocomial infections. The efficacy of newantimicrobials will depend on subsequent rigorous testing fortoxicity and side effects.However,even in the case of a product withsignificant side effects, the compound can provide a lead for thesubsequent development of safe but effective derivatives, either bychemical modification or by engineering biosynthetic modifications.Thus, there is the potential for these new antibiotics to make a majorimpact on healthcare in the EU, both at the level of the individualpatient and also on healthcare budgets by reducing treatment timesin hospitals.


AMDR

Centre for Microbial Biotechnology,Technical University ofDenmark

Department of Chemistry, University of Warwick, UnitedKingdom

Department of Microbiology/Biotechnology, EberhardKarls-Universität Tübingen, Germany

Department of Pharmaceutical Biology, Eberhard Karls-Universität Tübingen, Germany

School of Biomedical and Molecular Sciences, University ofSurrey, United Kingdom

Dipartimento di biologia cellulare e dello sviluppo,Universita di Palermo, Italy

Groningen Biomolecular Science and BiotechnologyInstitute, Rijksuniversiteit,The Netherlands

Institut de Genetique et Microbiologie, Université Paris-Sud,France

Institut für Chemie,Technische Universität Berlin, Germany

EntreChem SL, Mieres, Spain

Departamento de Biologia Funcional, Universidad deOviedo, Spain

Institute of Biotechnology of León, Spain

Institut National de la Recherche Agronomique,

Laboratoire de Génétique et Microbiologie,Vandoeuvre lesNancy, France

Libragen,Villeurbanne, France

Institute of Microbiology, Seoul National University, SouthKorea

Coordinator Dr Dyson, Paul

School of Biological Sciences

University of Wales Swansea,

Singleton Park,

Swansea SA2 8PP, United Kingdom

Phone: +44 1792 295667

Fax: +44 1792 295447

e-mail: [email protected]

Project web-site: www.swans.ac.uk/research/ActinoGEN/

Key words: antibiotics, actinomycetes, Streptomyces,antibiotic resistance, genomics

PartnersDepartment of Molecular Microbiology, John Innes Centre,Norwich, United Kingdom

Institute of Microbiology,Academy of Sciences of the CzechRepublic

Department of Chemistry, University of ManchesterInstitute of Science and Technology, United Kingdom

Acronym: ActinoGENProject number: LSHM-CT-2004-005224EC contribution: €9 395 102 Instrument: Integrated ProjectDuration: 60 monthsStarting date: 01/01/2005


SummaryVIRGIL is the first European surveillance network capable of addressing

current and emerging antiviral drug resistance developments in the field

of viral hepatitis and influenza. Focusing first on three major viral

diseases, influenza, viral hepatitis B and viral hepatitis C, our strategy

will be to build a sustainable, patient-oriented virtual institute on viral

drug resistance by integrating the currently fragmented European

capacities into interacting subnetworks or virtual departments. Being

approach- rather than virus-based, one objective of the proposal is to

demonstrate a proof of concept that the network structure and the

integration process will allow us to easily embrace future drug resistance

problems related to other human viruses as well as to new drugs that

are currently under development and will come in general use during

the life-span of the network.

ProblemAcute and chronic viral infections represent a major public healthproblem in Europe and worldwide, responsible for a major socio-economical burden.The development of new antiviral drugs and newdiagnostic tools in the past decade has played a major role in theimprovement of patient care, treatment of viral diseases and hasextended the quality and duration of human life. However, theirincreased use and misuse in medicine has given rise to viral drugresistance leading to treatment failure and enhanced costs for healthcare and society. Furthermore, there is no global programme atEuropean scale to develop strategies for the surveillance andcontainment of viral resistance to antiviral agents.Therefore, there isa clear need to implement a European programme to optimise patientcare and to minimise the emergence and spread of antiviral drugresistance.

AimThe overall objective of the VIRGIL Network of Excellence is to set upthe first-ever European Vigilance Network capable of addressing currentand emerging antiviral drug resistance developments that will allow forthe management of this critical problem in Europe. Coordinated byINSERM (the French Institute for Health and Medical Research), thenetwork’s activities started in May 2004 with the initial task of integratingthe fragmented European capacities and major expertise in the fieldinto a single coherent Network of Excellence.VIRGIL initially gathers55 organisations, including more than 60 academic laboratories andseven companies from 12 European countries.Focusing initially on threemajor diseases (viral hepatitis B, viral hepatitis C and influenza), itsmission is to build a sustainable, patient-oriented ‘virtual institute’

structured into interacting platforms that together will comprehensivelycover the problem of virus resistance to antiviral drugs.Being approach-rather than pathogen-based,the integration process and the generatedtools are flexible enough to embrace future drug resistance problemsrelated to other human virus infections. Until now, antiviral drugresistance has been determined by relying on single specialisedlaboratories and high standard research groups that are often onlycapable of addressing one particular aspect.The main objective of thenetwork will be to integrate clinical, technological and researchnetworks and platforms that will interact in a coherent and synergisticmanner, as each will provide a broad panel of specific tools for theothers.The network will crystallise biomedical research on commonobjectives targeting viral drug resistance that define specific activitiesand platforms. VIRGIL is structured into seven integrated platformscentred around the patients, each focusing on a topic contributingtowards the project objectives.

Expected resultsThe creation of a European Network of Excellence on the antiviraldrug resistance topic represents an opportunity to achieve real co-operation among leading scientists in the field.This should significantlyimprove our knowledge on drug resistance. VIRGIL will fill thefollowing gaps:

• VIRGIL will integrate into a coherent network leadinginstitutions expertise within Europe for antiviral susceptibility follow-up and testing.

• VIRGIL will set up centralised databases to provide a uniqueopportunity to track and model the emergence of resistance andits consequences for population transmission.

• VIRGIL will create a unique EU antiviral resistance samplearchive of serum and tissue samples and virus strains, which canbe used to test (anti)viral fitness/provide reference material fortesting new drugs on emerging ADR viral strains.

• VIRGIL-IMPACT will provide information about costs,morbidity, viral evolution, drug use, geography and otherpublic health interventions, and can provide a model system forother disease networks where antimicrobial resistance is anemerging problem.

• VIRGIL-MODELS will establish a platform that is capable of analysingantiviral drug resistance in all its facets through the implementationof in vitro systems (test tube or enzyme assays), cell culturesystems, and in vivo animal models.

• VIRGIL-DRUGPHARM will allow the formulation of novel testablehypotheses when dissecting which factors contribute to drugresistance in specific cohorts. In particular, pharmacokinetic para-meters such as the dose and the treatment schedule of aparticular drug will be analysed.


European vigilance network for the management of antiviral drug resistance

AMDRVIRGIL


• Microchip technology has already had a significant scientificimpact in cell biology but much less so in infection including virology.Therefore a successful outcome with early detection of drug-resistant mutations in influenza to anti NA and M2 drugs, or in viralhepatitis B and C to new specific inhibitors would have a majorimpact in a wide sense. Importantly the method could be applied toother viruses not at present in the network such as poxviruses,sinceit is expected that smallpox will rapidly become a target for newantiviral molecules. It should also be possible to design chips todetect entirely novel NA and HA molecules and in this manner thenetwork could also contribute to influenza pandemic planning.

Potential applicationsVIRGIL activities should result in an improved and standardisedmonitoring of drug resistance, with the development of new rapiddiagnostic tools and susceptibility testing. One achievement of theVIRGIL network will be to establish correlations between the differentclinical, genotypic and phenotypic analyses performed in expertEuropean laboratories to define new and internationally recognisedstandards for viral drug resistance testing. As an extension, thenetwork will ensure the spread of knowledge and technologicalinnovation in sites where a critical need for these technologies hasbeen identified, i.e. eastern and southern Europe. It will also fostereducation and knowledge of health care providers and physiciansregarding the optimal monitoring of drug resistance and up-to-datestrategies that reduce the risk of selection of resistant viral strains.Guidelines for clinical practice to monitor drug resistance but alsofor a rational use of antivirals will be generated and assessed.Theywill take into account the diversity of social, political and economicsettings within Europe.Education programmes targeting patients andthe general population will be organised to encourage compliance tomedical monitoring and therapy through understanding of science.Another objective of the VIRGIL network will be to constantlyevaluate new strategies to combat viral drug resistance.Therefore, itwill translate the results into new clinical trials for the optimal use ofdrug resistance assays as well as for the evaluation of novel treatmentstrategies to prevent or overcome development of viral resistance.To implement these strategies, partnerships with diagnostic andpharmaceutical industrial partners within and beyond the actualnetwork will be launched.

Furthermore, all these actions should allow us to establish a stableand long-lasting NoE at the European level with the capacity torapidly and reliably determine resistance to new drugs and todetermine drug susceptibility of emerging viral strains under theselective pressure of new treatments.This capacity to adapt and reactto new clinical situations based on the expertise of the teams and onthe possibility of including new partners during the duration of theproject will be a major characteristic of this network.This germ centrewill allow expansion and modification to create a network that cancover virtually any viral infection for which antiviral drug resistanceis clinically relevant.


AMDR

Coordinator Zoulim, Fabien

INSERM Unit 271 and liver department

Institut Universitaire de France

151 Cours Albert Thomas

69003 Lyon, France

Phone: + 33 4 72 68 19 70

Fax: + 33 4 72 68 19 71


Project web-site: www.virgil-net.org

Key words: antiviral, drug, resistance, hepatitis, influenza,flu, HCV, HBV, virus

Partners11 France

12 Germany

8 United Kingdom

2 Belgium

3 The Netherlands

6 Italy

4 Spain

1 Greece

2 Switzerland

1 Poland

3 Sweden

1 Austria

1 Israel

Acronym: VIRGILProject number: LSHM-CT-2004-503359EC contribution: €9 000 000Instrument: Network of ExcellenceDuration: 48 monthsStarting date: 01/05/2004



AMDRPNEUMOPEP

SummaryThe innovations of this project are the new targets, identification of

completely new lead compounds,a new approach to adjunctive therapy

and a new method of delivery of the compounds. Streptococcus

pneumoniae imposes a huge disease burden on humans:it is the primary

cause of pneumonia and it is the second most common cause of

meningitis.There is a pandemic of multi-drug resistant pneumococci

and treatment is compromised. Even if antibiotics kill the bacterium,

they can fail to prevent death or neurological damage after meningitis,

due to the acute toxaemia.The first event in toxaemia is release of pro-

inflammatory or toxic pneumococcal products, probably exacerbated

by antibiotics. The pneumococcal toxin pneumolysin fulfils both

definitions: it is directly toxic to mammalian cells and it stimulates release

of inflammatory mediators from host cells.For this reason,and because

the toxin is essential for the survival of the bacterium in vivo,pneumolysin

will be a target of this project.A second target will be the cell surface

proteinases involved in adhesion and invasion, which are important

virulence factors for the pneumococcus.These proteins represent new

targets and their validation as targets has been done.The new treatment

will be based on binding peptides isolated from a series of large phage

display libraries or based on small molecules identified by high

throughput screening. Following screening of the phage libraries the

most promising peptides will be evaluated on the basis of binding affinity

and neutralising action in vitro.The peptides and small molecules will be

formulated in chitosan for nasal delivery.

ProblemThis project is being undertaken in response to the need to find newmethods of treatment of disease due to Streptococcus pneumoniae.Thisbacterium is a major cause of community-acquired pneumonia,meningitis, bacteraemia and otitis media and it exhibits high rates ofmulti drug-resistance in countries worldwide.

More than ever before,modern drug discovery is dependent on high-throughput screening.Therefore,the drug discovery process is shiftingfocus from identifying suitable candidate drugs – which remains anessential but time-consuming goal – to identifying suitable leadcompounds in order to maximise the cost-effectiveness and speed ofthe subsequent lead optimisation process.

Aim• To identify lead compounds for the treatment of pneumococcal

disease by inhibition of the pneumococcal toxin, pneumolysin.

• To identify lead compounds for the treatment of pneumococcaldisease by inhibition of the pneumococcal zinc metalloproteases.

• To identify new methods for the delivery of the new anti-pneu-mococcal compounds.

Expected results• Isolation and identification of peptides and/or small molecules as lead

compounds for the treatment of pneumococcal disease.

• Use of the lead compounds, formulated in chitosan, for nasal deliveryof anti-pneumococcal drugs.

Model of pneumolysinmonomer

Peptide sequences specifically binding to pneumolysin or to metallo-proteinases (indicated as "Target" molecules in the picture) will beidentified through affinity selection on solid phase (microplates ormagnetic beads) of several different phage displayed random pep-tide libraries, having different length and level of constrain. Phageclones bearing specific peptide ligands will be isolated and the

sequence of the displayed peptide will be determined by sequenc-ing of the corresponding single-strand DNA. Characterization ofbiological properties of the selected peptides will be performed.

New methods of treatment of antibiotic-resistant pneumococcal disease



AMDR

Potential applicationsThe results from the project will lead to new treatments ofpneumococcal pneumonia, meningitis and bacteraemia and newformulations for delivery of treatment.Pneumococcal disease makessignificant demands on health care systems but the rapidly increasingrate of antibiotic resistance in pneumococcal strains is impacting onclinical management of pneumococcal disease. At one level theproject will confront this issue by producing new antimicrobialagents directed at hitherto unexploited targets.The project aims,however, to develop these new antimicrobial molecules targeted ata single, highly important bacterial species rather than taking thetraditional approach of narrow- and broad-range antimicrobial drugs.The use of targeted drugs is predicted to reduce the intensity ofselection for any particular resistance mechanism since no selectivepressure is applied to species other than the target organisms, thusreducing the pool of organisms contributing to the spread of anyresistance mechanism.Reduction in the frequency of resistance willsignificantly prolong the shelf life of any antimicrobial drug. Thetreatments developed from this project will also address thetoxaemia in pneumococcal disease that is not addressed byconventional antibiotics. The project will evaluate if a new drugdelivery system based on chitosan will enhance the effectiveness ofanti-infective compounds.

Coordinator Prof.Andrew, Peter W

Department of Infection, Immunity & Inflammation

University of Leicester

University Road

Leicester, LE1 9HN, United Kingdom

Phone: +44 116 2522951

Fax: +44 116 2525030


Project web-site: www.le.ac.uk/iii/eu/pneumopep

Key words: antibiotic resistance, Streptococcus, pneumonia,meningitis, pneumolysin, metalloproteinase

PartnersDr Oggioni, M R

Dipartimento di Biologia Molecolare

Università degli Studi di Siena

Policlinico Le Scotte (lotto 5; piano 1)

Siena, Italy

Prof.Teti, G

Dipartimento di Patologia e Microbiologia Sperimentale,

Università di Messina

Messina, Italy

Dr Gill, I J

Bioanalytical Department

West Pharmaceutical Services Drug Delivery & ClinicalResearch Centre Ltd

Nottingham, United Kingdom

Mr Jarosz,T

Essais Cliniques-Evaluation-Epidémiologie-Statistiques

Paris, France

Acronym: PNEUMOPEPProject number: LSHM-CT-2005-512099EC contribution: €1 500 000 Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/06/2005



AMDR

SummaryAMIS aims to use the strength of our own innate immune system to

design antimicrobial drugs for future generations.Antimicrobial proteins

in our immune system are often combined with inflammatory signals

in one single molecule.AMIS will take that same approach and reshuffle

different parts of different molecules to make novel effector molecules

that still have these combined functions but are optimally adapted for

therapeutic intervention. Within our innate immune system many

molecules have been identified over the last years that are involved in

direct or indirect clearance of bacteria.The consortium will select the

most promising and innovative compounds with this dual mode of action

and:

• design proteins with anti-microbial activity in combination with an

inflammatory trigger, targeting extra cellular bacteria

• design proteins with inflammatory priming capacity (without extra

anti-microbial activity); targeting intracellular bacteria

• discover new modulators to dampen inflammation.

ProblemThe tremendous success with which antibiotics have been used tocombat infectious diseases is under serious threat from the increasingdevelopment of antimicrobial resistance. Without new treatmentapproaches to address antimicrobial resistance, this threat willcontinue to rise.To fight infectious diseases effectively in the futurewe have to broaden the approaches in therapeutic intervention.Thereare three ways by which the therapeutic intervention of infectiousdiseases can be broadened.The first is to design drugs that have asmaller chance for resistance development (targeting evolutionaryconserved structures is one key element here).The second is to designdrugs that are as different in mechanism of action as we can envision.The third is to combine drugs. AMIS (Antimicrobials by ImmuneStimulation) combines these three strategies in a highly innovativeapproach.

AimActivators, receptors, effectors and inhibitors are an integral part ofthe complex mechanism of interaction in the innate immune system,combining cellular stimulation and anti-microbial action. Theseinteraction mechanisms form the core focus of the research projectenvisaged by the consortium. The underlying theory is that themultitude of triggers needed to get a full-blown immune response isan intrinsic prerequisite to keep the process localised.That is why wewill aim at subtle immunostimulation or priming,which will, in bacterialinfections,be accompanied by an extra trigger, locally provided by thebacterial products at the site of infection. In its pursuit of a novelapproach to address antimicrobial resistance, the consortium hasformulated three main research objectives.

Antimicrobials by immune stimulation

AMIS


Expected resultsMake an array of fusion proteins that combine strong antimicrobial withinflammatory signals so that these two actions work in concert. Bycombining the best that we can find in our innate immune system wecan tune the new molecules to perform better in certain specificinfections than Nature has provided so far.Furthermore we aim to learnfrom our innate immune system how to effectively recognise and kill abacterium for millions of years without developing major resistance.

Potential applicationsThe collaborative research in AMIS will lead to proof-of-principle for anovel treatment approach to address antimicrobial resistance bycombining the innate immuno-stimulation with the antimicrobial capacityof naturally occurring substances of the human innate immune system.Parts of that system have been proposed and tried before withantimicrobial peptides from insects and other species and activation ofthe immune system by bacterial compound [Toll Like Receptor (TLR)ligands or small molecules that affect the signalling pathway of TLRs] asexamples. However toxicity in the first example and over-activation ofthe immune system combined with redundancy in the second exampleare inherent drawbacks in these alternative approaches.

The consortium


AMDR

Coordinator Dr van Strijp, Jos

Eijkman Winkler Institute

University Medical Centre Utrecht

Heidelberglaan 100

3584 CX Utrecht,The Netherlands

Phone: +31 30 250 6528

Fax: +31 30 254 1770


Key words: immunology, infections, novel antimicrobialapproach, immune stimulation, fusion com-pounds

PartnersProf. Krönke, Martin

Institute for Midical Microbiology, Immunology and Hygiene

Medical Centre

University of Cologne

Cologne, Germany

Prof. Espervik,Terje

Department of Cancer Research and Molecular medicine

Norwegian University of Science and Technology

Trondheim, Norway

Prof. Peschel, Andreas

Faculty of Medical Microbiology, Cellular and MollecularMicrobiology Group

University Hospital Tübingen

Tübingen, Germany

Prof. Björck, Lars

Department of Cellular and Molecular Microbiology

Lund University

Lund, Sweden

Dr Haagsman, Henk P.

Department Public Health and Food Safety

Faculty of Veterinary Medicine

Utrecht University


Dr. Peter Antal-Szalmas

Department of Clinical Biochemistry and MolecularPathology

Medical and Health Science Centre

Debrecen, Hungary

Dr. Herman Groen

IQ Corporation

Groningen,The Netherlands

Dr. Shai Yarkoni

Target-In Ltd.

Kfar-Saba, Israel

Acronym: AMISProject number: LSHM-CT-2004-512093EC contribution: €2 100 000Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/01/2005


SummaryHuman pathogens emerging in the contemporary environment face two

main kinds of evolutionary challenges:

A. survival and growth in the antibiotic-rich milieu makes it essential

that the bacteria acquire genetic traits of resistance

B. successful drug-resistant strains must also be able to compete with

other members of the species for colonisation, geographic spread and

disease in the human host.

The main purpose of the programme PREVIS is to examine the interplay

of these two challenges and also obtain insights on how host factors

and ecological/societal factors (antibiotic use, day-care centre

attendance etc.) modulate the epidemiology of drug-resistant and drug-

sensitive pneumococcal disease in diverse settings in northern,southern

and eastern Europe.PREVIS will provide an integrating platform to study

important and unexplored aspects of microbial and host factors related

to pneumococcal disease/pathogenesis,epidemiology/transmission,and

molecular mechanisms for resistance development. A broadening of

knowledge on these issues should lead to improved and focused

treatment, prevention and intervention strategies towards these

common community-acquired infections.

ProblemStreptococcus pneumoniae remains among the most important causesof life-threatening community-acquired diseases such as pneumonia,septicaemia and meningitis, particularly in high-risk groups such asyoung children, HIV-infected individuals and the elderly. Theintroduction of penicillin and other antimicrobial drugs caused adramatic reduction in mortality of all pneumococcal diseases exceptmeningitis. However, pneumococcal disease attack rates have notdecreased and the annual global mortality rate of pneumococcaldisease is still estimated to be over one million deaths per year. In theUnited States, pneumococcal infections remained a major cause ofpotentially life-threatening diseases with fatality rates in a similar rangeas those of AIDS,prostate and breast cancer.Streptococcus pneumoniaeis also a major cause of upper respiratory tract infections such as otitismedia and sinusitis.While these afflictions are seldom life-threateningthey are major contributors to health care costs and antibiotic use.Not only is the human host the virtually exclusive target of pathogenicpneumococci but the nasopharynx is also the main ecologicalreservoir of this bacterial species. Up to 60% of healthy childrenattending day-care centres were found to be colonized by S.pneumoniae. Drug-resistant pneumococcal clones (DRPn) emerging

from this major ecological reservoir are widely spread in Europe andin other parts of the world, threatening effective antibiotic therapy.For decades penicillin has been the drug of choice for treatingpneumococcal infections,but increasing levels of penicillin resistance,up to 50% in some areas, has resulted in the use of alternativeantibiotics.However, this has led to the development of resistance tomany alternative antibiotics as well, and vancomycin is the last drugof choice, especially when treating invasive pneumococcal infectionscaused by DRPn clones, since vancomycin resistance has not beenobserved. Of major concern is the emergence and wide distributionof multiresistant isolates (those resistant to more than two differentclasses of antibiotics) globally, creating further treatment problems.

The PREVIS programme aims to address several major questions,such as:

• Why do pneumococci sometimes act as devastating pathogenscausing a severe disease with sometimes a fatal outcome, while inother instances cause a non-invasive upper respiratory tractinfection,or even just reside harmlessly in the nasopharynx withoutsymptoms of disease?

• Are those pneumococci found among healthy children of the samegenetic lineages as those pneumococci causing invasive disease?

• Are there differences in the severity and nature of diseases causedby DRPn and drug susceptible (DSPn)?

• How are transmissibility and virulence affected by antibioticresistance determinants?


Pneumococcal resistance epidemicity and virulence – an international study

AMDRPREVIS

Streptococcus pneumoniae


AimThe main objective of PREVIS is to examine the interplay betweenhow pneumococci acquire genetic traits of resistance and howsuccessful resistant and susceptible strains may cause colonisation,transmission and disease, involving both bacterial virulence propertiesas well as host factors.

Expected results1. determine the frequency and clonal types of DRPn and DSPn

causing invasive disease and colonising healthy carriers

2. clone- and serotype-specific estimates of disease potential forinvasive pneumococcal disease

3. using a microarray developed in PREVIS, from the two genomesequences of TIGR4 and R6 and comparative genomics, we aim atidentify factors involved in pneumococcal pathogenesis

4. whole-genome sequencing of a Streptococcus mitis strain, whichis a frequent source of heterologous genes and gene fragmentswhich may become building blocks of resistance determinants in S.pneumoniae

5. show whether antibiotic resistance determinants affect pathogen-host interactions and identify host factors important forsusceptibility to invasive pneumococcal disease

6. identify novel approaches to the development of antivirulence drugs

7. identify the genetic/biochemical mechanisms of the ‘fitness cost’ ofpenicillin resistance and compensatory mechanisms that must existin epidemic clones of DRPn

8. identify the role of viral illness and immunological/genetic factorsin the susceptibility of children to invasive pneumococcal disease

9. estimate the threshold levels of antibiotic consumption in thecommunity that select for resistance

10. develop a web-based data management infrastructure coupledwith advanced machine learning tools for automated data-miningof predictive associations.

Potential applicationsPneumococcal disease caused by both DRPn and DSPn results in asubstantial portion of the estimated health care costs of infectiousdiseases in Europe. Globally, mortality from pneumococcal diseaseshas remained among the highest of all infectious diseases. Yet thispotentially dangerous human pathogen also uses the healthy humancarrier as its global ecological reservoir. By gaining better knowledgeabout the spread of DRPn and DSPn, microbial and host factorsimportant for pneumococcal pathogenesis, mechanisms for thedevelopment of antibiotic resistance and the role of environmentalfactors such as antibiotic consumption for the emergence and spreadof antibiotic resistant pneumococci, we will create a platform forimproved treatment and more focused prevention and interventionstrategies.Also, as the prevalence of multi-resistant strains continuesto increase, creating further treatment problems, novel concepts formaking drugs are of major importance. In this project we intend todevelop lead substances for novel so-called anti-virulence drugs. If thisapproach turns out to be successful we will have a new drug fortreating pneumococcal infections irrespective of whether or not thebacteria are resistant to antibiotics.

Drug resistance


AMDR



AMDR

Coordinator Dr Henriques Normark, Birgitta

Department of Bacteriology

Swedish Institute for Infectious Disease Control

Nobels väg 18

171 82 Solna, Sweden

Phone: +46 84752413

Fax: +46 8302566


Project web-site: www.previs.net

Key words: Streptococcus pneumoniae, antibioticresistance, molecular epidemiology,pathogenicity, innate immunity

PartnersDr Ekdahl, Karl

Dept of Epidemiology

Swedish Institute for Infectious Diseases, SMI

Solna, Sweden

Prof. de Lencastre, Hermínia

Instituto de Tecnologia Químíca e Biológica (ITQB)

Oeiras, Portugal

Prof. Spratt, Brian

Imperial College London

Department of Infectious Disease Epidemiology


Prof. Kristinsson, Karl G

Landspitali University Hospital

Reykjavik, Iceland

Dr Jonsdottir, Ingileif

Landspitali University Hospital,

Department of Immunology

Reykjavik, Iceland

Prof. Melo-Cristino, J

Laboratory of Microbiology

Faculdade de Medicina de Lisboa (FML),

Lisbon, Portugal

Acronym: PREVISProject number: LSHM-CT-2003-503413EC contribution: €3 000 000 Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/01/2004

Prof. Normark, Staffan

Microbiology and Tumorbiology Center

Stockholm, Sweden

Prof. Hakenbeck, Regine

University of Kaiserslautern

Kaiserslautern, Germany

Prof.Wolf-Watz, Hans

INNATE pharmaceuticals

Umeå, Sweden

Dr Gudnason,Thorolfur

Directorate of Health-Infectious Disease Control.

Seltjarnanes, Iceland

Prof.Almeida, Jonas S

Instituto de Biologia Experimental e Tecnológica, IBET

Oeiras, Portugal

Dr Urbaskova, Pavla

National Institute of Public Health

Prague, Czech Republic


SummaryWe aim at the elucidation of the molecular mechanisms of resistance

to inhibitors of cell wall synthesis in bacteria responsible for severe

nosocomial and community-acquired infections.Our STREP is focused

on ß-lactams, the major class of antibiotics in current clinical use, and

on resistance due to modifications of the cell wall synthesising

machinery and to production of ß-lactamases, the most prevalent

mechanisms in Gram-positive and Gram-negative bacteria,respectively.

These studies will form a reference to globally assess the modifications

of the structure, function, and dynamics of the peptidoglycan assembly

pathways responsible for emergence of resistance including the 3-D

structure of relevant components and possible targets. It will identify

new ß-lactamases,determine their 3-D structure and elucidate different

aspects of the regulation of their gene expression and the mechanisms

responsible for their mobility.

ProblemAntibiotics are not like other drugs in that they act against bacteriaand not the human host.Therefore the evolution of resistance underthe selective pressure of antibiotics after exposure of populations(human, animal) raises major therapeutical issues. This programmeaddresses the general problem of resistance to antibiotics andconcerns the understanding of the mechanisms of resistance, inparticular to inhibitors of cell wall synthesis.Among these are the ß-lactams, one of the most important classes of antibiotics, if not themost broadly used antibiotics worldwide. The rates of ß-lactamresistance for many common species found in infections have reachedhigh levels in the community,as well as in the hospital.While in Gram-positive organisms this resistance is mainly due to altered targets, inGram-negative organisms, acquired resistance to ß-lactams isessentially due to the presence of plasmid-encoded ß-lactamases orthe over-expression of chromosome-encoded ß-lactamases.This latterresistance can be enhanced by associated impermeability or effluxmechanisms. Since many pathogens are multiresistant, there will bean eventual limitation in the choice of antibiotics useful for primarytreatment and therefore a promotion of a vicious circle facilitatingthe emergence of new resistances.

A) Penicillin-binding proteins (PBPs) and critical associatedfactors. The peptidoglycan is a complex structure, the synthesisof which involves multiple coordinated steps within and outsideof the cytoplasm.The complete disaccharide-peptide unit linkedto the lipid carrier, once translocated through the cytoplasmicmembrane, is polymerised by protein complexes involved in cellelongation (elongase) and division (divisome). These complexesinclude the PBPs (penicillin binding proteins) of classes A and Bthat belong to the superfamily of the penicilloyl serine transferasesand are the targets of the penicillins. According to the modulesthey contain, they display D,D-transpeptidase, D,D-carboxy-peptidase and glycosyltransferase activities. Production of D,D-transpeptidases that are inefficiently inactivated by the drugs,commonly referred to as low-affinity PBPs, is the main mechanismresponsible for clinically relevant ß-lactam resistance instreptococci, staphylococci, and enterococci. Due to thecomplexity of the peptidoglycan assembly pathway,analyses of themechanisms of resistance has been mainly limited to easilydetectable modifications of the drug targets, such as the level ofproduction of the PBPs and their interaction with ß-lactams.However,recent analyses support the view that genes non-essentialfor viability are required for expression of resistance mediated bylow-affinity PBPs and other factors.Among these are:

(i) biosynthetic enzymes adding the side chain to the pentapeptidestem;

(ii) regulatory factors, that control as yet unknown responses of thebacteria to the drugs; and

(iii) transglycosylases which appear to co-operate in an undefinedmanner with the D,D-transpeptidase acitvity of low-affinity classB PBPs for peptidoglycan polymerisation in the presence of ß-lactams.

In rare cases, mutations in these chromosomal genes have beendetected in resistant bacteria but the extent of such modificationsand the role of the encoded protein are largely unknown. Analysis ofthe role of other components of the divisome and the elongasecomplexes have not been developed since the metabolism of the lipid-linked peptidoglycan precursors and their delivery to thepolymerisation complexes is poorly understood.

B) ß-lactamases. Among clinical Gram-negative isolates, the majormechanism of resistance to ß-lactam antibiotics is related to theproduction of hydrolytic enzymes:the ß-lactamases.To counter thisproblem, the pharmaceutical industry has marketed novel classesof ß-lactams. However, the use of these new drugs was quicklyfollowed by the emergence of new ß-lactamases including those with

Combating resistance to antibiotics by broadening the knowledge on molecular mechanisms behind resistance to inhibitors of cell wall synthesis


AMDR COBRA


expanded-spectrum activity many of which evolved from previousexisting ß-lactamases.This process involved the three classes of ß-lactamases (classes A, C, and D) belonging to the superfamily ofpenicilloyl serine transferases, that also includes the PBPs, and theclass B enzymes regrouping the metallo-ß-lactamases (Zn++-dependent).While new enzymes are discovered almost every dayand have to be explored, the reason for the spreading of severalnovel enzymes world-wide remains unknown and the factorsmodulating their expression as well as the vehicles for mobility andspreading of these genes have to be thoroughly studied.

AimThis project focuses on the understanding of molecular mechanismsof resistance to ß-lactams and other cell wall inhibitors in clinicalGram-positive and Gram-negative pathogens. We aim at studyingdifferent enzymatic properties and structural features of class B PBPsinvolved in ß-lactam resistance, as well as different auxiliary proteins,among which the class A PBPs and other enzymes involved in thesynthesis of substrate structures used by these class A and B PBPs.We also intend to find, in the cytoplasmic and in membrane steps ofthe peptidoglycan synthesis,other critical factors, including regulators,interfering with the expression of resistance to cell wall inhibitorsand possible new resistance-conferring targets. The study of ß-lactamases will include an extensive search for, and characterisationof, novel extended-spectrum ß-lactamases and carbapenemases in

Gram-negative organisms. For several of these enzymes, geneexpression and the molecular basis of their dissemination will bestudied.The catalytic properties, the structure-activity relationshipsand the 3D structure of some of them will be determined with regardto their activities against the antibiotics.The contribution of additionalfactors, such as outer membrane permeability and efflux pumps, tohigh-level resistance to ß-lactams will be investigated in detail.

Expected resultsUnderstanding the role of those amino acid residues in PBPs that areessential for the expression of resistance and their contribution to thestructure of the PBP D,D-transpeptidase domains.

Understanding the biochemical role of the associated critical factors inthe pathway of peptidoglycan synthesis, their structure, and their rolein non ß-lactamase-mediated resistance; with respect to variousregulators, and understanding the mechanisms by which they interferewith the expression of resistance.

Understanding the diversity of the structures of the ß-lactamasesobserved and studied, and understanding the role of the amino acidresidues essential for their catalytic properties.

Understanding the genetic environment of the ß-lactamase genes andits contribution to expression of resistance, gene dissemination as wellas the associated role of porins and efflux systems in the expression ofresistance.

3 D model of the chromosomal L2 ß-lactamase of Stenotrophomonasmaltophilia involved in ß-lactam resistance of a pathogen found in cystic

fibrosis and nosocomial infections.


AMDR


Potential applicationsThis programme addresses the general problem of resistance againsta class of antibiotics widely used in the community and in hospitals.Any progress, even the smaller ones, in the understanding of thesemechanisms will be of benefit to academia,public health and industry.It will increase our knowledge of insufficiently explored and newmechanisms of resistance toward cell wall inhibitors. It will lead tothe deciphering and the discovery of novel mechanisms including therole of several auxiliary proteins involved in resistance.The isolationof ß-lactamases, PBPs and other components essential for theexpression of resistance to ß-lactams and other cell wall inhibitors,reinforced by knowledge of their 3-D structure, will allow for thefuture setup of assays to screen for new inhibitors and will improvedrug design.The knowledge of the sequence of different targets willbe used to create databases containing new ß-lactamases and newPBP alterations linked to resistance. Particular mutations responsiblefor resistance could then be used to develop sequence-basedmolecular diagnostic tools. Discovery of novel mechanisms ofresistance will result in the identification of new phenotypes helpfulfor the detection of resistance in clinical laboratories.This will aid inthe interpretation of susceptibility and resistance to different classesof cell wall inhibitors, in particular ß-lactams.

Finally,transmission and acquisition of resistance by new strains is oneof the major factors in resistance dissemination.A better knowledgeof these mechanisms should facilitate the recognition of the antibioticsmost powerful in selecting for the mechanisms studied.Understandingof the transmission mechanisms is a crucial step in preventingresistance as well as in guiding optimal antibiotic usage.


AMDR

Key words: resistance to antibiotics, cell wall synthesis-ing machinery, PBP, non-PBP factors andresistance, ß-lactamases, catalytic mecha-nisms, structural studies, gene acquisitionand mobility, Gram-positive and Gram-nega-tive organisms.

PartnersCentre d’Ingénierie des Protéines, Liège, Belgium

Department of Sciences, Swammerdam Institute for LifeSciences, Molecular Cytology,Amsterdam,The Netherlands

Microbiology, University of Kaiserslautern, Germany

Medical Microbiology, Zürich, Switzerland

Regulation of gene expression/Centro de biologia molec-ular ‘severo ochoa’, Campus universidad autonoma,Madrid, Spain

Biochemistry/Université Paris XI / IBBMC, Orsay, France

Department of Chemistry, University of Warwick, UnitedKingdom

IBS, Institut de Biologie Structurale, Grenoble, France

Bacteriology, University Paris XI, Le Kremlin Bicêtre,France

Servicio de Microbiologia, Hospital Universitario Ramony Cajal, Madrid, Spain

Antibiotic Resistance Monitoring & ReferenceLaboratory, London, United Kingdom

Molecular Microbiology, National Institute of PublicHealth,Warsaw, Poland

Department of Pathology and Microbiology, University ofBristol, United Kingdom

Dipartimento di Biologia Molecolare, Sezione diMicrobiologia, Siena, Italy

Inserm Transfert SA, Paris, France

Coordinator Prof. Gutmann, Laurent

Microbiologie

INSERM EMI0004 Université Paris VI,

Laboratoire de Recherche Moléculaire sur les Antibiotiques

15 rue de l’école de Médecine

75270 Paris CEDEX 06, France

Phone: +33 1 42 34 68 62

Fax: +33 1 423 25 68 12

E-mail: [email protected];[email protected]

Project web-site: http://www.antibior.com

Acronym: COBRAProject number: LSHM-CT-2003-503335EC contribution: €2 980 000 Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/02/2004


SummaryRecent genomic technologies allow the study of global physiological pro-

cesses in microbes.Their application to the study of pathogens allows

improved searches for new medicines to combat infection and to better

avoid the emergence of resistance against them. It will also help to

anticipate therapies for new emerging diseases and to devise treatments

to help individual patients to overcome each infection. Predictive

microbiology,based on genomic analysis,may also be used to anticipate

the presence of unexpected potential pathogens. Both industrial and

sustained public sector efforts are needed to fully develop the promising

potential of this research frontier of the microbial world.

ProblemThe discovery of new antibacterial agents against resistant micro-organisms is an urgent and vital need. All EU member statesunanimously agreed that antimicrobial resistance was no longer justa national problem, but a major international issue requiring acommon strategy at European level (The CopenhagenRecommendations Report from the European Union Conference on ‘TheMicrobial Threat’, September 1998, 1). Recommendations releasedfollowing this meeting expressed four important issues,among themthe need to carry out research to fight the problem of antimicrobialresistance.

The social costs incurred by the incidence of infectious diseases inthe population at large,and in particular the elderly and the productiveage sectors,are enormous.Hospitalisation costs per patient run aboveabout €500 per day. Curbing the spread of resistant pathogens willresult in the attainment of high standards in human health care,a maincomponent of the quality of life, as a clear priority for the EuropeanUnion. It will reduce social and public healthcare costs and willtherefore have a beneficial impact on the citizens of the EU. Specificallyit is anticipated that the ability to effectively treat microbial infectionswill reduce morbidity, and have a positive impact on healthmanagement policies of the EU member states.

AimTo discuss microbial functional genomics as a powerful and innovativetool to discover new cellular targets that will be used to counteractbacterial resistance to antibiotics and to further avoid the generationand spread of new resistances.

Expected resultsThe workshop conclusions will be centred on proposing to theEuropean Commission a realistic roadmap to implement a researchactivity based on functional genomics to tackle the problem ofantibiotic resistance and discovery with sufficient industrial, clinicaland academic participation to guarantee its long term success.

Potential applicationsHow genomics can help to combat antibiotic resistance?

Genomics has been applied to identify new inhibitable bacterialtargets, but it can be used as well to gain valuable knowledge on howbacteria behave during infection, how they respond when theirproliferation is challenged or when they are treated with an antibiotic.

Target identification

Comparative genomics yields information on the universality oftargets in important pathogens. Moreover, it identifies those genesthat being absent in humans and animals are less likely to produceproblems when their function is blocked. A recent genomic searchcomparing the genomes of three important pathogens, Haemophilusinfluenzae,Streptococcus pneumoniae and Staphylococcus aureus indicatesthat more than 350 bacterial genes are possible targets (Payne, D. J.Microbiology Today,2004,31:55-57). After finding that a gene may bea target, further work is required to obtain information on whatspecific property or domain of the encoded protein is the one thatcan be successfully inhibited. A substantial amount of additionalresearch may still be needed before an assay for HTS (high throughputscreening) can be devised and validated.

The future of genomics in target identification

Genomics can help to refine and validate targets by analysing changesin the expression of genes that take place in the microbes when theyare subject to stressful conditions that mimic the environmentconfronted during the process of infection.

Progress in molecular modelling and in the synthetic skills needed formimicking protein surfaces are still required to fully exploit theknowledge derived from the study of the interactome. In the futurethe study of the interactome will identify the precise domains in sometarget molecules that are required for the function of proteins thatestablish interactions required for the survival of the pathogen andfor its interaction with the host. If suitable mimics are synthesisedthey can be used as scaffolds to build an altogether new class ofbacterial inhibitors.


AMDR

Workshop on strategies to address antimicrobial resistance through the exploitation of microbialgenomics

micro-MATRIX


How to avoid the path to resistance

Pathogens become resistant to antibiotics by synthesising new proteinsor modifying part of their physiology. In most cases the acquisition ofresistance makes resistant bacteria less efficient to compete against theirnon-resistant relatives in the absence of the antibiotic.This extra burdencan in turn be minimised by the acquisition of compensatory mutationsthat counterbalance the decrease in fitness. Compensatory mutationsare difficult to revert and contribute in some cases to maintain aproportion of resistant individuals within pathogen populations(Andersson, 2003, Persistence of antibiotic resistant bacteria, CurrentOpinion in Microbiology 6: 452-456).

Resistance is both inheritable and transmissible. Blocking thehorizontal transfer of resistance,although of limited therapeutic value,is a possible way to prevent the spread of antibiotic resistance to thesusceptible pathogen populations.

Functional genomics supplies data on how bacteria respond todifferent environments by adjusting the rates at which different genesare transcribed. We can therefore obtain a global picture of thechanges that occur in bacteria when they are treated with an antibioticlead and deduce the likelihood of resistance emergence before thelead is further developed into a medicine.This will not only save effortson compounds that are prone to elicit resistance but will also provideinformation on how to anticipate resistance and devise proceduresto circumvent it before a new antibiotic is in clinical use.

Genomics of the antibiotic producers

One topic in which genomic research can help is the analysis of globalregulatory circuits in the antibiotic-producing organisms.Many effortshave been put into the application of genetic research to increase theamount of antibiotic produced by the producer organisms. Most ifnot all of them have not yielded practical results.

Many antibiotics are produced under suboptimal growth conditionsas products of secondary metabolism. Under those conditionsdeviations towards the production of a single compound may severelyupset the growth of the organism, resulting in a failure to increasethe net production of the desired compounds. A better understandingof the regulatory circuits that operate under suboptimal and stressfulconditions will allow the modification of the production of somesecondary metabolites without greatly disturbing growth.

DiagnosticsDNA arrays can speed up the diagnosis of infections.Moreover,the useof subgenomic arrays containing suitable sets of genes will easily identifyspecific strains of a pathogen. Once the technology is fully developedit will be possible to design antibiotic courses specifically tailored tohelp an individual patient to fight against one particular infection.


AMDR

Coordinator Vicente, Miguel

Centro Nacional de Biotecnología CSIC

Campus de Cantoblanco

28049 Madrid, Spain

Phone: +3491 585 4699

Fax: +3491 585 4506


Project web-site:

For the book of abstracts:

http://www.cnb.uam.es/~mvicente/full_book.pdf

For the final report:

http://www.cnb.uam.es/~mvicente/micro-MATRIX+cover.pdf

Key words: bacteria, essential functions, regulation,gene expression, stress response, patho-genesis

PartnersTel Aviv University, Israel

ITQB Universidade Nova de Lisboa, Portugal

Institute of Cell & Molecular Biology, University of Edinburgh, United Kingdom

Institut Pasteur, France

PROGENIKA Biopharma S.A., Spain

Acronym: micro-MATRIXProject number: LSSM-CT-2003-502801EC contribution: €2 980 000 Instrument: Specific Support ActionDuration: Four daysStarting date: 17/04/2004


• PROMEMORIA 88• NEWMOOD 90• APOPIS 93• GENADDICT 95• EUROSCA 97• NeuroNE 100• BrainNetEurope II 102• AUTISM MOLGEN 106• SYNSCAFF 108• EUROHEAD 111• SPASTICMODELS 113• NCL-models 116• NEUROKCNQPATHIES 118• X-ALD 120• PainGenes 122• GRIPANNT 124• STRESSPROTECT 126• INTERDEVO 129• NeuroDisseminator 131• EUROMEMO 132• ESNI course 2003 135• FENS Forum 2004 137• RABRE 139

Brain,neurological and psychiatricdiseases


SummaryThe PROMEMORIA project focuses on the role of cell recognition

processes in normal and dysfunctional plasticity, learning and memory

with the aim of developing compounds with a beneficial effect on

diseases involving cognitive impairment. The focus on neuronal cell

adhesion molecules is novel and unique. Recent research has shown

that these molecules play key roles in learning and memory.The project

includes a series of subprojects focused on gene discovery, structural

biology, synaptic plasticity at both the physiological and morphological

level, and a number of models of deficient plasticity, learning and

memory.

The Consortium consists of 18 leading teams from 11 countries, of

which two are new EU member states. It is composed of 14 academic

partners and 4 SMEs.The Consortium contains teams specialised in

genetics, protein chemistry, neurophysiology, neuroanatomy,

neurobiology, animal models of learning and behavior, in vivo test

systems for a very broad range of behaviour and learning phenomena.

Moreover, there is a considerable expertise in drug screening and

development.

An efficient dynamic management structure is proposed with four key

objectives:integration of research results and early identification of new

findings; training of future world leaders in this research area;

dissemination of results to scientists, patients and the general public;

the issue of 5-10 patents securing protection and transfer to European

industry of PROMEMORIA discoveries.

BackgroundCognitive impairment

In the western world, 6-10% of adults older than 65 years havedementia mainly due to Alzheimer’s disease. A large group ofelderly are suffering from so-called mild cognitive impairment, adiagnostic term applied to individuals who do not meet the clinicalcriteria of dementia or Alzheimer’s disease, but who are cognitivelyimpaired.

The therapeutic possibilities for treatment of cognitiveimpairment are currently very limited, emphasising the profoundneed for development of new therapeutic modalities.A problem isthe heterogeneous temporal and spatial distribution of the

corresponding drug targets.The study of the role of neuronal CAMshas so far been limited by technological problems and functionalinvestigations have been difficult. However, we have recentlydeveloped the first series of peptido-mimetics of a neuronalCAM (NCAM) and thereby created a new type of compound witha tremendous promise both as regards the understanding of thefunctions of CAMs at the molecular level and the development ofdrugs with beneficial effects on synaptic plasticity onneuroregeneration.

Neuronal cell adhesion molecules

Neuronal CAMs are known for their involvement in braindevelopmental processes,and recent evidence now indicates that theyalso participate in synaptic alterations in connection with memoryformation in adults. CAMs of particular importance include memberof the Immunoglobulin-(Ig) superfamily, Cadherins and Integrins.Particularly the roles of L1 and NCAM are now well supported byexperimental data.Neuronal CAMs in general are well known for theirinvolvement in processes of relevance to neuronal plasticity such asaxonal extension and guidance,cell migration,differentiation,survival,and formation of synapses.

Role of CAMs in memory formation

Evidence for a role of L1 and NCAM in memory formation comesfrom studies interfering with the functions of these molecules indifferent learning paradigms. Modifications of L1- and NCAM-mediated cell recognition appear to be a prerequisite for theformation of stable changes in synaptic communication.These changesare probably achieved through alterations in gene expression, post-translational modulations and turnover of the proteins.

Aim• to achieve a better understanding of the role of neuronal cell

adhesion molecules CAMs in the maintenance and modulation ofsynaptic and network plasticity and in cortical circuitry andinformation processes underlying learning and memory;

• to develop and validate a series of suitable animal models for studiesof memory function and dysfunction in diseases;

• to search for novel ligands and mimetics of neuronal CAMs formodulation of plasticity with the aim of developing therapeuticsimproving learning and memory

From cell-cell recognition to memory formation.New strategies for the treatment of dysfunctional plasticity, learning and memory


BRAIN, NEUROLOGICALAND PSYCHIATRIC DISEASES

PROMEMORIA


Expected resultsThe Consortium expects to discover new genes and proteins, identifynovel pathogenic mechanisms and define new therapeutic strategies,with clearly defined deliverables:

• new counterreceptors (ligands) of cell adhesion mole-cules will be identified, key proteins will be structurally char-acterised and binding sites will be localised (WP 1);

• experts in the field of neurophysiology will establish the role ofneuronal CAMs in maintenance and modulation of select-ed synapses and synaptic populations. Moreover, the role ofCAM signaling in triggering use-dependent and/or developmentalchanges in circuitry will be assessed (WP 2, 3, 8);

• new animal models for dysfunctional plasticity will be estab-lished, validated and employed for evaluation of learning andmemory under various conditions involving CAM-modulation(WP 4, 5, 6, 7);

• ligands will be developed interacting with the CAM bindingsites, either agonistically or antagonistically, through drug screen-ing or based on structural determinations. These studies areexpected to identify novel therapeutic strategies and new thera-peutic targets (WP 8);

• the unprecedented degree of collaboration between academicgroups and biotechnology SMEs in PROMEMORIA is expected toresult in a rapid translation of findings into new strong intel-lectual property, and subsequently into drug screening pro-grammes (WP 10, 11);

• the goal-oriented network will train a younger generation ofEuropean scientists to excellence within the highly integratedresearch area of plasticity, learning and memory (WP 9);

• at least five patent applications will be filed (WP 10).

Potential applicationsA considerable fraction of adults will encounter impairment inlearning and memory as they age, and age-related memory impair-ment often predates more serious neurological problems.Neurodegenerative diseases including Alzheimer’s disease,Parkinson’s disease, motor neuron diseases, stroke and demyelinat-ing diseases are rapidly becoming major health problems in devel-oped countries. Moreover, neurological injuries also may lead tocognitive impairment.


BRAIN, NEUROLOGICALAND PSYCHIATRIC

DISEASES

Coordinator Prof. Bock, Elisabeth

University of Copenhagen

Institute of Molecular Pathology

The Protein Laboratory

Blegdamsvej 3C

2200 Copenhagen N, Denmark


Project web-site: Under construction

Key words: genetics, cell adhesion molecules, cognition,dementia, neurodegeneration, drug dev-elopment

Partners1 Ireland

2 United Kingdom

1 France

2 Germany

2 Switzerland

2 Spain

1 Poland

2 Sweden

1 Israel

2 Denmark

1 Estonia

Acronym: PROMEMORIAProject number: LSHM-CT-2005-512012EC contribution: €9 700 000 Instrument: Integrated ProjectDuration: 48 monthsStarting date: 01/04/2005


SummaryThis is a major collaboration between 13 clinical and basic science

groups in 10 EU countries which addresses the evident need to

discover:

• new molecular mechanisms in the causation of depression

• new molecular mechanisms of effective drug-treatment.

We will measure three fundamental processes underlying depression

– the inability to experience pleasure,excessive sensitivity to stress and

negative appraisal of circumstances.This will enable us to cross-validate

findings in humans and animal models. In animals (rats and mice) we

will use a mixture of well-established and novel methods for inducing

genetic and mild stress-related changes in the three processes.We will

detect the molecular mechanisms involved by creating the

NEWMOOD microarray chip and measuring changes in gene

expression. Changes which are consistent across many models will

become targets for new treatments. In addition we will search for

neurochemical changes in how monoamine and other neurones are

regulated which are shared by the models.These too will become new

molecular targets.

Humans with varying genetic and environmental risk factors will be

compared on the three behaviours and on the brain systems and

neurotransmitters responsible using functional magnetic resonance

imaging.Gene-expression in the human postmortem brain will provide

further validation of animal findings and targets for treatment.

BackgroundUnipolar major depression is common and a leading cause ofmorbidity and mortality. In developed countries it is twice as commonin women as men, affecting 20% of women at some time in life.Theglobal burden of disease survey found it will be the fourth mostprevalent cause of disability-adjusted life years, accounting for about20% of the burden of disease (Murray 1997 Lancet 349:1436-1442).This is greater than the burden of common causes of death such ascardiovascular disease. In addition to its economic consequences,depression is a direct cause of death through suicide. There areimportant cohort effects – the age of onset of depression is steadilydecreasing each decade and it is no longer a disease of middle age.

Furthermore, there has been a remarkable increase in the rate ofsuicide in young males over the last 15 years in the EU. Indeed suicideis second only to road traffic accidents as the cause of death in the15 to 25 age band. Female gender and social and familial factorsincrease risk of depression but little is known about how theseinfluences work in the brain, least of all at the molecular level.Antidepressant treatment has improved in terms of tolerability andthus treatment adherence but drugs currently in use have the sameprimary mechanisms of action as 30 years ago and their downstreammolecular actions are obscure. Furthermore, at most 65% of newepisodes respond to drug-treatment and chronic, treatment-resistantdepression is a major health burden.

AimThe aim of this proposal is to combine new functional genomictechnologies with chemical analysis in an integrated multidisciplinaryapproach both to exploit hitherto overlooked genetic resources fornew antibiotics and, secondly, develop generic ‘superhosts’ toproduce these new antibiotics in high yields. ActinoGEN proposesthree parallel objectives to discover and develop new antibioticsbased on exploiting the genetic resources of actinomycetes,hithertothe major source of existing antimicrobials.The first of these is toactivate cryptic antibiotic biosynthetic pathways. Recent genomesequencing projects have revealed a genetic potential foractinomycetes to produce many more antibiotics than previouslyrecognised.ActinoGEN will explore how different cryptic pathwayscan be activated and then determine the structures and activitiesof the resulting new antimicrobials.The second approach will relyon the discovery of new antibiotic biosynthetic pathways fromdiverse actinomycetes. The number of actinomycete species thathave been isolated to date represents a small fraction of the totalin the environment. ActinoGEN will exploit the untapped geneticresource of as yet uncultured species to obtain antibioticbiosynthetic gene clusters that can direct synthesis of newantimicrobials. A third route to new antimicrobials is bycombinatorial biosynthesis. Biosynthetic genes from both new andexisting pathways will be combined to direct synthesis of newantibiotics with predicted structures. The design of new hybridmolecules will be related to improving antimicrobial activity. A fourthmajor aim, underpinning the Drug Discovery objectives, is theengineering of generic Superhosts for antibiotic production.A rate-limiting step to developing a new antibiotic is yield improvement.Post-genomic analysis permits, for the first time, a concerted andholistic approach to engineering generic Superhosts for use in theproduction of high yields of a wide variety of antibiotics.As part ofActinoGEN,this complementary activity is vital to greatly acceleratethe discovery and development of new drugs.

New molecules in mood disorders: a genomic,neurobiological and systems approach in animal modelsand human disorder



NEWMOOD


Expected resultsThe overarching aims are to identify:

• new molecular mechanisms in the causation of depression,specifically new candidate genes for diagnosis, prognosis andtreatment choice;

• new molecular mechanisms of effective drug treatment, specificallynew molecular targets for antidepressant drugs and novel candidatedrug treatments.

The technical aims are to:

• create a web-based core data-set of behavioural and neurobiologicalvariables common to human and animal vulnerability to thedepression endophenotype;

• create a new tool for research in depression: the NEWMOOD‘Depression’ microarrays;

• define a human pharmaco - fMRI signature for antidepressantefficacy;

• disseminate new and harmonised standards of research in affectivedisorders.

Expected results • the identification of differences in gene expression that are

consistent across a wide range of entirely different animal models;

• the detection of altered gene expression, neurochemical,neurophysiological and neuroendocrine regulatory mechanisms,which are common to a range of genetic, developmental andmechanistic animal models of vulnerability;

• the identification of candidate genes for diagnosis, prognosis andtreatment choice;

• a better understanding of the molecular mechanisms of depressionand other mood disorders;

• a greater understanding of the nature and extent of geneticpredisposition in depression.

Potential applications• the identification of new targets for drug therapies;

• the development of novel drug treatments;

• progress towards drug regimes tailor-made to suit individuals;

• ultimately, to reduce the overall morbidity and mortality due todepression and other mood disorders.



DISEASES

Coordinator Prof. Deakin, Bill

University of Manchester

Neuroscience and Psychiatry Unit

Room G.907, Stopford Building

Oxford Road

Manchester, M13 9PT, United Kingdom

Phone: +44 161 275 7427

Fax: +44 161 275 7429


Project web-site:

NEWMOOD website within http://projectplace.com

A public website will be created.

Key words: depression, stress, candidate genes, human,animal models, brain, neurochemical,neurobiological, neurotransmitters, anti-depressants, 5-HT

PartnersDr Lanfumey, Laurence

INSERM U 288

Faculté de Médecine Pitié-Salpêtrière

Paris, France

Prof. Corradetti, Renato

Università degli Studi di Firenze,

Dipartimento di Farmacologia Preclinica e Clinica

Florence, Italy

Prof. Lesch, Klaus Peter

University of Würzburg

Department of Psychiatry and Psychotherapy

Würzburg, Germany

Prof. Maldonado, Rafael

Universitat Pompeu Fabra

Laboratory of Neuropharmacology

Department of Experimental Sciences and Health

Barcelona, Spain




Prof. Harro, Jaanus

University of Tartu

Department of Psychology

Estonian Centre of Behavioural and Health Sciences

Tartu, Estonia

Prof. Steinbusch, Harry

University of Maastricht

Division Neuroscience

Maastricht,The Netherlands

Prof. Bagdy, Gyorgy

Head of Laboratory of Neurochemistry and ExperimentalMedicine

National Institute of Psychiatry and Neurology,

Budapest, Hungary

Dr Kelly, Paul A T

University of Edinburgh

Division of Clinical Neurosciences

School of Molecular & Clinical Medicine

Western General Hospital

Edinburgh, United Kingdom

Dr Sharp,Trevor

University of Oxford

Department of Pharmacology

Oxford, United Kingdom

Dr Hökfelt,Tomas

Karolinska Institutet,

Department of Neuroscience B3:4

Stockholm, Sweden

Prof. Del Río, Joaquín

University of Navarra Medical School


Pamplona, Spain

Dr Swiergiel,Artur H

Polish Academy of Sciences ("IGAB")

Institute of Genetics and Animal Breeding

Poland

Acronym: NEWMOODProject number: LSHM-CT-2004-503474EC contribution: €7 200 000 Instrument: Integrated ProjectDuration: 60 monthsStarting date: 01/05/2004


SummaryDegenerative disorders of the nervous system including Alzheimer’s and

Parkin-son’s are among the most de-bilitat-ing illnesses. There is

currently no treatment that can halt or prevent, let alone reverse nerve

cell degeneration. One hallmark common to these dis-orders is the

deposition of abnormal protein aggregates. APOPIS is designed to

elucidate the role of abnormal proteins in the pathogenesis of

neurodegenerative disorders and to develop methods for early

diagnosis and treatment of these devastating diseases.

BackgroundThe APOPIS programme is based on the information generated bythe recently completed sequencing of the human genome. APOPISwill make use of this information and employ state-of-the-arttechnologies in functional genomics, proteomics, bioinformatics, andneuroimaging, which will be combined with more traditionalapproaches such as epidemiological studies, transgenic modelorganisms and combinatorial chemistry in order to quickly identifyputative target genes and lead compounds for drug discovery.

AimThe first goal of APOPIS is to improve the understanding of thepathogenic mechanisms involved in neurodegenerative diseases applyingseveral complementary model systems and methodologies.The secondgoal is to advance the early clinical detection of these diseases, thusproviding a theoretical chance for clinical treatment before it is too late.The third goal of APOPIS is the development of effective strategies andefficacious drugs for the treatment and the prevention of these diseases.

Expected resultsAPOPIS is designed to elucidate disease mechanisms and to translatethe results into clinically useful products. Protein deposits seem to playan essential but as yet poorly understood role in disease progression.Therefore, by comparing a whole set of neurodegenerative diseasesafflicting different areas of the brain, it is expected to gain insight intocommon features in the underlying disease mechanisms, for instance,the causative agents or events for abnormal protein aggregation.Thesebreakthrough discoveries will lead to the identification ofpharmacological targets creating the basis for an effective drug designto halt the cascades involved in the disease processes.

Potential applications The advancement in clinical studies will lead to improved tools for theearly and differential diagnosis of neurodegenerative diseases.Immediateand reliable detection of neurodegenerative disorders is a prerequisitefor efficient clinical studies and finally for a successful treatment of thedisease. Intellectual property rights will be protected by patentapplications to ensure the seamless design and development of efficaciousand safe clinical products for the treatment and the prevention ofneurodegenerative diseases.


DISEASES

APOPIS


Senile plaque pathology differently stained in SweArc APP transgenic mice (A, B). © Lars Nilsson,

Uppsala University

Senile plaque associated markers in SweArc APP transgenic mice.Astrogliosis (strongly stained) around senile plaques (white arrows).

© Lars Nilsson, Uppsala University

Abnormal proteins in the pathogenesis of neurodegenerative disorders


Coordinator Prof.Adlkofer, Franz

VERUM Foundation

Pettenkoferstr. 33

80336 Munich, Germany

Phone: +49 89 5309880

Fax: +49 89 53098829


Project web-site: www.verum-foundation.de/apopis

Key words: early diagnosis, genetics, neurodegenerativedisorders, pathogenesis, protein aggregation,therapy

PartnersInstitute of Neurosciences, Swiss Federal Institute ofTechnology Lausanne (EPFL), Switzerland

Institute of Neuropathology, University Hospital Zurich,Switzerland

Bioinformatics and Molecular Genetics, University ofFreiburg, Germany

Wallenberg Neuroscience Centre, Lund University,Sweden

Groupe Hospitalier Pitié-Salptrière, Institut Nationale dela Santé et de la Recherche Médicale (INSERM), Paris,France

Université de Lille 2, France

Institut de Pharmacologie Moléculaire et Cellulaire,Centre National de la Recherche Scientifique,Valbonne,France

Centro de Biologia Celular/Laboratory of Neuroscience,Universidade de Aveiro, Portugal

Flanders Interuniversitary Institute for Biotechnoology,Center for Human Genetics, Leuven, Belgium

Cavalieri Ottolenghi Scientific Institute, FondazioneCavalieri Ottolenghi, Italy

Cellzome AG, Heidelberg, Germany

Department of Human and Animal Physiology, Universityof Athens, Greece

Department of Biochemistry, University of Munich,Germany

Division of Psychiatry Research, University of Zurich,Switzerland

Department of Neuropathology, University of Basel,Switzerland

MPI for Neurobiology, Max Planck Society for theAdvancement of Science, Martinsried, Germany

Laboratory of Neurodegeneration, International Instituteof Molecular and Cell Biology,Warsaw, Poland

Department of Public Health and CaringSciences/Geriatrics, Uppsala University, Sweden

Institute of Biochemistry, Swiss Federal Institute forTechnology, Zurich, Switzerland

Department of Neuroscience, Universita Vita-Salute SanRaffaele, Italy

Istituto de Recerca Biomedica de Barcelona, Parc Cientificde Barcelona, Spain

Phone: +34 9340 34902, fax: +34 9340 37225

Division of Psychiatry Research, University of Zurich,Switzerland

Clinic of Neurology, University of Marburg, Germany

EVOTEC NeuroSciences GmbH, Hamburg, Germany

Dementia Research Centre/The National Hospital forNeurology and Neurosurgery, University College London,United Kingdom

School of Medicine, University of Genova, Italy

Department of Biochemistry at the University of Naples,Italy

Institut für Organische Chemie, Universitaet Darmstadt,Germany

Institute for Clinical Neurobiology, University ofWürzburg, Germany

Structures & Biocomputing, European Molecular BiologyLaboratory, Heidelberg, Germany

Department of Neurology PO 41/Institute of Psychiatry,King’s College London, United Kingdom

MPI of Molecular Cell Biology and Genetics, Max PlanckSociety for the Advancement of Science, Dresden,Germany

Institute of Biochemistry, University of Zurich,Switzerland

Biological Chemistry/Institute of Life Sciences,The Hebrew University of Jerusalem, Israel

Department of Neurology, University of Cambridge,United Kingdom

Department of Biosciences, University of Kent atCanterbury, United Kingdom

Department of Molecular Genetics at the University ofAntwerp, Flanders Interuniversitary Institute forBiotechnology,Antwerp, Belgium

Neuroproteomics Research, Max Delbrueck Center forMolecular Medicine, Berlin, Germany

Acronym: APOPISProject number: LSHM-CT-2003-503330EC contribution: €8 995 518.39 Instrument: Integrated ProjectDuration: 36 monthsStarting date: 01/01/2004




SummaryAddiction is a brain disease, common in Europe, with deleterious

consequences on individual physical and psychological health,and serious

societal and economic consequences through criminality and violence,

decreased productivity and increased healthcare costs. In every family,

in a lifetime one can identify someone who has suffered from addiction.

Alcohol, nicotine or illicit drug use affects many people. Over 20 years

there has been little advance in the drug treatment for addiction, with

most new treatments addressing physical drug withdrawal rather than

treating drug craving and relapse.The contribution of genetic influences

to addiction liability has been recently recognised but the identification

of genetic risk factors and genes involved in the molecular basis of

addiction is a new major challenge for the post-genomic era.This project

is a collaboration between basic science groups,one SME and a leading

biotechnology company devoted to human studies on the role of genes

in complex diseases. This public-private partnership brings together a

highly innovative genealogical-led human genetics approach and a team

of researchers with Europe’s best genomic mouse models.The core of

the research effort will be the identification of genes associated with

drug addiction using an unbiased genome-wide approach.The strong

environmental component in the etiology of drug addiction has

presented a particularly difficult problem for genetic studies of this brain

disorder in the past.The groups of this consortium propose to meet

this difficult challenge by combining powerful animal genetics and gene

profiling strategies with a human genetic approach that is relatively

resistant to environmental modifications of the drug addiction

phenotype. Genes identified in this project will help to elucidate

dysfunction of genetic pathways in the addicted brain and provide new

targets for the development of novel therapies.

BackgroundThis is a major focused collaboration between 12 partners acrossEurope including one leading genetics company and an SME developedfrom the research success of one of the academic groups in thispartnership.The groups are spread across seven EU countries,includingtwo recently incorporated countries (Hungary and Poland) and oneassociated country (Iceland). It is an integrated multidisciplinary projectbringing together genome-wide gene identification studies in addictedpatients with genomic studies in the mouse, to identify common genesinvolved in addiction. The animal experiments bring together sevenleaders in genetic studies of addiction in Europe that have, and willfurther develop, a unique collection of gene knockout animals that canbe used to understand common underlying genetic mechanisms that

are responsible for predisposition to addiction.Their complementarymolecular genetics and neuroscience expertise provides a critical massof expertise to create a foundation of genetic information using state-of-the-art mouse models. These academic groups have linked with anIcelandic company,Decode Genetics,which is at the forefront in Europein the field of complex genetics in man.They bring a human researchcontribution to this Integrated Project of equivalent capacity to theanimal studies.The human experiments bring a unique and well-definedhuman population for large-scale gene analysis that will integrate withgenes identified in the mouse programme.

AimThe aim of the Integrated Project is to discover:

• new candidate genes that are involved in addiction using human andmouse approaches;

• new genetic mechanisms that are involved in addiction;

• new molecular targets for the treatment of addiction.

The human studies in this project will be carried out by DecodeGenetics in Iceland, using a genealogical approach to gene isolation,which is central to their success in mapping genes for complexdisorders. It is based on taking a list of patients with the phenotypebroadly defined, in this case addiction and subtypes of addiction,analysing it using the genealogy database to identify families, who willsubsequently be recruited for a genome-wide scan for linkage.Thegenealogical analysis of large cohorts not only detects how individualssegregate into large families but also provides information on therelationship between phenotypes.

The human genetic component of this project will be complementedby linkage studies in mice.This platform will generate a large cohortof phenotypically well-characterised mice from specifically designedgenetic crosses for linkage analysis.This analysis will provide chromo-somal loci and genes that contribute to drug vulnerability in animalmodels. Subsequent human association studies will then help todetermine if these genes also play a role in drug addiction in humans.

This project also brings together groups in Europe that have developedgene knockout animals of both the opioid and dopamine systems inthe brain.These systems are considered to be key players involved inthe mechanisms of addictive drugs and thus provide us with uniqueanimal model to identify genes involved in addictive processes. Thisproject extends the use of genetic models to identify genes thatcontribute to all components of addictive behaviour and also to studythe fundamental mechanistic basis of addiction. The key role of theopioid and dopamine systems in addiction enables us to use theknockout models to identify, using gene expression studies, potentialcandidate genes for addiction. In addition we propose to develop site-specific and inducible knockout animals, which will not only provideunique animal models for refined identification of addiction genes, butwill also provide further fundamental information on addictionmechanisms.

Genomics, mechanisms and treatment of addiction


DISEASES

GENADDICT



Expected resultsThe project will carry out genotyping and linkage analysis of familialmaterial to identify genes linked to addiction to individual substances,and to identify gender difference in gene specific linkage, as well asidentifying genetic links with specific psychiatric phenotypes. Theproject will dissect out potential genes that confer susceptibility toaddiction by identifying candidate genes from animal studies, andidentifying genotype-phenotype relationships for addiction.

The project will identify genes induced by addictive substances byexpression profiling in wild-type and gene knockout mice, and byexpression profiling in strains of mice with altered sensitivity tomorphine or cannabionoids. The project will identify if anxiety orstress are associated with drug abuse preference by phenotyping andquantitative trait loci analysis, and by evaluation of candidate genesfor association with drug addiction in humans and animal models.

The project expects to create conditional knockout mice with deletionsof either mu, D2 and proenkephalin genes and will verify theneurochemical disruption of these animals. In addition, the project willdevelop site-specific knockout mice, to delete receptors and peptidesin specific addiction related brain areas, and to analyse behavioural andneurochemical responses of site-specific deletion. In addition,we expectto characterise the involvement of opioid, dopamine and cannabinoidreceptors and opioid peptides in the addictive properties of nicotinestudying behavioural responses to nicotine in wild-type and knockoutanimals. Further, we expect to characterise the role of specific opioid,dopamine and cannabinoid genes in addictive neurochemistry by studyingneurotransmitter release in the nucleus accumbens of gene knockoutmice,studying G-protein receptor activation in gene knockout mice,andby studying electrophysiological changes in gene knockout mice.

Potential applicationsThe potential of a fuller understanding of the genomics of addictionis two-fold. Firstly, the opportunity to develop diagnostic tests toidentify an individual’s susceptibility to become addicted to drugs,givesa chance to protect vulnerable individuals more effectively. Secondly,new treatments for drug addiction which result from understandingthe genetics of addiction have the potential to reduce the economiccost of addiction,which impacts heavily on the sectors of health,work,social services and the judicial system.

The ultimate objective of this Integrated Project is to provide newknowledge that can be used by the participants or by Europeanpharmaceutical companies to develop new drugs for the treatment ofboth drug craving and relapse, which are core features of addictivedisorders, or for providing new drugs for treating physical dependenceand withdrawal from drugs of addiction. The scientific knowledgegathered will allow the consortium to identify specific genetic alterationsin addicted patients and to develop novel treatments tailored to themodulation of addictive processes that are under genetic control.

In addition, the production of novel knockout strains of mice withsite-specific and temporally regulated mutations represents a majortechnical advance in gene manipulation in animals.These models willenrich the scientific community and provide new means to study theroles of selected genes in not only addiction but also several otherdisorders of mood and pathological pain states.



Coordinator Prof. Kitchen, Ian

University of Surrey

School of Biomedical and Molecular Sciences

Guildford GU2 7XH, United Kingdom

Phone: +44 1483 689734

Fax: +44 1483 576978


Project web-site: To be developed.

Key words: Addiction, genomics, drug abuse, geneknockout, genealogy, alcoholism, opiates,dopamine

PartnersProf. Maldonado, RafaelUniversity Pompeu Fabra,Laboratory of Neuropharmacology,Department of Experimental Sciences and Health,Barcelona, SpainProf. Kieffer, Brigitte LInstitut de Génétique et de Biologie Moléculaire et CellulaireCNRS/INSERM/ULPIllkirch, FranceDr Borrelli, EmilianaInstitut de Génétique et de Biologie Moléculaire et CellulaireDirecteur de Recherche, INSERMIllkirch, FranceProf. Zimmer,AndreasLife & Brain GmbHLaboratory of Molecular NeurobiologyBonn, GermanyProf. Przewlocki, RyszardInstitute of Pharmacology Polish Academy of SciencesDepartment of Molecular NeuropharmacologyKrakow, PolandProf. Freund,Tamás FHungarian Academy of SciencesInstitute of Experimental MedicineBudapest, HungaryDr Thorgeirsson,Thorgeir EDecode ehf,Reykjavik, Iceland

Acronym: GENADDICTProject number: LSHM-CT-2004-005166EC contribution: €8 100 000Instrument: Integrated ProjectDuration: 60 monthsStarting date: 01/01/2005


SummaryTwenty two European groups from nine countries with an excellent

reputation of clinical, clinical-genetic and basic research on

spinocerebellar ataxias (SCA) will aim at developing a treatment

for patients suffering from this rare neurodegenerative disease.To

reach this goal, an international standard on the clinical evaluation

in form of a Core Assessment Programme for Interventional

Therapies of SCA (CAPIT-SCA) will be developed.The generation

of the world’s largest collection of information on SCA, the

European SCA Registry (EUROSCA-R), will ensure standardised

data acquisition and facilitate continuous recruitment of SCA

patients throughout Europe. The potential to include all larger

European SCA families into linkage analysis will lead to the

identification of new SCA loci and to the cloning of novel ataxia

genes. Genotype-phenotype correlations will follow. Such a

combined effort will offer a systematic large-scale search for genetic

modifier factors in SCA. EUROSCA will also implement strong

research projects to generate and characterise cellular and

transgenic models, which will allow a more defined study of the

pathogenesis and will serve as a tool for first therapeutic studies.

Five core facilities and training programmes will complement

research efforts and clinical work.

BackgroundSpinocerebellar ataxias (SCAs) consist of a highly heterogeneousgroup of progressive movement disorders usually manifesting in thethird to fourth decade of life and commonly lead to death after along duration of suffering for more than 20 years. The disease isinherited as an autosomal dominant trait. Since a cure is currentlynot available, the development of drugs for SCA will have greatimpact.The prevalence of SCA in Europe is not well known but isassumed to be less than 1:10 000. The high clinical and geneticheterogeneity is manifested by the description of 21 SCA associatedloci and there are several lines of evidence of further loci implicated.For nine of the SCA subtypes the underlying mutations have beendefined and shown to be caused by a trinucleotide repeat expansion,most of them within the coding region of the respective gene andencoding a polyglutamine chain. Pathohistologically, intranuclearinclusions are detected in the affected regions of the brain.However,the pathomechanism(s) underlying neuronal cell death and theregion specificity of the neurodegeneration remain unknown.

Deciphering these mechanisms will lead to the development of drugspreventing protein aggregation, neuronal death and stopping ordelaying the progression of these diseases.

AimDue to the low prevalence of SCA and because of its broad geneticheterogeneity, it is difficult to collect large numbers of patients.Therefore the characterisation of the underlying pathogeneticfactors and the potential to initiate large therapeutic studies arelimited.This project will implement a network structure spanningnine European countries to collect the world’s largest set ofgenetically defined patients (European SCA registry = EUROSCA-R). We will characterise these patients based on a novel set ofclinical data using clinical rating scales, structural imaging, andelectrophysiology to generate the largest and best characterisedSCA patient collection (Core Assessment Program forInterventional Therapies = CAPIT-SCA). The advantage of havingSCA families linked to a specific chromosomal region for which thegenetic cause has not been defined yet (SCA11, SCA13, SCA14,SCA21) will be further strengthened by providing additional familiesfor which genetic linkage is unknown. It is anticipated that somegenes will be cloned by EUROSCA within the next years. For thepatients themselves an oriented information network (EUROSCAweb portal) will be established allowing easier contact withspecialised clinics of neurology. The scientific research objectiveswill concentrate on the most frequent and important SCA subtypes(SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17) to decipher thepathogenesis of these diseases, to generate animal and cellularmodels, and to develop therapeutic strategies.All research groupswill get major support by highly specialised core facilities to producepoly- and monoclonal antibodies, to generate Drosophila models,to perform complex proteome and transcriptome analyses and todecipher interacting proteins.

European Integrated Project on spinocerebellar ataxias(EUROSCA): Pathogenesis, genetics, animal models and therapy


DISEASES

EUROSCA



EUROSCA consists of four sub-structures:(i) Generation of the world largest patient DNA registry

(EUROSCA-R), which will allow extraordinary opportunitiesto map novel gene loci, to identify novel SCA genes (SCA4,SCA11, SCA13, SCA14, and SCA21), and to study modifiergenes of the age at onset (in particular of SCA1, SCA2, andSCA3).

(ii) Development of the first Unified Ataxia Rating Scale (UARS),which will be used to generate a Core Assessment Programmefor Interventional Therapies (CAPIT-SCA). CAPIT-SCA isimportant to measure disease progression in SCA, one of themajor steps to objectively allow differentiation of geneticallydifferent SCA subtypes at the clinical level and one prerequisiteto monitor efficacy in clinical studies.

(iii) Pathogenesis of the most common SCA sub-forms (SCA1,SCA2,SCA3,SCA7,SCA17).To resolve these questions cellularand mouse models for most of the SCAs have already beengenerated (SCA1, SCA2, SCA3, SCA7); others are beingprepared (SCA17, and Drosophila models).These models willbe used in initial therapeutic studies.

(iv) Research groups are strongly supported by five core facilitiesto generate monoclonal and polyclonal antibodies, to generateDrosophila models, to analyse the transcriptome and theproteome and to build networks of interacting proteins.

Expected results• world’s largest DNA registry for SCA patients (EUROSCA-R);

• core Assessment Program for Interventional Therapies (CAPIT-SCA);

• new epidemiological data;

• risk prediction, modifier genes;

• defining new gene loci, disease gene cloning;

• disease models for SCA1, 2, 3, 6, 7, and 17;

• defining the pathogenesis common to polyQ type SCA;

• development of five potential drugs and testing in animal models.



Coordinator Prof. Rieß, Olaf

Eberhard Karls-Universitaet Tuebingen


Calwerstraße 7

72076 Tuebingen, Germany


Project web-site: http://www.eurosca.org/

Key words: brain research, degenerative disease, raredisease, neurodegeneration, spinocerebellarataxia, trinucleotide repeat disorders

PartnersInstitute of Child Health London, University College,London, United Kingdom

Klinik und Poliklinik für Neurologie, Universitätsklinikum,Bonn, Germany

Hôpital de la Salpêtrière, Institut National de la Santé et dela Recherche Médicale, Paris, France

Department of Biochemistry & Genetics, Istituto NazionaleNeurologico Carlo Besta, Milan, Italy

Cambridge Institute for Medical Research, University ofCambridge, United Kingdom

Department of Neurology, University Medical CenterNijmegen,The Netherlands

Department of Neurology, Université Libre de Bruxelles,Belgium

Department of Genetics, Institute of Psychiatry andNeurology,Warsaw, Poland

Department of Medical Genetics and Child Development,University of Pécs, Hungary




DISEASES

Acronym: EUROSCAProject number: LSHM-CT-2003-503304EC contribution: €9 450 000 Instrument: Integrated ProjectDuration: 60 monthsStarting date: 01/01/2004

Service of Neurology, Servio Cántabro de Salud, Santander,Spain

Department of Molecular Pathogenesis, University ofLondon, Institute of Neurology, London, United Kingdom

Ruhr-University Bochum,Department of Neurology,St. JosefHospital, Bochum, Germany

Neurogen Frankfurt, Johann Wolfgang von GoetheUniversity, Frankfurt/Main, Germany

Institut für Humangenetik, Universität Lübeck, Germany

Institut Jacques Monod, Centre National de la RechercheScientifique Paris, France

Neuroproteomics, Max Delbrück Centrum for MolecularMedicine, Berlin, Germany

Centre European de Recherche en Biologie et Medecine,IGBMC Illkirch, France

Department of Crystallography, Birkbeck College,University of London, United Kingdom

Molecular Structure Division,National Institute for MedicalResearch, London, United Kingdom


SummaryNeuroNE is Europe’s premier research network for the creation of novel

therapeutic approaches to neurodegenerative disease and

neurotrauma,which represent an urgent socio-economic and human

need.The NeuroNE consortium (22 academic groups,five SMEs and one

management partner in nine different countries) is taking a multi-

disciplinary (functional genomics and proteomics,physiology,chemistry,

clinical studies) and multi-faceted (disease mechanisms, biology of cell

death and survival,regeneration mechanisms,high-throughput screening,

gene- and cell-based therapies) approach to this problem. Among the

neurodegenerative diseases, the network focuses on Alzheimer's

disease (AD), Parkinson's disease (PD), Huntington's disease

(HD) and amyotrophic lateral sclerosis (ALS). Spinal cord injury

(SCI) will be the main model for neurotrauma.NeuroNE brings together

investigators from different backgrounds (basic scientists,active clinicians

and therapeutically-oriented SMEs) to work at all levels on the target

diseases using the methods of post-genomic science,molecular and cell

biology, animal models, therapeutic strategies and clinical studies.

Professional project management provides efficient integration,

realisation of scientific objectives and knowledge management. The

scientific infrastructure of the network includes shared NeuroNE-funded

core facilities in seven centres.The network has employed a team of

scientists based in the participating laboratories who will conduct

research and form collaborations among the different participants.The

network has a programme of scientific meetings that will consist of three

major international plenary meetings and ten scientific workshops on

specific topics.To feed back the benefits of integration into EU society,

the network is working with patient organisations, identified associated

research groups who will benefit immediately from our infrastructures,

and has opened network meetings to identified scientists from emerging

research centres.

AimNeurodegenerative diseases and neurotrauma represent one of thegreatest clinical and societal challenges of the coming century.As theaverage age of our population increases,the numbers affected by thesediseases of the nervous system will mushroom. The NeuroNEconsortium is addressing this problem by designing a long-termmultidisciplinary approach based on recent progress in the field ofneuronal degeneration and death together with a range of cutting-edge therapeutic strategies.

Expected resultsThe mechanisms involved in any neurodegenerative disease, inneurotrauma exhibit some unique properties and many shared elements.A limited number of basic technologies need to be developed which willhave an impact in many of these conditions.However,to be competitive,individual research groups usually focus on one particular disease. Onemajor impact of NeuroNE will be to accelerate the pace of discoveriesin neurodegeneration and neurotrauma by pooling expertise andresources, and focus on cross-disease and cross-discipline relations.Europe is currently home to some of the leading scientific groupsworldwide in the field of neurodegenerative diseases and neurotrauma.The generation of a network including these groups will generate majorsynergies, further enhancing the competitiveness of European scienceand biotechnology in these areas, and feeding forward into thedevelopment of new treatments by European pharmaceutical companies.

BackgroundIn the field of damage and repair of the nervous system Europe possessesscientific groups at least equal to those in other parts of the world.However their effectiveness is limited by fragmentation, lack of accessto research resources, lack of clinical testing tools, lack of integration ofeffort between large, medium and small industrial companies and afragmented intellectual property environment.The NeuroNE networkbrings together actors involved at all levels (from basic research to clinicalstudies and drug development) in studying many aspects of the problem(different diseases,different biological phenomena,different therapeutic

Predicted number of Europeans affected by Alzheimer's disease.From Wancata et al., 2003

Molecular mechanisms of neuronal degeneration: fromcell biology to the clinic



NeuroNE


strategies) in many countries.Together the members of the networkwill form an enterprise, integrated from basic science to clinical scienceto industry. Effective treatments for most of the diseases targeted bythe network have yet to emerge. The NeuroNE network and itscollaborators will accelerate the development of these treatments,which, because of the large number of patients affected by its targetdiseases, will be pharmaceuticals of great financial value.

Potential applicationsThe overall task of the network is to create within the EuropeanUnion the conditions for emergence of novel mechanism-basedtherapeutic approaches to neurodegenerative disease andneurotrauma.The NeuroNE scientists are convinced that researchon the basic mechanisms of these diseases will help to identifypharmacological targets that will be required for the development ofeffective drugs for the treatment and prevention of neurodegenerativediseases. The combination of clinical groups with academiclaboratories and biotech companies specialised in the field is uniqueon this scale in Europe, and can challenge the best elsewhere. It willform the basis for future translation of clinically relevant basicresearch into the clinics.Because of the growing importance of thesediseases for our ageing populations, these advances will have asubstantial impact, both socially and economically.



DISEASES

Coordinator Prof. Fawcett, JamesUNICAM Cambridge Centre for Brain RepairE.D. BuildingRobinson WayCambridge CB2 2PY, United KingdomPhone: + 44 1223 33 11 88Fax: + 44 1223 33 11 74E-mail: [email protected] web-site: http://neurone.nuxit.net/Key words: neurodegenerative diseases, neurotrauma,

translational research, network of excellence

PartnersSchool of Life Sciences, Institute of Neurosciences - LEN,Lausanne, SwitzerlandInterdisciplinary Center for Neurosciences, Neurobiology,Universität Heidelberg, GermanyCenter for Neurological Medicine, Neurology, Universityof Göttingen, GermanyDivision of Neurobiology, Lund, SwedenFMI, Basel, Switzerland Department of Pharmacological Sciences, University ofMilan, ItalyTECHNION, Rappaport Institute, Haifa, IsraelDepartment of Medical Research and ImaGene Program,Service Hospitalier Frédéric Joliot, Orsay, FranceINSERM, IBDM, Marseille, FranceLudwig-Maximilians-University,Adolf-Butenandt-Institute,Department of Biochemistry, Munich, GermanyKarolinska Institute, Department of Neuroscience, Divisionof Molecular Neurobiology, Stockholm, SwedenDepartment of Basic Neuroscience, Centre MedicalUniversitaire, Geneva, SwitzerlandMax-Planck Institute of Neurobiology, Department ofMolecular Neurobiology, Munich-Martinsried, GermanyNeurologische Klinik, Universität Ulm, GermanyDepartment of Neurology, Institute of Psychiatry London,United KingdomDepartment of Human Genetics, Catholic University ofLeuven, BelgiumNational Center for Biotechnology, CNB-C.S.I.C., Madrid,SpainBrain Research Institute, University of Zurich, SwitzerlandRita Levi Montalcini Center for Brain Repair, NeuroscienceDepartment,Turin, Italy IBDM, Campus de Luminy, Marseille, FranceVenetian Institute for Molecular Medicine, Padova, ItalyTROPHOS SA, Marseille, FranceXANTOS Biomedicine AG, Munich,GermanyGENETRIX, Madrid, SpainPHARMAXON, Marseille, FranceMEMOREC Biotec GmbH, Cologne, GermanyInserm Transfert, Paris, France

Acronym: NeuroNEProject number: LSHM-CT-2004-512039EC contribution: €8 300 000 Instrument: Network of ExcellenceDuration: 48 monthsStarting date: 01/01/2005

Paired helical filamentextracted from an

Alzheimer's disease brainimmunolabelled with an anti-tau antibody.With

the courtesy of Dr. MariasGracia Spillantini


SummaryBrainNet Europe II is a network of 19

established brain banks across Europe.

Having established a network of ten brain

banks in preparation for BrainNet Europe

II we now aim to integrate new members,

to spread excellence in collecting human

high-quality post-mortem brain tissue and

to foster research in the cellular and

molecular basis of neurological and mental

disorders and diseases, gender aspects and

the ageing process.

The main objectives of BrainNet Europe II

are:

1) to acquire and distribute well-

characterised and high-quality tissues for

basic research in neuroscience;

2) to provide a basis and quality control

system for RTD projects dealing with clinical or epidemiological

aspects of neurological and psychiatric diseases;

3) to standardise and harmonise neuropathological diagnosis;

4) to increase the awareness of standardised neuropathological and

clinical diagnosis in neurology and psychiatry at a European level;

5) to develop gold standards for tissue handling, safety aspects, quality

control and ethics.These standards will be the basis for using human

post-mortem brain tissue in new investigative techniques such as

expression profiling and proteomics;

6) to contribute to training and exchange of neuroscientists;

7) to use modern means of information technology to exchange data

within the network, to spread excellence and to disseminate

information to the general public.

These objectives will be reached by establishing a rigorous decision-

making and management system resting on the members of the Project

Coordination Committee and assisted by an SME accountant company.

Diseases of high frequency and outstanding medical and social

importance such as Alzheimer's,Parkinson's,motoneuron disease,prion

diseases, multiple sclerosis, schizophrenia and affective disorders will

be the focus of the network. In addition we will contribute to research

in rare diseases, a research branch which can only be worked on

successfully on an international European context.

BackgroundIn an era of rapidly growing knowledge about the biochemistry of thebrain, increasing insights into the genetics of brain diseases and agreater understanding of functional anatomy through various imagingtechniques, there is an increasing need for brain and tissue banking,i.e.the collection of brain tissue from well-characterised and diagnosedpatients.The reasons for this need are evident.While we collect evermore data and details about the biochemistry, molecular biology andphysiology of nerve cells in culture or even in functioning animal brains,while we can biochemically characterise the cell biological processesinvolved in some of the notorious neurological and psychiatricdiseases, there is still no clear picture emerging that would explainthe relation of single biochemical findings and the pathophysiology orclinical progression of human brain disease. Brain banking will not byitself solve all these problems.However,together with modern clinicaltechniques, including brain imaging on the one side and molecularbiology, genetics and biochemistry on the other, brain banking is at

Graphical presentation showing the interdependencies of the components of activities.WP, workpackage

Network of European brain and tissue banks for clinical and basic neuroscience



BrainNetEurope II


the interface of clinical and basic research on the brain and maytherefore contribute to both.

As systematic investigations have shown,more than 20% of idiopathicParkinson's disease cases or even more of the clinical diagnoses inthese diseases are in strong disaccord with post-mortemneuropathological diagnosis (Hughes et al. J Neurol Neurosurg Psychiatr,1992, 55:181).This is a serious problem of quality control in modernmedicine not restricted to Parkinson's disease. It is a particularproblem in an era in which powerful therapeutic tools have becomeavailable but autopsy rates and quality control are declining.

Establishing a network of brain banking will serve several purposes:first, to improve diagnosis and quality in neurology and psychiatry andsecond,to give an impetus to brain research.The network will containclinical data and will in the future incorporate genetic and imaginginformation.Future activities that go beyond our immediate plans willshow how much BrainNet Europe II will eventually be able tocontribute to clinical and basic brain research.

Diagnostic criteria as well as tissue handling procedures andpreservation techniques are related to scientific progress and thuswill change over time. It does not appear realistic to assume that oncethese procedural questions have found solutions they will bepermanent.Yearly consensus conferences will be held to keep up withscientific progress and to adjust criteria and procedures accordingly.

AimBrain diseases such as Alzheimer's and Parkinson's disease andpsychiatric disorders such as schizophrenia and major depression areamong the most devastating and most common illnesses in ourmodern-day world.With increasing life expectancy the aging nervoussystem and its diseases are looming large at the beginning of the newmillennium. Numerous local and multinational research projects inclinical and theoretical neuroscience are under way to take on thechallenge.Brain and tissue banks have been set up in many institutionsof member states of the European Union in order to support researchprojects on the biology of brain disease. It appears,however,that theseefforts have long been disparate. Integration of European brain bankshas been begun in a collaboration of ten brain banks in the 5thFramework Programme and is growing but needs further support.

The major objectives of this network of excellence are to bring theseindividual efforts together, to integrate new groups, to spreadexperience to other groups in order to maximise the benefits ofcollaborative brain banking. Brain and tissue banking at a Europeanscale is of particular importance to study genetic and environmentalinfluences of common diseases, to make possible studies on rarediseases and to guarantee reliable standardised morphologicaldiagnosis of brain diseases all over Europe. The latter is anindispensable prerequisite for good therapeutic studies.

BrainNet Europe started as a collaboration of ten brain banks andhas now been opened for the integration of new members.Fundamental work has been performed concerning ethical aspects,diagnostic standards, tissue handling and sampling protocols, as wellas data storage and exchange using various tools of information

technology. Many of the fundamental aspects of brain banking suchas Ethics in Brain Banking are in a state of permanent change as theintegration of European countries and culture progresses. Thesethemes therefore are in need of continual updates.

With the advent of novel molecular biological technologies such as massspectrometry, expression profiling, proteomics and (functional)genomics and their simplified application in pathology andneuropathology, it is now timely to harness these technologies forbrain tissue research. This in turn requires that we set standardsconcerning the quality of tissues to be used for the application ofcertain technologies.

This consortium of brain banks in Europe assembles the critical massnecessary to tackle brain banking in the post-genomic era. Inparticular we will approach the following areas:

1) managerial and ethical problems specific to brain banking. Thisincludes setting standards for safety in brain banking, agreeing onand using neuropathological criteria, performing technical anddiagnostic quality control exercises.

2) Brain Bank specific methodological research.This entails settingstandards for working with human brain tissue using moderntechnologies such as laser capture microscopy,mass spectrometry,expression profiling etc.Taken together this will be the basis forresearch into human brain diseases using various heuristic andhypothesis-driven approaches.

3) spreading of excellence beyond the network by using conventionalpublication in the scientific literature, giving talks at internationalmeetings in the neurosciences and using electronic media.

Expected results1. SHORT-TERM OBJECTIVES AND ACHIEVEMENTS

1) to generate and foster collaboration between different centresundertaking brain banking and associated research activities;

2) to maximise access to a range of tissues from particular diseases,collected from a number of different centres under standardconditions and with well documented clinical histories;

3) to maximise access to sufficient numbers of control casesappropriate to the disease of study;

4) to harmonise protocols for individual disease-directed research;

5) to develop methodologies which would have wide application inbrain banking, e.g. optimisation of different methods of freezingtissue;

6) to disseminate current skills in enlisting public support for, andinterest in, brain banking as a means of studying brain diseases;

7) to use the Internet for exchange of information, for raising scientificawareness regarding currently available tissue samples, forrefinement of current diagnostic criteria, for multi-centre validationof qualitative and quantitative research data, and for networkedtraining sessions;



DISEASES


8) to train young researchers in the use and application of humannervous system tissues for research, by means of short-termvisits to other centres, training fellowships, and workshops.

2. LONG-TERM OBJECTIVES AND ACHIEVEMENTS

1) to seek new ways to support the neuroscience researchcommunity, e.g. blood and DNA collections and the routineinclusion of non-CNS tissue samples in the Bank;

2) to invite other Brain Banks to join the network if it is successful,while being mindful of the need to preserve the viability andworth of the project;

3) to encourage the development of a collaborative ethos amongsmaller Banks and tissue resources on a national basis;

4) to encourage good practice and reduce duplication betweenBanks and tissue collections;

5) to ensure that additional nervous system diseases of highmorbidity and burden on healthcare resources are addressedwithin the network;

6) to ensure that high-quality samples are collected from rarediseases and from foetuses in order to encourage and facilitateresearch in ontogeny and unusual neuropathological material;

7) to devise strategies which lessen the impact of differentlegislative practices concerning autopsies in different Europeancountries;

8) to consider alliances with pharmaceutical and technologyindustries;

9) to consider inclusion of data regarding primate and transgenicresources;

10) participation in, and access to, a networked source of diseaseand control tissues of high quality will both stimulate andfacilitate the scientific output from individual centres, which inturn will help to secure ongoing funding for individual BrainBanks.

Management structure of BNE II




Università di Bologna Dipartimento di ScienzeNeurologiche, Bologna, Italy

Department of Neuropathology, National Institute ofPsychiatry and Neurology, Budapest, Hungary

Human Brain Tissue Bank, Department of Anatomy,Semmelweis University, Budapest, Hungary

Department of Neuropathology, Bereich HumanmedizinGeorg-August University Goettingen, Germany

Department of Psychiatry and Psychotherapy, SaarlandUniversity, Germany

Department of Neuroinflammation, Imperial College ofScience Technology and Medicine, London, UnitedKingdom

Laboratoire d´anatomie pathologique, Hospices Civils deLyon, Lyon, France

Clinical Neurochemistry Lab, Julius MaximiliansUniversity Würzburg, Germany

GABO Gesellschaft für Ablauforganisation,Informationsverarbeitung undKommunikationsorganisation mbH & Co. KG, Munich,Germany



DISEASES

Coordinator Prof. Kretzschmar, Hans

Ludwig Maximilians Universitaet Muenchen

Institute of Neuropathology and Prion Research

Feodor-Lynen-Str. 23

81377 Munich, Germany

Phone: + 49 89 2180 78000

Fax: + 49 89 2180 78037


Project web-site: www.brainnet-europe.org

Key words: brain bank, neuroscience, genomics, pro-teomics

PartnersDepartment of Neuroscience and Neurology,Neuropathology section, University of Kuopio, Finland

Pathology (Neuropathology), School of Clinical andMolecular Medicine, University of Edinburgh,United Kingdom

Huddinge Brain Bank, Karolinska Institute, GeriatricDepartment, Neurotec, Stockholm, Sweden

Institute of Neurology, University of Vienna, Austria

Division of Neuropathology and Neurology 5, IstitutoNazionale Neurologico Carlo Besta, Milan, Italy

Institute Neuropathology, Hospital de Bellvitge,Universitat de Barcelona, Spain

Laboratoire de Neuropathologie Raymond Escourolle,Institut National de la Santé et de la Recherche Medicale,Paris, France

Department of Neuropathology, King`s College London,United Kingdom

Netherlands Brain Bank Foundation, Amsterdam,TheNetherlands

Department of Pathology / School of Medicine, Nationaland Kapodistrian University of Athens, Greece

Acronym: BrainNetEurope IIProject number: LSHM-CT-2004-503039EC contribution: €7 740 000 Instrument: Network of ExcellenceDuration: 60 monthsStarting date: 01/07/2004


SummaryThe Autism STREP group will pool data from 425 previously

ascertained multiplex families and perform a meta-analysis to identify

the top 6 susceptibility regions.The top susceptibility regions will then

be tested in genetically isolated populations of Finnish and Friesland

singleton trios to search for extended haplotypes that may further

refine the critical regions. Brain expressed candidate genes in these

narrowed regions will be tested for mutations and association with

autism. In parallel, previously identified potential candidate genes will

be tested for mutations/association in the combined sample of

multiplex families.

BackgroundAutism spectrum disorders are handicapping, neurodevelopmentaldiseases of childhood that persist into adult life and which usually ariseon the basis of a complex genetic predisposition.The brain basis ofautism remains contentious, although post mortem studies provideclear evidence of neuropathology with a prenatal onset. Identifyingsusceptibility alleles is a key for understanding the molecular andcellular nature of the brain dysfunction and for developing rationalpreventative and treatment strategies to improve quality of life.Although there has been significant progress towards identifyingsusceptibility alleles,this has not yet been achieved by research groupsworking independently.

Aim1.To perform a meta-analysis of linkage in all multiplex families and

search for extended haplotypes in two isolated populations.

2.To test brain expressed candidate genes in 6 regions of linkage formutation and association with autism.

3.To test named candidate genes for mutations/association withautism in multiplex families.

4.To assess and genotype new multiplex and singleton families.

Expected results1. Identification of top 6 linkage regions in combined multiplex sampl

and analysis of parent of origin and methylation effects in candidategenes

2. Identification of extended haplotypes for the top 6 regions inFinnish and Netherlands singleton trios.

3. Identification of any mutations/aetiological variants in brainexpressed candidate genes in top 6 linkage regions.

4. Identification of any mutations/associations in named candidategenes.

Using European and International populations to identifyautism susceptibility loci



AUTISM MOLGEN




DISEASES

Coordinator Prof.Anthony James BaileyThe Chancellor, Masters and Scholars of the University ofOxfordUniversity Section of Child and Adolescent Psychiatry ParkHospital for ChildrenOld Road, HeadingtonOX3 7LQ Oxford, United KingdomPhone: +44 1865 226517Fax: +44 1865 [email protected] web-site: not yet establishedKey words: Autism, Neurology, genetics, rare disease

PartnersProf. Patrick Farrar BoltonKings College LondonChild Psychiatry & MRC Centre for Social, Developmental &Genetic PsychiatryLondon, United KingdomProf.Ann Simone Le CouteurThe University of NewcastleChild and Adolescent Psychiatry/Mental Health School ofClinical SciencesNewcastle upon Tyne, United KindgomDr. Lennart PedersenCenter for AutismeBagsvaerd, DenmarkProf. Marion LeboyerInstitut National de la Santé et de la Recherche MédicaleINSERM U513Creteil, FranceProf. Bernadette RogeUniversité de Toulouse Le MirailCentre d'Etudes et de Recherches en Psychopathologie(CERPP)Toulouse, FranceProf. Fritz PoustkaJohann Wolfgang Goethe-UniversitätsklinikumKlinik für Psychiatrie und Psychotherapie des Kindes- undJugendaltersFrankfurt, GermanyProf. John TsiantisNatinoal and Kapodistrian University of AthensDepartment of Child Psychiatry,Athens University MedicalSchool,“Agia Sofia” Children's HospitalAthens, Greece

Prof.Agatino BattagliaStella Maris Clinical Research Institute for Child &Adolescent NeuropsychiatryCalambrone, ItalyDr. Maretha de JorgeUniversity Medical CenterDepartment of Chile and Adolescent PsychiatryUtrecht,The NetherlandsProf. Rudolf MinderaaStichting Universitaire en Algement Kinder- enJeugdpsychiatrie Noord-NederlandFaculty of Medical Sciences, Groningen UniversityDepartment Child and Adolescent PsychiatryGroningen,The NetherlandsProf. Christopher GillbergGoteborg UniversityDepartment of Child and Adolescent PsychiatryGöteborg, SwedenDr. Irma JärveläHelsinki University Central HospitalLaboratory of Molecular GeneticsHelsinki, FinlandDr.Thomas BourgeronInstitut PasteurGroupe a 5 ans, Human Genetics and Cognitive FunctionsParis, FranceProf.Annemarie PoustkaDeutsches KrebsforschungszentrumMolecular Genome AnalysisHeidelberg, GermanyProf. Elena MaestriniAlma Mater Studiorum - Università di BolognaDipartimento di Biología Evoluzionistica SperimentaleBologna, Italy

Acronym: Autism MolgenProject number: LSHM-CT-2004-512158If not, proposal number: 512158EC contribution: €2 000 000 Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: tbd


SummaryThe development of neural circuitry is a vastly complex process,

and the role of many of its components - notably the control of

neuronal morphology, the formation of specific synaptic connections

as well as the localisation of key synaptic proteins - is still very poorly

understood. In this frame the present project aims to reach a more

comprehensive understanding of cortical networking during

development, in particular of genes and their products governing

complex molecular mechanisms driving synaptic structuring and

organisation during development of cortical networks and

circuitries.

This project integrates the information about the role of different

candidate genes/proteins in synaptic formation,remodelling and function

and it capitalises on results obtained in in vitro systems and translates

them to clinical application. The final aim is to identify key steps

responsible for defect of development associated to mental

retardation.Since intellectual performances are directly related to brain

development and plasticity of excitatory synapses and these are

generally located in cortical neurons, the project focuses primarily on

these structures.

The proteins identified as important factors in

the development of functional synapses are

then studied for their implications in the

development of synaptic dysfunctions using

different animal genetic models of mental

retardation.

Thus the project:

i) characterises gene products responsible for

synapse formation and function

ii) assesses the role of mutation/deletion of

selected genes in synaptic function in in vitro

systems and in intact organisms

iii) analyses the impact of mutations of

scaffolds in driving mental retardation.

BackgroundIt is still unclear how the complex and finely tuned network ofprotein-protein interactions defining both the presynapticcytomatrix and the postsynaptic compartment of cortical synapsesare regulated during development. It is well known thatdevelopment of CNS synapses in vivo follows a stereotyped pattern.Thus, during development - as well as during synaptic activity - aprofound rearrangement in synaptic protein composition anddistribution occurs. These changes induce functional andmorphological modifications allowing a reset of neuron activity inorder to better respond to a new environment. Such a modificationrepresents the basis of structural dynamics of synapse, a processthat has a crucial role in development of the neuron system.

Several of these changes occur at the synaptic,cytoskeletal and scaffoldproteins level that represents a large proportion of the entire neuronproteoma. In fact chemical synapses are characterised by electron-dense cytomatrices on both sides of the synaptic junction. On thepre-synaptic side dense projection or cytomatrix assembled at theactive zone (CAZ) defines the site of neurotransmitter release andit is thought to organise membrane trafficking events underlying thesynaptic vesicle cycle. On the post-synaptic side the post-synapticdensity (PSD) defines the neurotransmitter reception apparatus andis believed to anchor and cluster neurotransmitter receptors, ionchannels, and cell adhesion molecules and to connect them to the

Synaptic scaffolding proteins orchestrating corticalsynapse organisation during development



SYNSCAFF


subsynaptic cytoskeleton and to elements of the postsynaptic signaltransduction machinery.

In particular the identifications of scaffolding proteins as essentialcomponents of CAZ and PSD structure, has revealed new insightsinto the molecular and assembly mechanisms of the synapticapparatus.

In many cases multiple protein-protein interaction among scaffoldingand other synaptic relevant proteins have been described,highlightingtheir appropriateness in driving the assembly of the synapse duringdevelopment.

Nevertheless,the discrete/distinct mechanism by which these proteinsparticipate in the regulation of synaptic development and functionremain largely unknown.

Disturbance of dendritic spine shape, synaptic function andorganisation of scaffolding proteins and receptor may lead to abnormaldevelopment of cortical circuitry.The functional outcome of thesedisturbances is read as a defect of plasticity of these structures,a defectthat may lead ultimately to mental retardation.

AimThe major goal of the present project is to reach a betterunderstanding of cortical networking during development and inparticular of genes and their products governing the complexmolecular mechanisms driving synaptic structuring and organisationduring development of cortical networks and circuitries.

In fact although genomic studies strongly contributed to ourknowledge on genes responsible for cortical development(identifying more than 437 gene products in foetal human brain),it is known that the development of neural circuitry is a vastlycomplex process, and the role of many of its components - notablythe control of neuronal morphology, the formation of specificsynaptic connections as well as the localisation of key synapticproteins - is still very poorly understood.

This project integrates the information about the role of differentcandidate genes/proteins in synaptic formation, remodelling andfunction and it capitalises on results obtained in in vitro systemsand translate them to clinical application, with the final aim toidentify key steps responsible for defect of development associatedto mental retardation. Since intellectual performances are directlyrelated to brain development and plasticity of excitatory synapsesand these are generally located in cortical neurons, the projectfocuses primarily on these structures.

Thus, the hypothesis that genes involved in the dynamicorganisation of pre- and post-synaptic compartment - studied indetail by the consortium - may be responsible for some aspects ofbrain dysfunction leading to mental retardation, are tested.

The final goal is thus to define the molecular portrait of the corticalsynapse during development, the key localisation of gene productswithin the synaptic structure, which will possibly lead to thedefinition of key genes involved in mental retardation.

Expected resultsThe development of neural circuitry is a vastly complex process,and the role of many of its components - notably those that controlneuronal morphology, formation of specific synaptic connectionsas well as the localisation of key synaptic proteins - are far frombeing fully understood, although an alteration of this structuredramatically compromises brain function.This project contributesto expand the knowledge in synapse formation during developmentnot only by identifying key genes involved in this project but alsoproviding a picture of the correct spatial localisation of theseproteins in the synaptic space, the latter being fundamental tounderstand their unique and specific role.Thus specific expectedresults will be:

• characterisation of gene products responsible for synapseformation, and function focusing on:

• the molecular scaffold cytomatrix of cortical synapses, identifyinginteracting elements with already known components andanalysing their function at molecular and cellular level;

• the molecular scaffold organising the post-synaptic domains andtheir role in sorting, targeting and function of ionotropic andmetabotropic membrane receptors;

• the intercellular processes dynamically regulating the assemblyof synaptic elements and determining the functional propertiesof the newly formed spines, i.e. phosphorylation processesmediated by different classes of kinases.

• Evaluation of the role of mutation/deletion of selected genes insynaptic function in in vitro systems and in intact organism.

• Evaluation of the impact of mutations of scaffolds in driving mentalretardation.

Potential applicationsSYNSCAFF generates novel information on the mechanismsunderlying synapse formation during development with reflectionon the causes of mental retardation.This is a major contribution,as the biological mechanisms underlying mental retardation remainobscure. This novel information is also used to devise newinnovative diagnostic tools in order to allow for an early diagnosisand possibly treatment of these diseases.

In addition, in a larger scale, most of proteins responsible for thestructural organisation of the synapse are involved not only indevelopmental disorders but also in some aspects of synaptic lossin neurodegenerative disorders. Thus, results obtained in theconsortium have a larger impact, being applicable to several fields.SYNSCAFF provides new molecular targets for treatment. Thissecures transfer of results generated to compounds that wouldhave in the future an impact on the early diagnosis of mentaldisorders.



DISEASES


Coordinator Di Luca, Monica

University of Milan

Department of Pharmacological Sciences

via Balzaretti, 9

20133 Milan, Italy

Phone: + 39 02 5031 8374

Fax: + 39 02 2048 8250


Project web-site: www.synscaff.org

Key words: cortical development, scaffolding proteins,presynaptic cytomatrix, postsynaptic density,glutamate receptors

PartnersMulle, Christophe

Univ Bordeaux 2 - CNRS UMR 5091

Inst Francois Magendie

Bordeaux, France

Fagni, Laurent

Laboratoire de Génomique Fonctionnelle

UPR CNRS 2580

Montpelllier, France

Debanne, Dominique

Institut National de la Santé Et de la Recherche Médicale

INSERM U464 Ionic Channels

Marseille, France

Prof. Lüscher, Christian

Departments de Pharmacologie et Physiologie Service deNeurologie

Clinic of Neurology (Department NEUCLID), Lab forAddiction Science

Switzerland

Muller, Dominique

Faculty of Medicine, Pharmacology (Department APSIC)

Centre Médical Universitaire

Switzerland

Gundelfinger, Eckart D

Leibniz Institut für Neurobiologie

Abteilung für Neurochemie und Molekularbiologie

Magdeburg, Germany

Sala, Carlo

Consiglio Nazionale delle Ricerche

Institute of Neuroscience

Milan, Italy

Calabresi, Paolo

NeurosciTorVerRome - Dipartimento di Neuroscienze

Università di Roma Tor Vergata

Rome, Italy

Blahos, Jaroslav

Institute of Experimental Medicine

Czech Academy of Science

Prague, Czech Republic

Jebavy, Lukas

BioTest s.r.o.

Konarovice, Czech Republic

Finocchiaro, Carla

CF Consulting SrL

Milan, Italy

Acronym: SYNSCAFFProject number: LSHM-CT-2004-511995EC contribution: €1 900 000Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/01/2005






DISEASES

SummaryMigraine is a common chronic pain syndrome for which effective and

well-tolerated prophylactic agents are much needed. Increased

knowledge of migraine pathophysiology is a prerequisite. In

EUROHEAD the genetic and neurobiological basis of the initiation of

migraine attacks, the aura, and migraine pain will be investigated. A

second focus of the EUROHEAD Consortium is to promote and

disseminate knowledge on clinical and neurobiological science of

migraine and other primary headache syndromes.

BackgroundMigraine is characterised by recurrent attacks (lasting 1-3 days) ofdisabling headache,associated symptoms and, in one-third of patients,neurological aura symptoms.Over 12% (two-thirds of which is female)of the general population have migraine attacks regularly (median18/year).WHO rates migraine in the highest class of most disablingchronic disorders.Migraine-related annual costs in the EU amount to€10 billion.Acute attack treatments are satisfactory in less than halfof patients. Effective and well-tolerated prophylactic migraine agentsare needed.

Genetic factors are involved in themechanisms for the attack, aura andpain. Rare familial and commoncomplex types of migraine might sharecommon genes and pathways.Unravelling the genetic andneurobiological basis of migraine byidentifying and validating migrainegenes and studying their functionalinvolvement with various techniques inpatients and experimental models willincrease our knowledge andawareness of migraine as a seriousneurobiological disorder.

AimEUROHEAD aims to unravel thegenetic and neurobiological basis ofthe migraine. To this extent,EUROHEAD will identify andvalidate migraine genes and studytheir functional involvement withstate-of-the-art techniques in

patients and experimental animal models. In addition, theEUROHEAD Consortium wants to promote and disseminate theexisting and newly acquired knowledge of the underlying clinical andneurobiological science of migraine syndromes among clinicians,scientists, patients and general public worldwide.

Expected resultsIn the EUROHEAD project, a Centre of Excellence has beenestablished in which many of the expert groups on primaryheadaches are involved. Among the expected results are theidentification and validation of (new) loci and gene variants formigraine, the analysis of functional consequences of migraine-associated gene variants and mutations in cellular and animal models,the correlation of genotypic data with migraine-endophenotypes,an evaluation of headache science in Europe,and importantly furtherpromotion and dissemination of knowledge and awareness in thecommunity on this serious disorder.

Potential applicationsEUROHEAD research will be important for a better understandingof the pathophysiology of migraine and future drug development.

Migraine genes and neurobiological pathways

EUROHEAD


Coordinator Prof. Ferrari, Michel


Department of Neurology

Albinusdreef 2, NL

2300 RC Leiden,The Netherlands

Phone: +31 71 526 2895

Fax: +31 71 527 8253


Project web-site: www.eurohead.org

Key words: headache, migraine, pain, genetics,neurobiology, man, transgenic mousemodels, response, treatment

PartnersProf. Palotie,Aarno

University of Helsinki

Finnish Genome Center

Helsinki, Finland

Prof. Goadsby, Peter

Institute of Neurology

University College London

Headache Group


Prof. Pietrobon, Daniela

Universitá degli Studi di Padova

Dipartimento di Scienze Biomediche Sperimentali

Padova, Italy

Dr. Casari, Giorgio

Fondazione Centro San Raffaele del Monte Tabor

Human Molecular Genetics Unit

Department of Neuroscience

Milan, Italy

Prof. Diener, Hans-Christoph

Universität Duisburg Essen


Essen, Germany

Prof. Olesen, Jes

Glostrup University Hospital

Danish Headache Center

Dept. Neurology

Copenhagen, Denmark

Prof. Schoenen, Jean

University of Liège

Department of Neuroanatomy & Neurobiology

Faculty of Medicine Headache Research Unit

Liège, Belgium

Prof. Nappi, Giuseppe

IRCCS Neurological Institute "Casimiro Mondino"

Pavia, Italy

Acronym: EUROHEADProject number: LSHM-CT-2004-504837EC contribution: €3 200 000 Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/05/2004






DISEASES

SPASTICMODELS

SummaryNeurodegenerative disorders,a heterogeneous

group of chronic progressive diseases, are

among the most puzzling and devastating

diseases in medicine. Indeed they are

characterised by onset in adult life, distinct

clinical phenotypes,and specific degeneration of

subsets of neurons and axons. Hereditary

spastic paraplegia (HSP) is a disorder that results

in progressive weakness and spasticity of the

lower limbs affecting approximately 1 in 10 000

individuals.Heterogeneity characterises HSP in

both clinical and genetic aspects.Little is known

about the pathogenesis of HSP and

consequently no specific treatment is available

to prevent, cure or delay progression of

symptoms of HSP. Electrophysiological and pathological findings point

to the corticospinal tracts,dorsal columns and the spinocerebellar fibres

as the structures primarily affected by HSP.

Two main pathogenetic hypotheses for the neurodegeneration seen in

HSP, as well as other neurodegenerative conditions, have recently

emerged, suggesting that impaired mitochondrial function and/or

defective subcellular transportation mechanics play a crucial role.In fact,

HSP-causing mutations have been found in gene products involved in

mitochondrial function, such as paraplegin and HSP60, and axonal

trafficking, such as kinesin and, possibly, spastin and spartin. This

consortium of European groups intends to provide a multi-faceted

comprehensive approach to study the pathogenesis of HSP with a

particular emphasis on the role of mitochondrial dysfunction and

impaired axonal transport, through the production and extensive

characterisation of seven novel mouse models for this disease,in parallel

with the recently developed paraplegin null mutant. The proposed

strategy is a highly integrated effort to study the function of several

HSP genes,with the final goal of identifying common mechanisms leading

to axonal degeneration,which will be potential targets of a therapeutic

intervention in the long term.

BackgroundHereditary spastic paraplegia (HSP) consists of a heterogeneousgroup of neurodegenerative diseases characterised by progressivelower-limb weakness and spasticity and subtle impairment of thevibratory sense. Age of onset is quite variable, generally between10 and 40 years old. HSP has been classified traditionally as ‘pure’or ‘complicated’, depending on whether spastic paraplegia is theonly symptom or whether it is found in association with otherneurological abnormalities, such as optic neuropathy, retinopathy,extrapyramidal symptoms,dementia, ataxia,mental retardation anddeafness.

Neuropathological analyses of tissues from a small number ofindividuals with pure HSP have shown axonal degenerationinvolving the more distal portions of the longest motor andsensory axons of the central nervous system (i.e. the crossed anduncrossed corticospinal tracts, the fasciculum gracilis and thespinocerebellar tracts).A specific pattern of degeneration is seenin HSP, during which the cell bodies remain largely intact whilethe degeneration is principally limited to the cell axon and maybe a ‘dying back’ axonopathy, beginning distally and proceedingtowards the cell body.

A more precise classification of HSP forms therefore originates fromthe inheritance pattern,which may be autosomal dominant,autosomalrecessive or X-linked recessive.So far,21 loci have been mapped (listedSPG1 to SPG21);however,causative mutations have been found in ninegenes only.Mutations in the cell adhesion module L1, L1CAM (SPG1)and in the proteolipid protein, PLP (SPG2) cause X-linked forms ofHSP characterised by defects in the development of the corticospinaltract and in axonal-glial interactions,respectively.Little is known about

Semithin section of the spinal cord of a 8 month-old

paraplegin-deficientmouse showingaxonal swelling.

Genetic models of chronic neuronal degeneration causing hereditary spastic paraplegia


known autosomal HSP genes encoding spastin (SPG4), paraplegin(SPG7),atlastin (SPG6),spartin (SPG20),aspardin (SPG21),while Hsp60is a well-characterised shock-response protein (SPG13) and the neuralspecific kinesin gene KIF5A (SPG10) is a member of the kinesinsuperfamily of molecular motors that transport cargoes alongmicrotubules.

Atlastin is a novel GTPase that has sequence homology to membersof the dynamin family of large GTPases, particularly guanylate bindingprotein-1. Spartin is responsible for Troyer Syndrome, an autosomalrecessive HSP, and is homologous to proteins involved in endosomemorphology and protein trafficking of late endosomal component.Aspardin is responsible for Mast syndrome (a spastic paraplegia,autosomal recessive with dementia). Both spastin and paraplegin areAAA proteins, ATPases associated with different cellular activities.Members of this superfamily of ATPases exert chaperon-like activitiesand mediate assembly and disassembly of macromolecular structuresinvolved in different cellular processes.

Paraplegin resembled a family of mitochondrial metalloproteaseswell-characterised in yeast and was shown to localise in themitochondrion.Mutations in paraplegin cause neurodegeneration inan autosomal recessive form of HSP,but the pathogenetic mechanismof this disorder, in particular the role of mitochondria, is presentlynot understood.

Observations of members of this Consortium (Partners 1 and 4)show that paraplegin and the homologous protein AFG3L2constitute the m-AAA protease complex. Mitochondria of HSPpatient (SPG7) have indeed a functional deficit that could result fromimpaired protein quality control, causing an accumulation ofmisfolded proteins within the mitochondrial matrix.An additionalmitochondrial protein, Hsp60, has been found mutated in a formof HSP.Hsp60 is a representative of the type I chaperonin subfamilyof molecular chaperones that are involved in folding of bacterial,mitochondrial and chloroplast proteins. Type I chaperonins arehighly conserved throughout evolution and play an important rolein quality control of proteins, which seems to be a preferentialmitochondrial target for SPG13 and SPG7.

Differently, some evidence from transfectionexperiments show that spastin interacts withmicrotubules and seems to modulate microtubuledynamics, an essential attainment for maintenance oflong axons,beside a still unclear possible role at nuclearlevel. Only little is known, however, about the functionof this protein and its role in the pathology of HSP.

The specificity of the axonal damage in HSPapparently contrasts with the wide distribution andrange of functions carried out by the few geneproducts known to cause the clinical phenotypes.However, we think to envisage two possiblepathogenetic mechanisms. The mitochondrial wayseems to affect neuronal metabolism, in particular atthe axon extremity, by reducing the available energy.On the other hand, the cellular trafficking impairmentwould limit the turnover of fresh molecules andorganelles to and from the periphery of neurons.Both

mechanisms would result in a dying-back effect, typical of this lateprogressive neurodegeneration.

A possible unifying alternative mechanism can be hypothesised:impaired mitochondrial function generates huge aberrantmitochondria, which engulf the peripheral cellular trafficking.

AimCurrent therapies provide only symptomatic relief; none significantlyalter the course of disease.Therefore, there exists a major medicalneed that demands the development of new and more informedtherapeutics for the efficacious treatment of neurodegenerativediseases.While many diseases of the motor neurons have no knowngenetic component, recent investigations have begun to identify thecausative genes for some familial forms. In turn, this leads to thepossibility of transgenic animal models of human disease, which inprevious studies have substantially contributed to the identificationof many promising new therapies. A major limitation to the study ofneurodegenerative disease is that the affected tissues are notaccessible until after death, hampering studies of the early stages andthe progression of the pathological features. Animal models wherethe genes mutated in human HSP are modified are an important toolto overcome this obstacle.

Expected resultsThis consortium of European groups intends to provide a multi-faceted approach for the study of the HSPs and these mechanisms.Although the molecular basis has been unravelled for several formsof HSP in the last few years, the mechanisms resulting in axonaldegeneration in this disease are still largely unknown. Howeveranimal models offer an important tool to overcome this obstacle.The objectives of this work package are:1) the generation of mousemodels for different forms of HSP; 2) the phenotypiccharacterisation of these models according to common,standardised protocols.



Electron micrograph of the spinal cord of a12-month-old para-

plegin-deficient mice show-ing segmental swelling of a

longitudinally cut axon.Filamentous aggregatesand and degenerating

mitochondria accumulatein the axoplasm.




DISEASES

A critical component of the proposed project is the developmentand characterisation of a number of mouse models of hereditaryspastic paraplegia, which include: spastin (SPG4), paraplegin (SPG7),Hsp60 (SPG13), spartin (SPG20),Afg3l1 and Afg3l2 and prohibitin.This comprehensive range of models affords this project aninvaluable resource for the study of disorders of the motor neuron,in particular the hereditary spastic paraplegias. We will use thisresource, in parallel with a range of cell models and other studies,to examine two hypotheses for motor neuron degeneration:defective mitochondrial function, and abnormal subcellulartransportation mechanics.

Coordinator Dr Casari, Georgio

San Raffaele Scientific Institute

DiBit

Via Olgetttina, 58

20132 Milan, Italy

Phone: + 39 02 2643 3502

Fax: + 39 02 2643 4767


Project web-site: http://www.spasticmodels.org/ (under construction).

Key words: hereditary spastic paraplegia, paraplegin,spastin, spartin, HSP60, motoneuron, mousemodels.

PartnersDr Rugarli, Elena

TIGEM

Naples, Italy

Prof. Langer,Thomas

Universität zu Köln

Institut für Genetik,

Cologne, Germany

Prof. Bross, Peter

Aarhus University Hospital Skejby Sygehus

Brendstrupgaardsvej

Århus N, Denmark

Dr Crosby,Andrew

St. George’s Hospital Medical School


Prof. Deufel,Thomas

Instituts für Klinische Chemie undLaboratoriumsdiagnostik

Universitätsklinikum Jena

Jena, Germany

Acronym: SPASTICMODELSProject number: LSHM-CT-2003-503382EC contribution: €1 900 000 Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/01/2004


SummaryThe aim of the NCL-models project is to reveal pathogenetic

mechanisms in neuronal ceroid lipofuscinoses.Our goal is to carefully

characterise the individual NCL proteins to further understanding of

their normal roles and the molecular mechanisms by which loss of

their function leads to neurodegeneration.The data we obtain will

also have significant implications for other disorders,providing insights

into the cellular processes that influence neuronal death and ageing.

The project uses a multidisciplinary approach, in which a key element

is the generation of novel models for NCL.These models, including

cell, yeast, nematode and mouse models will then be used to study

the pathogenetic mechanisms of NCLs by a variety of techniques

including molecular genetics, cell biology, mRNA and protein

expression profiling, proteomics, and morphological approaches.The

combination of top-level European NCL scientists will facilitate the

integration of research capacities across Europe, increasing coherence

and providing critical mass of investigators. The integrated

multidisciplinary research enables direct interactions between

technology and biology and will provide the knowledge base essential

for the rational design of therapeutic interventions.

BackgroundThe neuronal ceroid-lipofuscinoses (NCLs) are collectively the mostcommon inherited progressive encephalopathy of childhood.Each formof NCL is characterised by the progressive death of cortical neuronsand these rare diseases provide an excellent model to define themolecular events that result in neurodegeneration. Using genomicapproaches we have identified six genes mutated in different forms ofNCL: PPT1, CLN3, CLN5, CLN6, CLN8, and cathepsin D. Deficienciesin these proteins result in a group of fatal disorders with clinicalpresentation that ranges from infantile lethality to later onset and moreprotracted forms. Despite the identification of these proteins, theunderlying pathogenetic mechanisms remain unclear.

AimThe project has been divided into seven specific objectives:

1) to analyse the localisation, transport and molecular interactionsof the individual NCL proteins in neuronal and non-neuronal cellmodels;

2) to generate and analyse yeast and nematode models for differentforms of NCL;

3) to further characterise the neuronal phenotype of the five existingmouse models and to develop one novel mouse model of NCL;

4) to define the mechanisms and selectivity of neurodegeneration inthe model organisms;

5) to develop and use bioinformatic tools for efficient analysis ofthe metabolic pathways involved in neuronal degeneration;

6) to organise effective European research training in the functionalgenomics of neurodegeneration;

7) to integrate the complex data arising from different modelsystems in order to understand the cellular pathogenesis uniqueto each NCL or in common between the NCLs therebyproviding the knowledge base for future drug development.Additionally, actions to raise public participation and awarenesswill be taken.

Expected resultsThe present project will significantly add to our knowledge of thefunction of the NCL proteins, the mechanisms of neurodegenerationand the disturbed metabolic pathways underlying each form of NCL.This project will lead to better understanding of the maintenance ofthe nervous system,and will provide the knowledge base for designingtherapy, and essential tools for evaluating subsequent therapeuticapproaches.

Research training is an extremely important part of thismultidisciplinary programme and one central task is to organise andmonitor the research training of young scientists devoted to functionalgenomics and neurobiology. Exchange of these junior investigatorsbetween laboratories will help to provide them a thorough trainingin different techniques. It is also expected that exchange of youngscientists between laboratories of the collaborative network willfacilitate the achievement of the research goals of the NCL-modelsproject.

Potential applicationsThe ultimate impact of the proposal is in providing the basis fortherapeutic approaches for these progressive, fatalneurodegenerative disorders of childhood.The entire NCL-modelsnetwork aims at improving the health of NCL patients and qualityof life for families affected by this major paediatric neurodegenerativedisease.The economic development and impact produced by theseresearch achievements will be assessed during the course of theproject. Once these research data influence, initiate or enhancetherapeutic activities and form the basis of clinical trials, economicbenefits will be expected not only for the manufacturers of eventualtherapeutic regimens but also via lowering disease costs incurredby NCL patients and their families.

Dissecting neuronal degeneration:Neuronal ceroid lipofuscinoses from genes to function



NCL-models




DISEASES

Coordinator Dr Jalanko, Anu

National Public Health Institute, Department of MolecularMedicine, Biomedicum Helsinki

P.O. Box 104

00251 Helsinki, Finland

Phone: + 358 9 4744 8392

Fax: + 358 9 4744 8480

E-mail:[email protected]

Project web-site: www.nclmodels.org

Key words: neurological disorder, neurodegeneration,neuronal death

PartnersDr Peltonen-Palotie, Leena


University of Helsinki and Department of MolecularMedicine

National Public Health Institute Biomedicum

Helsinki, Finland

Dr Mole, Sara E

Department of Paediatrics and Child Health

Royal Free and University College Medical School

University College London, Bloomsbury Campus


Dr Mitchison, Hannah

Senior Lecturer in Molecular Genetics

Department of Paediatrics and Child Health

Royal Free and University College Medical School

University College London,


Dr Lehesjoki,Anna-Elina

Neuroscience Center

Department of Medical Genetics and Folkhälsan Instituteof Genetics

Biomedicum Helsinki


Dr Tyynelä, Jaana

Institute of Biomedicine/biochemistry


Dr Cooper, Jon D

Pediatric Storage Disorders Lab

Department of Neuroscience

Institute of Psychiatry

King's College London


Dr Taschner, Peter

Department of Human Genetics

Sylvius Laboratories


Dr Braulke,Thomas

University Hospital Hamburg-Eppendorf

Hamburg, Germany

Acronym: NCL-modelsProject number: LSHM-CT-2003-503051EC contribution: €2 000 000Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date:01/01/2004




NEUROKCNQPATHIES

SummaryMutations in three KCNQ genes are associated with rare monogenic

neurological disorders prompting us to study the cell biology underlying

these disorders, and to identify the processes that control KCNQ

channel function. The biochemical and biophysical affects of these

mutations in the channels,their modulation by second messengers,and

the physiological significance of protein-protein interactions will be

addressed. Because some mutations in the KCNQ loci do not appear

to lie in the coding region, we will study the transcriptional control of

these genes. Furthermore, mouse models will be produced to gain a

more precise idea of the pathology of these diseases. Finally, the

molecular basis for drug specificity will be analysed to define the mode

of action as well as to identify and characterise new drugs that affect

the function of these channels.

BackgroundOf the rare monogenic neurological disorders caused by mutationsin KCNQ potassium channels, neonatal convulsions (BFNC), a rareautosomal-dominant disorder, are caused by mutations in KCNQ2and KCNQ3, whereas in KCNQ4 they cause progressive hearingloss.These genes are responsible for the M-current and KCNQ4may contribute to the short electrical time constants needed inneurons of the auditory pathway. Since KCNQ5 can alsocontribute to this current, it too may provoke neurologicaldisorders.

The intracellular C-terminal domain of KCNQ mediatesinteractions with other subunits and proteins. This region is alsoimportant for efficient surface expression selective retention,endocytosis and intracellular trafficking, as well as the subcellularlocalisation of KCNQ channels. However, although proteins thatinteract with KCNQ subunits have been identified, the signalscontrolling these processes remain unknown. Similarly, theregulation of the M-current by neurotransmitters is poorlyunderstood and the intracellular second messengers involvedremain elusive. Nevertheless, information is available regarding theinfluence of phospholipase C (PLC), PKC activation, the release ofinternal calcium, PIP2 and CaM binding on the function of M-channels.To help us clarify the mechanisms by which the cell biologyof these channels is controlled and how it may be affected in humandisease, it is clear that we must study the relationships betweenthese regulatory proteins.

The M-current is a target of acetylcholine and it is thought to playa role in learning and memory, and in epilepsy. Indeed, KCNQchannel modulators may have therapeutic potential in thetreatment of epilepsy, neuropathic pain and neurodegeneration. Forthis reason, we must understand more precisely how thesemodulators of KCNQ channels work to fully explore thistherapeutic potential.

Finally, KCNQ channelopathies provide an example of theimportance of gene dosage in inherited diseases.Thus, mutationsthat only moderately reduce the expression of a KCNQ gene couldcause neurological disorders and mutations responsible forproducing a disease may lie outside the coding region.

AimThe principal aim of this project is to determine the role of M-channels in neuronal and non-neuronal physiology, and tounderstand the cellular basis of rare neurological syndromesassociated with KCNQ channel dysfunction. The function andpotential role of KCNQ5 in disease will also be assessed in mutantmice. Conditional KCNQ knock-out mice will aid in furtherelucidating the involvement of the M-current in neuronal plasticityand we shall also analyse the role of KCNQ channels in humandeafness in greater depth. We aim to understand the processesunderlying cellular targeting and trafficking of the channels and toidentify targeting signals within the channel.We will study the roleof associated proteins and second messenger systems in regulatingM-channel function as well as the interactions between suchelements, and we will identify and study the role of the KCNQligands in channel function. We also plan to study how theexpression of these genes is regulated. Finally, the role of M-channels in neuropathic pain processing warrants deeperinvestigation and we plan to identify the molecular determinantsfor the pharmaceutical regulation of these channels,which may helpin developing more selective drugs

Expected resultsWe expect to gain a much better understanding of the cell biologyof these channels and the way in which disease-causing mutationsaffect these processes. Furthermore, light will be shed on how thebehaviour of these channels is modulated by associated proteins,neurotransmitters and second messenger systems, as well as theinteractions that occur between these elements. We expect toobtain important insights into the role of KCNQ channels indifferent human conditions, creating the basis for novel therapies.

Cell biology of rare monogenic neurological KCNQ disorders



DISEASES


This aspect will be enhanced by augmenting our understanding ofthe action of drugs that alter the activity of these channels. Finally,we hope to advance both our understanding of the transcriptionalcontrol of the genes encoding these proteins.

Potential applicationsThe potential applications that might arise from this project involvethe possible therapeutic benefits of treating the diseases that arisedue to mutations in these genes as well as in neuropathic pain.Furthermore, it is likely that the insights into the way that thesechannels are modulated will also be applicable to other diseasescaused by similar proteins, within and outside the nervous system,as well as to diseases involving other types of proteins.

Coordinator Dr Villarroel, Alvaro

Consejo Superior de Investigaciones Científicas

Unidad de Biofisica CSIC-UPV/EHU

Universidad del País Vasco

Barrio Sarriena S/N

48940 Leioa (Bilbao), Spain.

Phone: + 34 94 601 3225

Fax number: + 34 94 601 3360


Project web-site: www.KCNQ.com

Key words: neurobiology, cell biology, rare diseases,monogenic, ion channels, mouse models,KCNQ, Kv7, potassium channels, struc-ture/function, gene expression, proteininteractions, cell physiology, electrophysi-ology

PartnersCentre for Molecular Neurobiology, Hamburg University,Germany

Department of Physiology, University College London,United Kingdom

Department of Physiology, Institute of Basal MedicalSciences, Medical Faculty, University of Oslo, Norway

NeuroSearch A/S, Ballerup, Denmark

Unité de Génétique des Déficits Sensoriels, INSERMU587, Institut Pasteur, France.

Department of Neuroscience, Section of Pharmacology,University of Naples Federico II, Italy

School of Biochemistry & Molecular Biology, Universityof Leeds, United Kingdom.

Acronym: NEUROKCNQPATHIESProject number: LSHM-CT-2004-503038EC contribution: €1 900 000Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/04/2004


SummaryOur ultimate goal is to develop new therapies for X-linked adreno-

leukodystrophy (X-ALD), the most frequent inherited monogenic

demyelinating disease of the central nervous system (1:18,000). X-

ALD is characterised by extensive phenotypic variability, which is

not correlated to ALD genotype, and leads to death in boys due to

cerebral demyelination and to motor disability in adults due to spinal

cord degeneration. Allogenic bone marrow transplantation, proven

to be beneficial in X-ALD, can be applied only to a limited number

of X-ALD patients.Thus, there is no treatment for the majority of

patients, in particular those with the severe cerebral form of X-ALD

and adults with adrenomyeloneuropathy (AMN). Understanding of

the pathogenesis is necessary for the development of novel

therapeutic strategies.The still unresolved transporter function of

the ALD protein will be studied in reconstituted liposomes.To get

further insight into the pathogenesis of X-ALD, we aim to identify

genes and proteins that are differentially regulated in the target

tissues of patients with cerebral ALD and AMN using Affymetrix

analysis of differential mRNA expression and a proteomics approach

based on MALDI-TOF mass spectrometry. Additional approaches

such as mapping of quantitative trait loci will be applied to identify

modifier genes that may contribute to the phenotypic variability of

X-ALD.We will generate new mouse models that represent a wider

phenotypic spectrum of the disease for a more efficient evaluation

of therapeutic strategies. Furthermore, we will evaluate four

promising new therapy strategies: ALD gene transfer into

haematopoietic stem cells, into mesenchymal stem cells, and by

direct injection of viral vectors, and pharmacological induction of a

related gene as a substitute for the deficient ALD gene. Only the

joint effort of the highly qualified partners of this proposal will allow

achieving our ambitious aims.

BackgroundX-ALD is the most common (1:18 000) genetic disorder affecting themyelin within the central nervous system (CNS). It affects boys(between 5-12 years), adult males (20-50 years), and women (> 40years).All forms of X-ALD are characterised by severe neurologicalabnormalities frequently resulting in early death. X-ALD is

biochemically characterised by the accumulation of fatty acids withmore than 22 carbon atoms (very-long-chain fatty acids;VLCFA); butthe role of VLCFA accumulation in the pathophysiology of the diseaseremains unknown.The gene affected in X-ALD codes for a proteinthat is probably involved in the transport of VLCFA into a specificintracellular organelle, called the peroxisome.The ALD protein is anABC (ATP-binding-cassette) half-transporter, which forms eitherhomo- or heterodimers with two other homologous peroxisomalABC half-transporters,the ALD-related protein and PMP70.Like manyother ABC transporters, the ALD protein binds and hydrolyses ATPto become functional. VLCFA are considered good candidatesubstrates for transport across the peroxisomal membrane by theALD protein,but proof of such transport has yet to be demonstrated.In addition,different combinations of heterodimers may have differentsubstrate specificity.

Although being a monogenic disorder, X-ALD shows a widephenotypic variation even within families. There is no correlationbetween the phenotype and the type of ALD gene mutation or thelevels of VLCFA in fibroblasts or plasma of X-ALD patients. Thisphenotypic variability ranges from severe cerebral forms that lead todeath in 5 to12-year-old boys to mild paraparesis (adrenomyelo-neuropathy, AMN) in adults at 25-50 years of age. The lack of anygenetic or biochemical tools to predict the phenotype of X-ALDhinders the development of preventive or therapeutic approaches.Among the neurometabolic diseases, X-ALD is unique by theoccurrence of a striking brain inflammatory response that resembles,but is distinct from, that observed in multiple sclerosis. Thisimmunological response is the main neuropathological factor thatseems to differentiate the severe cerebral forms of X-ALD from AMN.There are some speculations in the literature about how thisinflammatory response may lead to the death of oligodendrocytes,but its trigger and mechanism are unknown. Since X-ALD isconsidered a genetic disease with loss-of-function and in the absenceof data suggesting that VLCFA are metabolised differently in humansand in rodents, it seemed probable that complete inactivation of theAld gene in mice would mimic the clinical symptoms observed in X-ALD patients. The Ald-deficient mice develop a neuropathologicalphenotype late in life that resembles AMN, but no cerebraldemyelination.It is hypothesised that the expression of ‘modifier’ genesand/or epigenetic factors contributes to the susceptibility orresistance to develop cerebral demyelination both in X-ALD patientsand Ald-deficient mice.The only therapeutic approach proven to bebeneficial in X-ALD is allogenic bone marrow transplantation (BMT).BMT can reverse or stabilise cerebral demyelination when theprocedure is performed in boys at an early stage. However, thisprocedure is associated with a significant mortality risk (10-25%) andcan only be offered to a limited number of X-ALD patients.Thus,thereis no treatment for the majority of X-ALD patients, in particular thosewith the severe cerebral form of X-ALD or adults with AMN.



X-ALD

X-linked Adrenoleukodystrophy (X-ALD): pathogenesis,animal models and therapy



DISEASES


Aima) to identify the natural substrates for the ALD protein and other related

peroxisomal ABC half- transporters (ALD-related protein and PMP70)whose overexpression, at least partially, overcomes the biochemicaldefect observed in X-ALD cells;

b) to resolve the role of VLCFA in the pathogenesis of X-ALD;

c) to get insight into the pathogenesis of X-ALD,we aim to identify genesand proteins that are differentially regulated in the brain of patientswith childhood cerebral ALD and AMN;

d) identification of the modifier genes that may contribute to thephenotypic variability of X-ALD;

e) to characterise in detail the neurodegenerative features of the existingmouse models of X-ALD and to generate new models that representa wider phenotypic spectrum of the disease;

f) to establish a new generation of lentiviral and AAV vectors for genetherapy and to test the efficacy of gene therapy approaches in mousemodels aiming at targeting the ALD gene ex vivo in haematopoieticstem cells and in vivo directly to oligodendrocytes;

g) to evaluate the ability of autologous mesenchymal stem cells as apotential treatment for presymptomatic and adult X-ALD patients;

h) to identify drugs that can stimulate the expression of the ALD-relatedgene.

Potential applications and expected resultsPrediction of the phenotype will allow the establishment of a preventiveand phenotype-adapted treatment for all X-ALD patients identified atbirth by systematic screening. X-ALD patients already have increasedVLCFA levels at birth, which would enable neonatal screening.Furthermore, clarification of the pathogenesis of X-ALD and thedevelopment of new models of X-ALD will allow new therapeuticstrategies to be developed and the efficacy of the current envisagedtherapeutic approaches to be tested. Preliminary results obtained withALD gene transfer in X-ALD CD34+ cells and with the pharmacologicalup-regulation of the Aldr gene in Ald-deficient mice suggest that thesestudies will lead to phase I/II clinical trials in X-ALD patients.

Coordinator Prof. Berger, JohannesMedical University of ViennaCenter for Brain Research Division of NeuroimmunologySpitalgasse 41090 Vienna, AustriaPhone: + 43 1 4277 62812Fax: + 43 1 4277 9628E-mail: [email protected] words: degenerative diseases, gene therapy,

genomics

PartnersProf. Aubourg, PatrickInstitut National de la Santé et de la Recherche MedicaleINSERM U561 – Service Pédiatrie C Hopital Saint Vincent de PaulParis, FranceDr Pujol,AuroraInstitut de Recerca Oncologica (IRO)Centre de Genetica Medica i Molecular (CGMM)Hospitalet de LlobregatLlobregat, SpainProf.Nave,Klaus-ArminMax Planck-Gesellschaft zur Förderung der Wissenschaft e.V.Department of NeurogeneticsMax Plank Institute for Experimental MedicineGöttingen,GermanyProf.Wanders,Ron J AAcademic Medical CenterUniversity Hospital AmsterdamDepartment of PediatricsLaboratory for Genetic Metabolic Diseases,Amsterdam,The NetherlandsDr.Geigle,PeterCELLMED AGAlzenau,Germany

Acronym: X-ALDProject number: LSHM-CT-2004-502987EC contribution: €1 800 000 Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/04/2004




SummaryChronic pain undermines the health and welfare of millions of EU

citizens and carries enormous financial costs. Individual variability in

the burden of pain has traditionally been attributed to psychosocial

factors. However, new data indicate that there is an important

heritable predisposition to pain, particularly to the development of

chronic pain after neural injury (neuropathic pain). Pain susceptibility

genes are intrinsically hard to detect in human lineages and

populations.This STREP adopts the alternative approach of exploiting

new rodent models of neuropathy to uncover pain susceptibility loci

and associated neurobiological processes, using

inbred mouse strains that show high versus low pain

phenotypes.

Linkage analysis and positional cloning, together

with expression arrays and a variety of electro-

physiological and neurochemical methods applied to

primary sensory neurons, will be used to identify

the biological causes of contrasting pain phenotype.

The strategy is to identify genetic and cellular

variables that co-vary with pain phenotypes across

strains. With mouse candidate genes in hand,

identification of the human orthologs is feasible.We

stress that our project does not aim to find genes

that affect susceptibility to specific disease entities

that may be painful. Rather, we focus on genes and

processes that determine the amount of pain felt

by an individual in the presence of a specific disease

state or degree of tissue injury. That is, we will investigate pain

susceptibility genes rather than disease susceptibility genes. Such

genes, and the neural processes with which they are associated, are

expected to affect pain intensity irrespective of the proximate cause

of the neural damage: trauma, surgery,neoplasm, infection or disease.

Results will provide essential background for the development of novel

prognostic,diagnostic and treatment options for chronic pain sufferers,

with major benefits also for their families, employers and European

economies.

Heritability of chronic neuropathic pain

PainGenes

Different strains of inbred mice show dramatic, heritable, differences in pain sensitivity.A? Response of 11 mouse trains tested in the neuroma pain model. B.The same strainstested for neuropathic tactile hypersensitivity on the hindpaw.Analysis of across strain

correlations and differences can illuminate pain genetics.




DISEASES

Coordinator Devor, Marshall

Hebrew University of Jerusalem

Department of Cell and Animal Biology

Institute of Life Sciences,

Jerusalem 91904, Israel


Key words: chronic pain, gene, microarray, nociception,neuropathic pain, neuropathy, pain, pain sus-ceptibility

PartnersJDarvasi,Ariel


Department of Ecology, Systematics and Evolution (ESE)

Institute of Life Sciences

Jerusalem, Israel

Yakir, Benjamin


Department of Statistics

Jerusalem, Israel

Tal, Michael

Hebrew University-Hadassah Jerusalem Israel

Department of Anatomy and Cell Biology

Schools of Medicine and Dentistry

Ein Kerem, Jerusalem

Wiesenfeld-Hallin, Zsuzsanna


Department of Laboratory Medicine

Division of Clinical Neurophysiology

Huddinge University Hospital

Stockholm, Sweden

Fried, Kaj


Center for Oral Biology, Novum

Karolinska Institutet,

Huddinge, Sweden

Reeh, Peter

University of Erlangen-Nuremberg

Institute of Physiology and Experimental Pathophysiology

Erlangen, Germany

Pethö, Gabor

University of Pecs

Department of Pharmacology and Pharmacotherapy

Faculty of Medicine,

Pecs, Hungary

Michaelis, Martin

Aventis Pharma Deutschland GmbH

Frankfurt/Main, Germany

Acronym: PainGenes Project number: LSHM-CT-2004-502800EC contribution: €1 600 000 Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/05/2004




SummaryExcitotoxicity contributes significantly to neuronal cell death in a

number of neurological conditions including stroke,head trauma,and

Huntington’s disease.The recent discovery of the proteins that anchor

and interact with glutamate receptors opens a new strategical

approach to cytoprotective therapy. The present project aims at

exploiting this conceptual advance to provide a platform for

cytoprotective therapies that do not interfere unduly with synaptic

transmission.

Glutamate receptor interacting proteins (interactors) serve dual

purposes.They determine the level and site of glutamate receptor

expression within the cells and connect the receptors to specific

intracellular signalling pathways. Both roles are interesting from a

therapeutical perspective.Thus, excitotoxicity might be alleviated by

modulation of the surface expression of glutamate receptors, as well

as by interfering with their downstream signalling.

The first part of the project aims at providing a more complete picture

of the functional roles of interactors (WP1-3). It is envisaged that we

will be able to identify novel interactors and that we will be in a

position to understand, at a molecular level, how the different

interactors connect with glutamate receptors and with each other.

This part of the project will also elucidate the principles that govern

the turnover and surface expression of glutamate receptors and the

mechanisms that couple the individual receptors to specific

downstream effectors of excitotoxicity.

The second part (WP4 and 5) aims at exploiting the increased insight

obtained through the first part of the project to design ways to

alleviate excitotoxicity in different model systems. In designing these

experiments the complex of glutamate receptor interacting proteins

will be viewed as a nodal point in orchestrating the surface expression

of receptors and in activating appropriate and inappropriate

(excitotoxic) signalling pathways.

The present project will be based on a unique combination of methods

that draws full advantage of the technological advances made over

the last few years.

Project main goalsExcitotoxicity contributes significantly to neuronal cell death in a numberof neurological conditions including stroke, head trauma, andHuntington’s disease.The recent discovery of proteins that anchor andinteract with glutamate receptors opens a new strategic approach tocytoprotective therapy. The present project aims at exploiting thisconceptual advance to provide a platform for cytoprotective therapiesthat do not interfere unduly with synaptic transmission.

Key issuesThe main objective of the present project is to exploit the recentadvances in this field to provide a platform for cytoprotective therapiesthat do not interfere unduly with synaptic transmission.

Measurable objectives (detailed below) include:

• identification of at least five new proteins that interact with glutamatereceptors;

• unravelling the precise mechanisms for at least five protein-proteininteractions in supramolecular glutamate complexes;

• identification and characterisation of five different tools forinterfering with protein-protein interactions;

• identification of at least ten putative pro-survival genes;

• evaluating the cytoprotective potential of the above tools and targetsin in vitro models;

• test tools and targets with cytoprotective potential in whole animalischemia models, ending up with at least three novel strategies withobvious clinical potential.

The novel strategies thus identified will be of obvious commercialpotential.The further development and clinical assessment of theseis outside the scope of the present project.

It is envisaged that the project as a whole will considerably increase ourunderstanding of the molecular and cellular mechanisms and pathwaysin excitatory amino acid induced cell death and neuronal survival.

This project is divided in two parts.The objective of the first part isto obtain a more complete picture of the functional roles ofinteractors.The objective of the second part is to exploit the increasedinsight obtained through the first part of the project to design waysto alleviate excitotoxicity in different model systems.In designing theseexperiments the complex of glutamate receptor interacting proteinswill be viewed as a nodal point in orchestrating the surface expressionof receptors and in activating appropriate and inappropriate(excitotoxic) signalling pathways.

Glutamate receptor interacting proteins as novel neuroprotective targets

GRIPANNT




DISEASES

Technical approach The project also has several objectives in relation to technologydevelopment.

Thus we will:

• design and use blocking peptides to disrupt specific protein:proteinbinding events involving defined glutamate receptor subunits and, ifappropriate, down-stream protein interactions;

• use and further develop fluorophore technology such as spectralvariants of GFP, pH-sensitive GFP (pHluorin) and photoactivatableGFP (PA-GFP) to monitor protein movement in neurons;

• design and optimise siRNAs and hairpins for the targeted knock-down of specific proteins;

• exploit viral delivery systems for highly efficient expression ofpeptides, modified proteins or siRNAs in neurons in culture and invivo;

• make use of existing and newly developed transgenic mice that eitherlack specific protein(s) or express modified versions of proteins ofinterest (e.g. epitope-tagged GluRs).

Expected achievements/impactThe potential impact of identifying novel strategies for cytoprotectivetherapy is enormous.

After more than two decades of intensive research we are still leftwithout a single cytoprotective drug for clinical use. Should wesucceed in identifying novel approaches to curb excitotoxicity, andshould these strategies eventually prove useful in a clinical setting, theimpact would be on a par with the discovery of the firstantihypertensive drugs.

Coordinator Petter Ottersen, Ole

University of Oslo

CMBN

Postboks 1105 Blindern

0317, Norway

Phone: +47 22851299

Fax.+47 22851488


PartnersHenley, Jeremy

Bristol University

Senate House

Bristol, United Kingdom

Rønn, Lars Christian

NeuroSearch A/S

Ballerup, Denmark

Kaczmarek, Leszek

Instytut Biologii Doswiadczalnej im. M. Nenckiego PAN

Warsaw, Poland

Bading, Hilmar

Heidelberg University

Heidelberg, Germany

Pin, Jean Baptiste

Fluofarma SA

Pessac, France

Roepstorff, Peter

University of Southern Denmark

Odense M, Denmark

Choquet, Daniel and Mulle, Christophe

CNRS

Paris, France

Bordeaux, France

Davanger, Svend

Universitetet i Oslo

CMBN

Blindern, Norway

Acronym: GRIPANNTProject number: LSHM-CT-2005-005320EC contribution: €1 785 000Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/06/2005


SummaryExcitotoxicity (EXC), neuronal death from excessive stimulation,

contributes to a plethora of neurodegenerative conditions including

cerebral ischemia and seizure-induced death. Stress-activated

protein kinases (SAPKs) of the JNK and p38 families have been

identified as novel mediators of EXC death which is mainly executed

by existing proteins demanding post-translational modifications.

STRESSPROTECT members have (a) demonstrated that specific

TAT-fused peptide inhibitors of the JNK pathway confer lasting

neuroprotection against seizure-induced and ischemic cell death

with an extended therapeutic window, (b) analysed the individual

apoptotic actions of SAPK isoforms, and (c) provided important

insights into signalling from glutamate-receptors. STRESSPROTECT

gathers the European elite for SAPK signalling in the brain and for

neuroprotection against EXC by pharmacological intervention in

these pathways, and proposes a novel therapeutic concept against

EXC. STRESSPROTECT provides synergistic research activities

addressing the organisation and function of SAPKs signalling with

molecular genetics,proteomics, signalosome-analysis, and molecular

pharmacology including pharmacokinetics. At the end

STRESSPROTECT has identified EXC-related SAPK signalosomes

and delivered novel inhibitor peptides against SAPK signalling

underlying EXC-mediated degeneration. STRESSPROTECT will

identify (a) proteins in upstream regulatory complexes induced by

EXC, (b) the downstream targets mediating EXC, (c) specific

protein-protein interaction sequences as targets for functional

inhibition of SAPK signalling, (d) extend the neuroprotective value

of existing inhibitory peptides, (e) develop novel TAT-fused peptides

inhibiting particular loci in the stress kinase pathways, (f) devise ways

of targeting peptides specifically into EXC-affected cells and (g)

carefully defines the risk-benefit ratio prospective to

implementation in clinical trials.

BackgroundTo achieve clinically useful neuroprotection against excitotoxicity(EXC) is currently one of the major challenges to medical research.It is the main mechanism underlying neuronal death in allhypoxic/ischemic and traumatic brain damage and in epilepsy, andcontributes also to most neurodegenerative diseases.EXC is triggeredby the excessive activation of ionotropic glutamate-receptors,particularly the NMDA (N-methyl-D-aspartate) subtype, but thepropagation of intraneuronal signalling to degenerative executionremains obscure.

Despite intensive study of the mechanisms of EXC and considerablesuccess at neuroprotection in animal models, there are no approvedcurrent treatments against EXC in humans,and neuropharmacologicaltreatments of epilepic disorders do not confer anti-excitotoxicity.Thereasons for these failures are multiple, but we would mention two ofthe main problems.

Unwanted side effects of the neuroprotection: drugs that inhibitthe NMDA receptor itself cause psychotic-like reactions andmemory loss in humans; and in animal models, while these drugsdo rescue some neurons, they also cause the vacuolation and eventhe death of others.

Shortness of the therapeutic time-window: these NMDA antagonistsare generally found to be ineffective if given more than 2-3 hours afterthe onset of the ischemic event,which is too short for most practicalpurposes. Most of the neuronal death occurs much later than this 2-3 our limit, reflecting complex pathways between the initial calciumentry and the ultimate death effectors, and it seems plausible that alonger time window and a reduction in side-effects might be achievedby targeting specific stress-activated pathways well downstream of theinitial calcium-activated events.

Recently, this strategy has been adopted by members of thisconsortium, focusing on the c-Jun N-terminal kinase (JNK) pathway.This led to the demonstration that peptide inhibitors of the pathwayprotect against several forms of EXC, and in particular confer strongprotection against ischemic cell death even when administered 6-12hours after the insult. Despite the promise of this neuroprotectivetherapy,which could in principle already be extended to clinical trials,it has to be admitted that the underlying cell biology is still largelyunknown and it is unclear whether it can be extended to other EXC-

Inhibition of stress activated protein kinase signalling asa therapeutic strategy against exitotoxicity



STRESSPROTECT


related conditions.Furthermore,there is evidence that a second MAPkinase pathway, p38, is also involved in cerebral ischemia and otherexcitotoxic conditions. And while no negative side-effects of thepeptide inhibitors have so far been discovered, they cannot bediscounted. Hence, more research is needed to clarify the signallingpathways involved in a variety of cell biological and clinically relevantexcitotoxicity models,and techniques need to be developed to targetspecifically the cells and pathways responsible for excitotoxicity-related degeneration while sparing healthy cells and pathways withoutdeleterious action.

The project will bring together cell and molecular biologists,cell deathexperts,neuropharmacologists and neurobiologists with expertise incerebral ischemia and seizures and in behavioural analysis, to analysethe two main stress kinase pathways (JNK and p38) at molecular,cellular and system levels. The ultimate aim will be to developneuroprotective peptide drugs and effective protocols to be evaluatedin rodent models of focal cerebral ischemia and kainate-inducedepilepsy.The project´s goals addresses all the objectives. It proposesa novel therapeutic concept against excitotoxicity (EXC) in particularfollowing ischemia and seizure. STRESSPROTECT will develop novelpharmacological inhibitors against stress kinases (p38 and JNK).STRESSPROTECT provides synergistic research activities addressingthe organisation and function of SAPK’s signalling with moleculargenetics, proteomics, signalosome-analysis and molecularpharmacology including pharmacokinetics.

Expected resultsEXC is involved in almost all neurodegenerative diseases andprocesses. Nevertheless, our proposal focuses on ischemia andkainate-induced seizures as classical models of EXC. In consequence,STRESSPROTECT exemplifies the potential impact of basic researchon clinically relevant diseases.

Cerebrovascular disorders constitute a worldwide health problem.According to the French College of Neurological Teachers, strokeconstitutes the third largest cause of mortality, with about 150 000new cases every year in France. In Belgium, the annual incidence ofstroke falls between 200-230 per 100 000 inhabitants,with a mortalityrate of 21% and 30% of affected patients becoming dependent onothers. In Italy, the incidence of stroke is about 10 in 100 000,with lessthan 5% of strokes occuring in subjects younger than 45 years. InSwitzerland, more than 12 000 new cases occur per year (AZPDAstrazeneca). In the United States, stroke ranks also in third positionas a cause of death and more than 600 000 cases were recorded during1997 (National Center for Health Statistics). It has been calculated thata stroke occurs every 53 seconds in North America.The cost of stroke

is very high, not only due to the high incidence of the disorder, butalso due to its long-term detrimental consequences. In the UnitedKingdom,it has been calculated that the care for every patient affectedby stroke costs more than 15 000 pounds over five years, informalcare costs excluded. In Sweden and in the Netherlands, specialcomputer or statistical models have been implemented in order totackle the difficulties related to cost-evaluation of stroke at the nationallevel. In the United States, is has been evaluated that the cost of strokeduring 2003 will be $51 billion with more than $6 billion for informalcare-giving. In Taiwan, it has been calculated that the median cost perpatient can be multiplied by a factor of approximately 15 dependingon stroke severity as assessed by the initial neurological score.

As already discussed, current therapeutic strategies are hardlyeffective, difficult to use (mainly due to a short therapeutic windowfollowing stroke), and may have serious side-effects, includingpotentially lethal consequences.The advent of new therapies basedon JNK inhibitors with negligible side-effects and extended therapeuticwindow may drastically influence both stroke consequences andsocietal cost.As already discussed, cell-penetrating inhibitors of JNKsproved to be protective when administered 6 to 12 hours aftercerebral ischemia in neonatal and adult rodents. If confirmed inhumans, such an extended therapeutic window would profoundlymodify the treatment opportunities against stroke.Today, a limit ofthree hours after thrombolytic treatment strongly reduces thenumber of patients susceptible to benefit from the intervention.Theextended neuroprotective effects of treatment using JNK inhibitorswould dramatically increase the number of patients which could betreated before the end of the therapeutic window.As a consequence,JNK inhibitors do not simply represent a new treatment strategy withincreased potency as compared with current therapies, but mayincrease the population of patients that may be treated. Finally, theidentification of peptide sequences for inhibition of specific kinasessignalling will open a novel field of pharmacological approaches andbiological activities.

Potential applicationsThe development of domain-specific peptide inhibitors will selectivelytarget pathological signalosoms with a limited risk for side effects.Suchinhibitors might be useful for neurological and non-neurologicaldiseases.



DISEASES




Coordinator Prof. Herdegen,Thomas


University of Kiel

Hospitalstrasse 4

24105 Kiel, Germany

Phone: + 49 431 597 3502

Fax: + 49 431 597 3522


Key words: excitotoxicity, genomics, neurodegeneration,proteomics, stroke, stress kinases

PartnersJDr Bonny, Christophe

Unit of Molecular Genetics

University of Lausanne

Lausanne, Switzerland

Dr Castagné,Vincent

Porsolt SAS

Le Genest-Saint-Isle, France

Prof. Clarke, Peter Geoffrey

Department of Cell Biology

Lausanne, Switzerland

Dr Coffey, Eleanor

Turku Centre for Biotechnology

Turku, Finland

Dr Courtney, Michael

Department of Neurobiology

A.I.Virtanen Institute

Kuopio, Finland

Dr Hardingham, Giles Edward

Department of Preclinical Veterinary Sciences


Edinburgh, United Kingdom

Prof.Vercelli,Alessandro

Department of Anatomy

University of Turin

Turin, Italy

Acronym: STRESSPROTECTProject number: LSHM-CT-2004-005310EC contribution: €1 499 560Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/01/2005


SummaryThe neural assembly underlying the formation of functional networks

in the cerebral cortex constitutes one of the most complex neuronal

systems in the brain.Much of this complexity arises during development

through the interaction of two distinct neuronal types,the glutamatergic

projection neurons and aminobutyric containing (GABAergic)

interneurons. Recently interneuron dysfunction has been associated

with severe neurological and psychiatric disorders (e.g. epilepsy,

schizophrenia and bipolar disorder). In order to achieve true progress

in the understanding of cortical development and of neurological

diseases associated with cortical interneuron dysfunction, a complete

account of the development of its neuronal constituents is essential. In

that sense, despite the detailed picture that is emerging about the

development of cortical projection neurons, the mechanisms

underlying the development of interneurons in the cerebral cortex have

remained poorly defined.The overall goal of our project is to obtain a

comprehensive definition of the cellular and molecular mechanisms

controlling the development of cortical interneurons. With the

information obtained from the analysis of the normal development of

cortical interneurons,we also plan to generate mouse models to study

the consequences of cortical interneuron deficiency.

BackgroundDefects in cortical neural circuitry are most likely to underlieimportant neurological and psychiatric illnesses, such as epilepsy,schizophrenia and major affective disorders. Remarkably, a rapidlygrowing body of data suggests that some of these defects may ariseas a consequence of abnormal development of the cerebral cortex.

Thus, the study of cortical development is important, not only tofurther our understanding of this complex phenomenon,but becausecortical malformations are now recognised as causing significantproportions of cognitive and neurological disorders.

Until the discovery that projection neurons and interneurons of thecerebral cortex follow different developmental programmes(reviewed in Marín & Rubenstein Nat Rev Neurosci 2: 780-90, 2001),the analysis of cortical malformations was observed from a unitaryperspective, i.e. gene mutations would affect equally the developmentof both projection neurons and interneurons, producing corticaldysfunction.The recent findings on the subcortical origin of corticalinterneurons, however, have provided with a new standpoint tounderstand cortical disorders. In this new context, gene mutationsaffecting cortical projection neurons would not necessarily perturbthe development of cortical interneurons, and vice versa.This laterobservation is extremely important for the understanding of complexcortical disorders, since it is becoming evident that gene mutationsexclusively affecting the development of a given subtype of corticalinterneurons would not cause macroscopic malformations in thecerebral cortex, and therefore would be impossible to detect withstandard imaging techniques (e.g. fMRI). Obviously, the fact that thecerebral cortex looks ‘grossly’ normal does not mean that its functionis also normal. Indeed, dysfunction of cortical interneurons has beenrecently associated with severe neurological conditions (e.g.epilepsy),and important psychiatric disorders, such as schizophrenia or bipolardisorder (Benes & Berretta Neuropsychopharmacology 25:1-27,2001.).In schizophrenia, for example, morphological abnormalities arerelatively subtle.Nevertheless, there is increasing evidence suggestingthat GABAergic neurotransmission is altered in the prefrontal cortexof schizophrenic patients. Specifically, a number of post-mortemstudies suggest that the number, distribution, neurochemistry orsynaptogenesis of cortical GABAergic interneurons could be alteredin schizophrenia (Lewis & Lieberman, Neuron 28:325-34,2000).Thus,elucidating the mechanisms that regulate development of corticalinterneurons is likely to be essential for understanding and,eventuallytreating, major psychiatric disorders.

AimThe general goal of the project is to obtain a comprehensive definitionof the cellular and molecular mechanisms controlling thedevelopment of cortical interneurons.To reach this aim, we will takea multidisciplinary approach by combining novel bioinformatic andgenomics applications, cutting-edge imaging techniques, andconventional cellular, molecular and electrophysiologicalmethodologies. In addition, we will develop new genetic tools toengineer developmental models of cortical disorders involvinginterneuron deficiency.

Migrating corticalGABAergic interneurons inculture.The image showsthe typical morphology ofmigrating cells, with a long

leading process and ashort trailing process.

Cortical interneurons havealways the same morphol-

ogy when migrating.

Gene networks in cortical interneuron development:modeling interneuron function in health and disease

INTERDEVO



DISEASES


Expected resultsSuccessful execution of the project will result in: i) new knowledgeof the mechanisms underlying the specification,migration and terminaldifferentiation of cortical interneurons, and ii) generation of newdevelopmental models of cortical disorders resulting frominterneuron deficiency.

Potential applicationsThere is increasing evidence suggesting that research on the developmentof cortical interneurons is fundamental for understanding the etiologyof a number of important human disorders, ranging from epilepsy orlearning disabilities to major psychiatric illnesses such as schizophrenia,bipolar disorder or autism. In addition to increasing knowledge on thebasic mechanisms controlling the development of cortical interneurons,our research programme goes one step further in trying to exploit thefull potential of genome information to underpin applications to humanhealth.Thus, the production of mouse models of cortical interneurondeficiency will have a clear impact on improving the diagnosis andunderstanding of human cortical developmental disorders.

Differentiated cortical neurons in culture.The image shows an exampleof one of the possible morphological phenotypes observed in differenti-ated cortical neurons. Multiple genes control the fate of distinct corticalinterneurons, determining their morphology, location and connections.

Coordinator Dr Marín, Oscar

Consejo Superior de Investigaciones Científicas andUniversidad Miguel Hernández

Instituto de Neurociencias de Alicante

Universidad Miguel Hernández, Campus de San Juan

03550 San Juan de Alicante, Spain

Phone: + 34 96 591 9384

Fax: + 34 96 591 9561


Key words: brain development, cerebral cortex,GABAergic interneuron, neurological disor-ders, epilepsy, schizophrenia, patterning,migration, synaptogenesis, neurophysiology

PartnersFoundation for Research and Technology – Hellas,University of Crete Medical School and Institute ofMolecular Biology and Biotechnology, Heraklion, Greece

Medical Research Council, London, United Kingdom

MRC Anatomical Neuropharmacology Unit, Oxford,United Kingdom

Ecole Normale Superieure and Centre National de laRecherche Scientifique, UMR 8542, RégionalisationNerveuse, Paris, France

Oryzon Genomics, Barcelona, Spain

Fundación para la Investigación Biomédica del HospitalUniversitario Ramón y Cajal, Madrid, Spain

Telethon Institute of Genetics and Medicine, Naples, Italy

Acronym: INTERDEVOProject number: LSHM-CT-2004-005139EC contribution: €2 000 000 Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/01/2005






DISEASES

SummaryThe NeuroDisseminator project aims at creating functional maps of

the human cerebral cortex by analysing PET and fMRI studies in a

homogenous way. The studies are submitted from collaborating

laboratories in Europe, and the statistical results are stored on a

database distributed on DVD to all contributors.

BackgroundThe main objective in functional neuroimaging is to map the location ofcerebral functions. However, a single study only reveals just a fewfunctions for some regions while these regions are probably contributingto many more functions,together with other regions in a larger network.NeuroDisseminator solves this issue by collecting many functional PETand fMRI studies from a number of laboratories in Europe and analysesthem in a homogenous way.The statistical results are stored in a databasecalled NeuroGenerator,which can be accessed with a visualisation andquery tool.It is possible for the submitters to access the database throughthe Internet and it is also distributed on DVD to all the contributors.

AimThe overall aim of the NeuroDisseminator project is to create afunctional map of the cerebral cortex.This is only possible by collectingmany PET and fMRI studies.Thus,the NeuroDisseminator project nowaims at increasing the number of studies in the NeuroGeneratordatabase and distributing the database to the collaborators. Anothergoal is to perform research and develop ideas regarding meta-analysisof these studies.

Expected resultsThe first version of the database has already been distributed,containinga fraction of the experiments collected so far.We expect to release asecond version soon.Within the NeuroDisseminator project, we alsoexpect to publish some meta-analysis studies

Potential applicationsWith metaresearch across studies,one may gain new knowledge aboutthe cerebral cortex and its functions.New hypotheses can thus be madeby combining the results from different functional experiments.This isonly possible with the proper tools, such as the NeuroDisseminatorvisualiser and query tool.A possible application is to use the databaseto find new hypotheses about the cerebral cortex.

Sagittal view ofsomatosensory

activationsfrom theNeuro-

Generatordatabase

3D view of somatosensory activations from the

NeuroGenerator database

Neuroimaging laboratories sharing data through a database

Coordinator Prof. Roland, PerKarolinska InstitutetDivision of Brain ResearchDepartment of NeuroscienceRetzius väg 8, SE171 77 Stockholm, SwedenPhone: + 46 8 5248 7785Fax: + 46 30 90 45E-mail: [email protected] web-site: www.neurogenerator.orgKey words: PET, fMRI, database, cerebral cortex,

functional neuroimaging

PartnersSvenssonCenter for Parallel ComputersRoyal Institute of TechnologyStockholm, Sweden

Acronym: NeuroDisseminatorProject number: LSSM-CT-2003-504752EC contribution: €400 000Instrument: Specific Support ActionDuration: 36 monthsStarting date: 01/01/2004

NeuroDisseminator


SummaryMolecular and cellular cognition is a rapidly moving research area which

is at a crossroads between basic neurobiology and clinical

neuroscience. At the end of 2002 a new scientific organisation, the

Molecular and Cellular Cognition Society (MCCS,www.molcellcog.org),

was established with the aim of facilitating exchanges between

laboratories in this research field and to promote neuroscience at the

general public level.This document deals with the organisation of the

first European Meeting, as a satellite of the Federation of European

Neuroscience Societies (FENS) meeting, effectively held in Lisbon on

8-9 July 2004.On day 1,the first oral presentation session was followed

in the afternoon by a single poster session. On day 2, two oral

presentation sessions were scheduled, for a total of 21 speakers, 100

posters and 300 participants.In addition to invited speakers coming from

Europe, Japan and USA, one third of the oral presentation had been

selected from posters. Eight fellowships were awarded to junior

scientists allowing them to participate in the meeting.

BackgroundA major emphasis of the LifeSciHealth Priority area ‘studying the brainand combating diseases of the nervous system’, which must beimplemented within the 6th Framework Programme, is fully justifiedby the increased prevalence of neuropsychiatric diseases in highlydeveloped countries. Recent statistics considering disability ratherthan mortality in our society place eight brain disorders amongst thefirst ten most relevant diseases, including major depression,neurodegeneration (mainly Alzheimer’s and Parkinson’s), alcohol anddrug abuse.

Despite the apparent heterogeneity at the clinicallevel, research in neuroscience of the last decadehas clearly demonstrated that most of these braindisorders share some common symptoms at thelevel of cognition, which in a broad sense includesboth explicit and implicit forms of learning andmemory. Indeed,clinical assessment for depressionand Alzheimer’s disease often consider loss ofmemory and emotional disturbances as importantearly pathological evidence while patients affectedby other diseases such as Parkinson’s andHuntington’s always manifest cognitive symptomsat end stages.Moreover,early onset disorders suchas attention deficit hyperactivity disorder (ADHD),mental retardation and epilepsy invariably correlatein their severe forms with poor school perfor-

mance and/or low IQ scores.Finally,drug addiction and alcohol abuseare believed to have a strong cognitive component, significantlyaffecting relapse and mental dependence.The convergence betweenbrain pathology and cognitive dysfunction is possibly even moreevident at cellular and molecular level. It is widely believed that thelarge majority of mental disorders are complex and often chronicdiseases, caused by maladaptive changes in information processing,which result in functional and often anatomical alterations at the levelof neural circuitry and neuronal signalling.The field of molecular andcellular cognition has been one of the first contemporaryneuroscience branches to combine molecular and behaviouralapproaches to study inter- and intracellular communication and tohave significantly contributed to clarify long-term mechanisms ofsynaptic adaptation. Quantitative analyses of behavioural parametersby means of pharmacological and electrophysiological tools have beenenhanced, starting from the early 1990s, by new powerful genetictechniques such as gene targeting and transgenesis in the mouse.Thesetechnologies have been introduced with enormous success andprovided important experimental evidence that molecular changes inspecific brain areas underlay changes in synaptic plasticity, cognitionand behavioural responses. For instance, mouse mutants for thetranscription factor CREB have been useful not only in determiningthe role of gene expression in memory formation and consolidationbut also to study its role in brain diseases such drug addiction andmood disorders. Moreover, the technologies of conditional andreversible mutagenesis in vivo that have been especially developed inmemory research to circumvent developmental side-effects of themutations studied are now available to study long-term neural changesassociated with neuropsychiatric disorders. Conversely, geneticallymodified mouse strains,such as ‘knock-out’ for monoamine receptors,that were originally generated to study psychiatric disorders such asaddiction and anxiety,may be also useful to dissect cognitive processes.

The advent of post-genomic and proteomic analyses holdconsiderable promise for the study of the cellular and molecularevents that regulate synaptic activity and behaviour. Identification of

First European meeting on molecular and cellular cognition

EUROMEMOBRAIN, NEUROLOGICALAND PSYCHIATRIC DISEASES




DISEASES


‘specific’ gene products in subsets of neurons that may be activatedupon learning is a major technological and economical challenge whichneeds to be developed in collaboration with pharmaceuticalcompanies. In this respect, one of the proponents of the presentapplication has pioneered this approach. Our precise understandingat the cellular level of the molecular mechanisms underlying normaland pathological synaptic plasticity in discrete brain areas is readilybecoming an essential goal for identifying new, more specific drugtargets for innovative treatments.However,validation of new potentialtargets as well as the development of new drugs will necessarilyrequire appropriate animal models, in which the relevant moleculeshave been either deleted from the brain or modified in theirexpression level, activity, or structure. Finally, to process all thisinformation and integrate it in a coherent picture of the cognitiveprocesses that range ‘from molecules to mind’, it will be necessary toexploit innovative neuroinformatic and statistical tools.

For all these reasons we believe that the first European Meeting onMolecular and Cellular Cognition is an excellent opportunity fordeveloping this research field in our continent and it will provide anopportunity for the clinical and pharmaceutical world, as well as forjunior researchers,to interact with top scientists coming from Europe,North America and Japan.

AimOur aim is to provide a European forum for the development ofmolecular and cellular approaches to study cognition, emotion andbehaviour.Furthermore,we believe that a significant integration at thislevel between basic science, pharmaceutical research and clinicalscience will provide theoretical and practical foundations for futuretreatments of neurological and psychiatric disorders.

i) Fostering European researchin the field of molecular andcellular cognition

The birth of the field of molecularcognition was in 1992 with theseminal papers of Alcino Silva(Susumu Tonegawa’s laboratory,Nobel laureate) and Seth Grant(Eric Kandel’s laboratory, Nobellaureate) on the CaMKII and Fynprotein kinases ‘knockout’ mice,respectively. Although previousresearch by means of pharma-cological inhibitors started toinvestigate the behavioural cor-relates of drug action, Silva andGrant for the first timedemonstrated that the loss ofintracellular signalling moleculesmay produce deficits in long-termplasticity and long-term memory.Despite the meteoric developmentover the last decade of this field inthe USA, a significant lag exists in

Europe, where only few laboratories have used molecular and geneticapproaches to dissect cognitive processes in experimental animalmodels.This is particularly disappointing since European research hasalways been a leading force in neuropsychopharmacology, both inacademia (e.g. Daniel Bovet, Nobel Laureate) and in pharmaceuticalindustries.The organisation of the first European meeting in Molecularand Cellular Cognition has therefore the crucial goal of helping to fillthe gap between US and European research in this new field.Additionally,this important meeting will also promote interchanges among Americanand European laboratories.

ii) Developing interactions between pharmaceutical industryand basic research

Although it is always difficult for individual researchers to establishfruitful industrial connections as mentioned above, this is perhapsmore so in the rapidly evolving field of molecular cognition, wherethere is great opportunity for translational research. It is obvious thatthe scientific platform we are proposing may provide the ideal settingfor a closer interaction between the academic world and the Europeanindustries interested in neuroscience.

iii) Interacting with psychiatrists, neurologists andneuropsychologists

One of the main goals of our meeting is to create an interface betweenbasic scientists and clinicians. Just as an example, the recentexperimental evidence provided by Nader, Ledoux and Alberini thatconsolidated memories can be weakened by pharmacologicaltreatment during subsequent recall have considerable clinicalpotential. However, rigorous clinical research is needed before thesefindings can be shown to be clinically relevant.Stimulating interactionswith clinicians is therefore a priority of our proposal and theirparticipation in the meeting is highly encouraged.


iv) Providing additional opportunities for women and easternEuropean scientists

Women scientists are underrepresented, especially at the principalinvestigator and/or professorial level in most areas of science. Indeed,this is true in the field of cellular molecular cognition and we areworking toward reverting this trend. For example, of the sevenscientists involved in the organisation of the meeting, only two arewomen. In addition, with the future enlargement of the EuropeanUnion to eastern European countries it is also a high priority for usto involve researchers from those nations.Therefore, we plan to actin two ways. First, we will provide fellowships to encourage femalescientists and eastern Europeans workers to come to this meeting.Second, we will select their most interesting posters for oralpresentations. Due to the often prohibitive costs of attending NorthAmerican meetings, this may be the only chance for many potentiallyoutstanding investigators from these groups to meet leading scientistsin the field in such a context. This meeting will also be useful forestablishing personal contacts as a prerequisite for future jobopportunities (e.g. postdoctoral training) and collaborations.

Expected results and potential applicationsThe impact of brain disorders on cognition, emotion, behaviour andpublic health is enormous.Changing demographics in European countriesmakes it imperative to decrease the morbidity of the aged population.As the proportion of people over retirement age increases, so will theburden of supporting them, borne largely by those in the workforce.Reducing the morbidity of neurodegenerative diseases is clearly a criticalpublic health issue in developed countries.Cognitive decline in the elderlyis one of the most immediate and destructive symptoms, often being aprelude to dementia and loss of independence, putting a major burdenon families and on the healthcare system. Similarly, the ability of peopleof working age and younger to contribute to society must be sustained.Psychiatric disturbances such as mood disorders and addiction to drugsand alcohol are a major impediment to this contribution,and one of themost destructive influences in society.This fundamental knowledge is asine qua non,in the immensely complex field of psycho-therapeutics,forthe creation of strategies which might decrease,if not eliminate problemsarising from these disorders, that affect so devastatingly both theindividual and society. Understanding the basic molecular and cellularmechanisms of normal and pathological brain function is now a key goalof animal model studies.Most currently available technologies have beenapplied in the field of learning and memory, in which quantitative andreproducible tests are available to measure objective behaviouraloutputs.While it is not predictable at present as to what extent whichof these studies may lead to the discovery of new treatments fordisorders of the nervous system, it is nevertheless very important thatEurope foments the interaction between basic research,clinical researchand the industrial world. Such interactions will provide the basis foreffective translational research in the field of memory and cognition andat the same time will create new opportunities for developing small- tomedium-size biotechnology companies devoted to specific tasks, suchidentification of early diagnosis tools for neurodegenerative diseases ordiscovery of drugs improving memory, mood or attention.

In addition to this meeting,the Molecular and Cellular Cognition Societywould like to continue to foster the field in Europe through futureinitiatives and meetings, as well as having a role in the education of thegeneral public on key findings in the field, including their limitations andimplications for health and society.We strongly believe that good sciencecannot be self-sustaining.On the contrary, the best of research can onlybe achieved by frank and open interactions between scientists and thegeneral public.This is particularly true for issues concerning cognitiveneuroscience, a natural focal point for discussion and debate for thehumanities and the natural sciences. For example, philosophical andhealth-related questions, such as the mind-body problem, the role ofpsychoactive drugs in medicine and recreation, the impact ofneuropsychiatric diseases and their medication,have a far-reaching impacton health, ethics, legislation and on society in general.

Coordinator Brambilla, Riccardo

Centro San Raffaele del Monte Tabor

San Raffaele Research Institute

Va Olgettina 58

20132 Milano, Italy

Phone: + 39 0226 434 876

Fax: + 39 0226 434 767


Project web-site: www.molcellcog.org

Key words: molecular and cellular cognition, learningand memory, neuronal plasticity, psychiatricdiseases

Acronym: EUROMEMO Project number: LSSM-CT-2003-503373EC contribution: €19 650 Instrument: Specific Support ActionDuration: 18 monthsStarting date: 01/06/2003






DISEASES

SummaryNeuroimmunology aims to define the mechanisms underlying the

immune-mediated pathology of diseases in the central and peripheral

nervous system.The final goal is to be able to prevent and/or treat

these diseases, multiple sclerosis being the most prominent. The

European School of Neuroimmunology (ESNI) has been established

to be a European framework for continuous educational programmes

in neuroimmunology,and also to promote trans-national research co-

operation in the field. Yearly ESNI teaching courses have been a

cornerstone to fulfil these aims. The objectives of the 4th ESNI

Teaching Course in Barcelona in September 2003 were to improve

both research and clinical practice through increased international co-

operation and combine basic and clinical research groups working on

translational projects.

BackgroundNeuroimmunology is a rapidly expanding field aimed to define thepathogenic mechanisms underlying immune-mediated disease of thecentral and peripheral nervous system. The final goal is to definetargets to establish new and efficient therapeutic projects.Neuroimmunology is a translational field of research owing to itsability to study molecular and cellular pathogenic mechanisms, toestablish animal models and to develop new therapeutic approaches.Major neuroimmunological diseases are multiple sclerosis,myasthenia gravis, paraneoplastic disorders, encephalitis, myelitis,Guillain-Barré syndrome and myositis. Disorders withneuroimmunological aspects are stroke, Alzheimer’s disease andParkinson’s disease. Neuroimmunological diseases are thereforemajor contributors to the burden of disease, loss of function,disability and lost life years in Europe.

AimThe aim of ESNI and of the 4th ESNI course is to foster high-qualityneuroimmunological research and collaboration throughout Europe.This will also improve good clinical practice. Improved co-operationbetween research groups in Europe, especially betweenneuroimmunology,neurogenetics and neuro-proteomics,was also anaim in integrating basic science and clinical topics in true translationalresearch. Further aims were to improve co-operation betweeneastern and western Europe, and being aware of giving equalopportunities to female and male research participants.The teachingcourse should be a contact forum between senior and juniorresearchers, between basic and clinical research, building a trans-European network.

Expected resultsThe 4th ESNI course took place in Barcelona,Spain,on 28 September– 1 October, 2003. Each of the four days was organised as a majorsession on innate immunity and brain functions, neurodegenerationand immunoregulation, relevance of autoandibody research inneuroimmunology, and immunotherapy in neuroimmunology.Therewere 32 talks with speakers from 11 different countries.There weremore than 250 participants,95% from Europe,and 20% from easternEurope.There were an equal number of female and male participants.Sixty travel grants were distributed, and nearly all participants fromeastern Europe were assisted in this way.One half of the participantswere medical doctors, one half basic scientists. The course wasorganised with formal talks, informal discussion sessions, andorganised tables for lunch with the expert where the participantscould choose their mentor and discussion partner.A CD-ROM wasproduced with the full scientific content from the teaching course.This was distributed to all participants.Questionnaires with free textcomments were returned from a majority of participants.The follow-up work of the project has included planning of further ESNI teachingcourses, neuroimmunological research and education activities, andjoint projects within and outside the EU framework programmes.

Potential applicationsThe application of the results of this project should lead both toimproved research in neuroimmunology and to better treatment,diagnosis and prevention of neuroimmunological disease.The courseshould foster international collaboration on high-quality projects andgive increased knowledge and skills to all participants.The ESNI workshould also increase the interest and awareness of the challengeswithin this field, and by this improve the framework for research andoptimal clinical practice for neuroimmunological diseases.

European School of Neuroimmunology (ESNI);4th Teaching Course – Barcelona

ESNI course 2003


Coordinator Prof. Gilhus, Nils Erik


Haukeland University Hospital

5021 Bergen, Norway

Phone: + 47 5597 5000

Fax: + 47 5597 5165


Project web-site: www.esni.org

Key words: neuroimmunology, teaching course, neuro-science, multiple sclerosis

PartnersProf. Montalban, Xavier

Unitat de Nevroimmunologia Clinika

Hospital Vall D’Hebron

Barcelona, Spain

Prof. Martino, Gianvito

Department of Biotechnology

San Raffaele Scientific Institute

Milan, Italy

Prof. Graus, Francesc

Servicio de Nevrologia

Hospital Clinic I Provincial

Barcelona, Spain

Prof. Probert, Lesley

Laboratory of Molecular Genetics

Hellenic Pasteur Institute

Athens, Greece

Prof.Willison, Hugh


Southern General Hospital

Glasgow, Scotland

Acronym: ESNI course 2003Project number: LSSM-CT-2003-502993EC contribution: €50 000 Instrument: Specific Support ActionDuration: 10 monthsStarting date: 01/07/2003






DISEASES

SummaryThe 4th Forum of European Neuroscience, held in Lisbon on 10-14

July 2004, was one of the largest European meetings in the field of

basic and clinical neuroscience.Topics addressed ranged from genes

and molecules implicated in brain function and dysfunction, to the

physiopathology and therapy of diseases such as major

neuropsychiatric and neurodegenerative disorders. A special

emphasis was given to translational science, i.e. how recent basic

scientific findings can rapidly and successfully contribute to

significant advances in the management of brain diseases with a high

individual and socio-economic impact.

The Forum included nine plenary and 12 special lectures, 56

symposia, seven technical workshops and approximately 3000

poster presentations from over 4500 participants. Two special

sessions took place, in association with the European DANA

Alliance for the Brain, and with the European Brain Council.

The main objectives of the Forum were: 1) to contribute to the

advance of neuroscience research, especially in Europe, by bringing

together experts from all over Europe and beyond, to present and

discuss their latest findings with their peers; 2) to promote

education in neurosciences, facilitating the participation of young

researchers and PhD students, by providing specially reduced

registration fees and stipends, and organizing one workshop on

education in neuroscience in Europe; 3) to boost the collaboration

and scientific networks between European laboratories, including

eastern European countries, as stipends were available for both

young and senior scientists from those countries.

The Forum was particularly relevant to the objectives of the Specific

Programme ‘Integrating and strengthening the European Research

Area’, under the topic ‘Specific brain research support actions’. In

addition, it contributed to the objectives of establishing a European

Brain Research Area, as set out in a conference organised by the

European Commission on September 2003.

BackgroundThe Federation of European Neuroscience Societies (FENS) is anon-profit organization that includes over 15 000 Europeanneuroscientists from all specialities in this field, affiliated in nationalneuroscience societies from 24 European countries (Armenia,Austria, Belgium, Czech Republic, Denmark, Finland, France,Georgia, Germany, Greece, Hungary, Israel, Italy, Norway, Poland,Portugal, Romania, Russia, Spain, Sweden, Switzerland, TheNetherlands, Turkey, United Kingdom), as well as fivemonodisciplinary multinational societies (the European BehaviouralPharmacology Society, the European Brain and Behaviour Society,the European Society for Neurochemistry, the Federation of theEuropean Psychophysiology Society and the InternationalBehavioural and Neural Genetics Society).

The FENS Council designated the Sociedade Portuguesa de Neuro-ciencias (SPN) to organise the 4th Forum of EuropeanNeuroscience in Lisbon on July 10-14,2004.The SPN is a non-profitscientific organization affiliated to FENS.

The FENS Forums of European Neuroscience are the largestscientific meetings organized in Europe, and some of the largest inthe world, in the field of basic and clinical neuroscience, attractingmost European neuroscientists, but also scientists from all over theworld.The scientific programme of the Forum was established byan independent international Scientific Programme Committee,composed of senior scientists from different fields of neuroscienceand from many European countries. The scientific programmecovered topics ranging from basic neurobiology, e.g. genes andmolecules implicated in normal brain functioning, but also innumerous neurological and psychiatric dysfunctions, to the physio-pathology and therapy of diseases such as epilepsy, Alzheimer’sdisease or schizophrenia.

4th Forum of European Neuroscience

FENS Forum 2004


AimThe main objectives of the FENS Forum of European Neurosciencewere:

1) to contribute to the advance of neuroscience research, speciallyin Europe, by bringing together experts from all over Europe, aswell as from other continents, to present and discuss with theirpeers their latest findings;

2) to promote education in neurosciences, facilitating theparticipation of young researchers and PhD students, byproviding specially reduced registration fees, grants and stipends,and organizing one workshop on education in neuroscience inEurope;

3) to boost the establishment of collaborations and scientificnetworks between laboratories all over Europe, including easternEuropean countries; special grants and stipends for participantsfrom those countries will also be available;

4) to raise public awareness of brain research by disseminating tothe general public the most relevant findings presented at theForum, and by promoting a special symposium on ‘PublicAwareness of Brain Research’.

By bringing together such a large number of Europeanneuroscientists, with different personal perspectives and levels ofdifferentiation ranging from senior scientists to PhD students, anadditional objective was to provide the environment for informaldiscussions on topics relevant to the promotion of Europeanneurosciences, such as the promotion of an European BrainResearch Area, the establishment of European Post-graduateNeuroscience Programmes, the improvement of post-doctoralactivities in Europe in order to avoid the ‘brain drainage’,mechanisms for supporting post-docs working outside Europe toreturn to their own countries, etc.

Expected resultsThe abstracts of almost 3 000 scientific communications werepublished in an abstract book (FENS Forum Abstracts, volume 2, 2004)that is citable and covered by Current Contents,Medline and all majorindexing services.Abstracts are also available at the Forum websiteand on CD. Therefore, the presented research findings weredisseminated to the entire scientific community, well beyond theparticipants of the Forum.

A professional press office was in charge of spreading out to thegeneral public the most relevant findings presented at the Forum.Moreover, a special symposium was dedicated to ‘Public Awarenessof Brain Research’.

Potential applicationsThe Forum represents a significant added-value to brain research inEurope,as specialists from all European countries had the opportunityto present to their peers their latest findings in virtually every fieldof the neurosciences. Neuroscientists from non-European countriesalso participated,further contributing to the advance of neurosciencesin Europe and elsewhere. A special session, co-organised with theEuropean Brain Council, was held on ‘Brain Research in Europe:structuring European Neuroscience. New perspectives’, as a follow-up to the meeting organised by the European Commission onSeptember 2003 on ‘Brain Research in Europe’.



Coordinator Prof. Castro-Lopes, José

Sociedade Portuguesa de Neurociencias

Instituto de Histologia e Embriologia

Faculdade de Medicina do Porto

Alameda Hernani Monteiro

4200-319 Porto, Portugal

Phone: + 351 225 091 468

Fax: + 351 225 505728


Project web-site: www.fens2004.org

Key words: neuroscience, scientific meeting, Europe,research

PartnersProf Mervyn Bibb

John Innes Centre, Norwich, United Kingdom

Acronym: FENS Forum 2004Project number: LSSM-CT-2004-005100EC contribution: €190 000 Instrument: Specific Support ActionDuration: 15 monthsStarting date: 01/01/2004




DISEASES

SummaryIn this project the costs of brain disorders in Europe are estimated and

a next step is suggested: analysis of the funding of brain research

(neuroscience) in Europe. Both private funding and public funding will

be analysed and divided into categories according to function or disease

target.A comparison of the results will be made across countries within

Europe, as with the USA and Japan. Furthermore, the project contains

an assessment of the potential benefits of further funding efforts for

neuroscience in Europe in relation to costs.Several methods for testing

this will be used, and results from a another project on the economic

burden of brain diseases in Europe will be used for comparison.The

results from the assessments shall be compared with studies performed

in other research areas and indicate the best possible use of funding

allocation for research in Europe in future.These kinds of studies are

missing in Europe, and hence this project shall be a pioneer in an area

receiving more and more attention in the research community as well

as in policy discussions in the European setting.

BackgroundBrain research has not been sufficiently high on the European agenda.The spending on brain research in Europe is much lower than similarspending in the United States or Japan,and is not commensurate withthe burden of these diseases or to the importance of understandingthe normal brain. It is generally accepted that Europe led in brainresearch until approximately 10 or 20 years ago. At that time thisrole was taken over by the United States and the gap betweenEuropean brain research and United States’ brain research continuesto widen. A similar consideration is true for Japan although thiscountry produces a considerably lower quantity of brain research.Brain research is extremely important for the biotech industry, anddrugs for brain diseases together represent the biggest single futureindication for drugs.The present project will contribute to increaseunderstanding of the importance of new treatments for brain diseasesand, hopefully, via stimulating the interest in brain research and viaincreased and focused (and efficient) funding for brain research willhelp to increase European competitiveness in this field.

AimTo investigate the funding resources for brain research in Europe andassess the potential benefits and costs related to neuroscience of furtherefforts for brain research in Europe in the future. More specifically theobjectives of the study are to:

1. analyse the resources used for brain research (neuroscience) in Europeand to compare overall research efforts;

2. compare the size and allocation of funding for neuroscience in Europewith resources used in the USA;

3. assess the potential benefits in relation to costs of further efforts forbrain research in Europe through several tests:

a. relating the total current funding for brain research in Europe with thetotal economic burden of brain diseases in Europe

b. assessing the value of brain research to health improvement and lifeexpectancy in Europe

c. assessing the cost-effectiveness of further funding for brain research inEurope

4. disseminating the above results to clinical and basic scientists,patients,politicians, other decision-makers and to people of Europe.

Expected resultsThe project will result in the best possible estimates of public andprivate research spending for brain diseases in Europe, as well asprovide an estimate of the economic benefits for Europe fromprevious advances in brain research, and an estimate of the potentialbenefits from further investments in different areas of brain research.The RABRE project will provide a framework for assessing the valuefor society of medical research in general and brain research inparticular, and set the stage for a discussion about priorities to andwithin brain research (neuroscience).

Potential applicationsThe results will be directly useful for legislators and administratorsconcerned with priorities for investments in life sciences andbiotechnology for health.Moreover, it is expected that the results of thepresent study will be important for policy development both at Europeanlevel as well as at national level in Europe.The results from the projectwill provide solid information on the value of further research inneuroscience in Europe.Hence, it is anticipated that the results shall bea basis for decision-makers in the political and scientific communities inEurope.

Resource allocation to brain research in Europe

RABRE




Coordinator Prof. Olesen, Jes

European Brain Council

Glostrup Hospital


Nordre Ringvej

2600 Glostrup

Copenhagen, Denmark

Phone: + 45 43 23 30 36

Fax: + 45 43 23 39 26


Project web-site: www.ebc-eurobrain.net

Key words: brain disorder, brain disease, neuroscience,health economics, economics, epidemiology,funding, cost-benefit, cost-effectiveness,Europe

PartnersProf. Jönsson, Bengt

Stockholm Health Economics

Stockholm, Sweden

Acronym: RABREProject number: LSSM-CT-2005-013043EC contribution: €300 000 Instrument: Specific Support ActionDuration: 18 monthsStarting date: 01/01/2005


• MIMAGE 142• GEHA 144• EMBIC 146• Cells into Organs 148• LINK-AGE 150• ANABONOS 152• OSTEOGENE 154• AGEACTION 156

Human development and ageing


SummaryThe overall aim of this programme is to assess the role of

mitochondrial function in ageing and lifespan control.The strategy used

is to discover mechanisms that show evolutionary conservation

between invertebrate and mammalian model systems.A unique matrix

of model organisms (yeast, Podospora anserina, Caenorhabditis elegans,

Drosophila melanogaster, mouse and rat) and cell culture systems is

used. Specific questions will be experimentally tested.The following

age-related issues are addressed: (i) modulation of mitochondrial

reactive oxygen species (ROS) by different means, (ii) relevance of

molecular and cellular pathways to maintain a ‘healthy’ population of

mitochondria, (iii) nature and impact of signalling pathways on

mitochondrial activity, (iv) effects of dietary restriction on

mitochondrial activity, (v) novel age-related mitochondrial functions.

The participating laboratories have a strong commitment for

collaborative work and ideally complement each other. Some of the

partners extensively collaborated in the past or are collaborating

presently in the field of research addressed in this IP. They are working

with different model organisms and systems, most are well

experienced in the field of experimental biogerontology,and they each

have a specific expertise in different fields of research ranging from

advanced biochemistry, cytology, genetics to molecular biology.This

consortium is in the unique situation of performing competitive

research with other programmes aimed at identifying and

characterising mechanisms of ageing that are conserved in most

species,hence called 'public' mechanisms of ageing. At the same time,

the IP complements European activities that follow other strategies

(e.g., comparing mitochondrial parameters from human tissues of

different human populations) to elucidate the role of mitochondria

in human ageing.

ProblemAgeing as the progressive loss of function and consequently anincrease in morbidity is a serious social problem.Today,social securityand health insurance systems are collapsing. Almost every day newstrategies to safeguard these systems (e.g. by increasing the rates tobe paid by the individual) are discussed in politics and large parts ofthe European population are fear that their pensions will be lost inthe near future.With an increasing proportion of the elderly in thepopulation in the next decades this problem will keep growing and a

‘war of the generations’ is expected.A solution will only be possibleby an integrated approach:political decisions (e.g. restructuring socialand health insurance systems) and substantial scientific advances tounderstand the basics of biological ageing and to use thisunderstanding to intervene in the processes of ageing.

Unfortunately, although in the last three decades more informationabout the molecular mechanisms of ageing have been established, innot one biological system are these mechanisms sufficientlyunderstood in detail. However, it is generally accepted that majorconserved or ‘public’ mechanisms exist in addition to mechanismswhich are species-specific or ‘private’. Unravelling the ‘public’mechanisms of ageing is thought to be of special importance becausethese seem to be the mechanisms of general relevance.Our strategyis to elucidate these mechanisms in various biological systems.At theorganism level, the two fungi Saccharomyces cerevisiae (yeast) andPodospora anserina, the nematode Caenorhabditis elegans, Drosophilamelanogaster, mice and rats offer important advantages forexperimental research (e.g.short life-time,accessibility to genetic andmolecular analysis) and therefore are preferred ageing models. Inaddition, cell cultures are investigated extensively.

AimThe specific aim of this project is to unravel the molecular conservedmechanisms of ‘normal’ or ‘healthy’ ageing.The strategy is to use avariety of systems with a special emphasis on organismic ageing.Thesemodels are clearly independent ‘complete’ organisms with a longhistory of evolution, but are much less complex in their organisationthan humans. The consortium, however, does include sub-projectsstudying cell culture systems as well. As well as different cell culturesfrom ‘normal’ subjects one important premature ageing model,Cockayne Syndrome, is included.The consortium covers a variety ofageing models,a prerequisite for the identification and characterisationof ‘public’ ageing mechanisms. A very important advantage of theselected systems is that they are accessible to experimentation.Therefore, specific questions can be asked and, due to the short life-span of some of the systems, can be addressed experimentally in away that is not possible in higher organisms like humans. Moreover,a variety of long-lived mutants are available. The analysis of thesemutants has contributed and will continue to contribute significantlyto what is known about basic molecular pathways governing ageing.The consortium is in the situation of being able to go considerablybeyond those investigations which in the past has generated a hugebody of essentially correlative data.

Role of mitochondria in conserved mechanisms of ageing


HUMAN DEVELOPMENTAND AGEING

MIMAGE


Expected results1.The establishment of efficient procedures for the isolation of

coupled mitochondria in Podospora anserina and Caenorhabditiselegans.

2.The establishment of procedures for efficient measuring of reactiveoxygene species in Podospora anserina and Caenorhabditis elegans

3.The establishment of procedures for the efficient identification ofoxidatively damaged proteins and for monitoring mitochondrial lipidperoxidation.

4. Identication and definition of the impact of exogenous andendogenous factors/ components (e.g. uncoupling proteins,nutrition) which affect oxidative stress on mitochondrial functionsand ageing.

5. Determination and characterisation of specific mitochondrialfunctions (mtDNA stability, mtDNA repair, heat shock proteins,turnover of mitochondria) affecting lifespan and ageing.

6. Demonstration that and how different signaling pathways(retrograde signalling, cAMP/PKA, and insulin/IG1 signalling) affectmitochondrial functions.

7. Identification and characterisation of additional (novel) age-relatedmitochondrial functions causatively linked to ageing.

Potential applicationsThe general knowledge generated in this project may in the futurebe used to develop specific interventions into the ageing process ofbiological systems.



Coordinator Prof. Osiewacz, Heinz D

Botanical Institute, Johann Wolfgang Goethe-University

Marie-Curie-Str. 9

60439 Frankfurt, Germany

Phone: + 49 69 798 29264

Fax: + 49 69 798 29363


Project web-site: to be created

Key words: ageing, mitochondria, model systems, reac-tive oxygen species, molecular mechanisms

PartnersZoological Institute, Johann Wolfgang Goethe-University,Frankfurt, Germany

Institute of Genetics, University of Salzburg,Austria

Faculty of Chemistry, Physical Biochemistry,TechnischeUniversität Darmstadt, Germany

Laboratory of Genetics,Wageningen University,TheNetherlands

Institute for Biomedical Aging Research,AustrianAcademy of Sciences. Innsbruck,Austria

Acronym: MIMAGEProject number: LSHM-CT-2004-512020EC contribution: €7 400 000 Instrument: Integrated ProjectDuration: 60 monthsStarting date: 01/01/2005


SummaryGEHA will identify genes involved in healthy ageing and longevity,

which allow individuals to survive to advanced old age in good

cognitive and physical function and in the absence of major age-

related diseases.The work plan is:

(i) to collect 2800 long-lived (90+) sibpairs and 2800 unrelated

younger control subjects from ten European countries and

China;

(ii) to perform a genome scan in all the sibpairs (Affected SibPair

Analysis, ASP) in order to identify new chromosomal regions

harbouring putative longevity genes, followed by positional

cloning and mutational analysis and preceded by LD block

structure in CEPH families;

(iii) to thoroughly investigate in cases and controls three candidate

regions in chromosomes 4,11 and 19 that according to previous

studies are involved in ageing and longevity;

(iv) all the recruited people will be genotyped for mitochondrial

DNA haplogroups and C150T mutation known to play a major

role in ageing and longevity.

Gender-specific genes involved in healthy ageing and longevity in

women and men stratified for ethnic and geographic origin and

APOE genotype will be identified; a longitudinal survival study to

assess the impact of the identified genetic loci on 90+ people

mortality will be performed; mathematical and statistical models

capable of combining genetic data with demographic characteristics,

health status, socio-economic factors, lifestyle habit will be

developed.

ProblemIn 2000, 69 million people worldwide were aged 80 or over. Thispopulation is the fastest-growing segment of the population.By 2050the 80+ years old group is expected to increase five-fold to 377 millionand represent 4.4% of the population.The number of nonagenarianswill reach 63 million by 2050, which is an eight-fold increase.Centenarians currently estimated at 167 000 will reach a projected5.3 million worldwide. Europe is the area where population ageing ismost advanced. This demographic explosion makes it criticallyimportant to identify the factors involved in ageing devoid of majordiseases and disabilities, contributing to increase the number of oldEuropean citizens in good health.Clues concerning such healthy ageing

can be found by studying the selected group that survives past age90. A network of geriatricians, demographers, geneticists andstatisticians is involved in GEHA to investigate the genetic basis ofthe ageing process in humans.

It is predicted that in addition to new information on the genesgoverning healthy ageing, innovative bioinformatic algorithms,demographic/mathematical models and powerful statisticalapproaches will be developed as a result of GEHA.

AimMajor goals of GEHA project are:

1. to recruit 2800 long-lived sibpairs and 2800 younger controlsubjects from 17 geographic areas for genome scanning in orderto identify chromosomal regions involved in longevity and healthyageing;

2. to perform bioinformatic, functional genomics and proteomics andmolecular biology studies on the longevity regions/genes and genevariants resulting from ASP analysis and Linkage Disequilibrium(LD) mapping;

3. to test whether ethnically different populations share the samegenes involved in ageing and longevity;

4. to verify if the genes involved in longevity and healthy ageing inthe European population are the same in an ethnically differentpopulation such as the Chinese;

5. to ascertain the role played in human longevity by three candidateregions;

6. to verify in different populations the role of mtDNA haplogroupsas putative genes affecting longevity,and to study their interactionwith the newly emerging longevity nuclear genes;

7. to identify gender-specific genes differently involved in healthyageing;

8. to stratify the sample according to APOE genotype, the onlygenetic marker which so far has been found to be associated withreduced longevity in a variety of populations;

9. to develop innovative analytical strategies capable of combiningall the data collected (clinical,socio-economical,related to lifestyle,demographic and genetic);

10. to evaluate the importance of genetic factors on the mortality ofthe recruited sibpairs.

Expected resultsThe project should help in identifying biological and non-biologicaldeterminants of successful/unsuccessful ageing and longevity, and inparticular genes and gene variants as new and innovative targets fordiagnostic and therapeutic strategies of age-related pathologies and

GEnetics of Healthy Ageing

GEHAHUMAN DEVELOPMENTAND AGEING





disabilities. These findings will represent a starting point for newactivities to be developed and exploited by the European biotechcompanies which are part of the GEHA consortium.The followingoutcomes are expected:

- development of ad hoc protocols, standardised at European scale,for the assessment of the health status of the oldest old;

- development of new ad hoc algorithms capable of combining clinical,social and genetic data in order to identify subgroups of old peopleat higher risk for the development of age-related diseases/disabilities;

- development of ad hoc microarrays for the assessment ofsuccessful/unsuccessful healthy ageing;

- development of molecular biology methods capable of exploiting theknowledge related to the genes associated with healthy ageing andlongevity to counteract the activity of genes related to major age-related diseases and disabilities.

Potential applicationsThe genetic approach of GEHA, combining ASP analysis and LDmapping, is applied to a very large number of 90+ sib pairs and youngercontrol subjects newly recruited across Europe. This experimentaldesign will allow:

(i) an independent genetic mapping of any chromosomal areas ofspecial interest;

(ii) a comparison between Sardinia (with its unusual enrichment ofmale centenarians) and Finland (with their unique geneticcharacteristics) with other European countries;

(iii) a comparison of the data obtained on the genetics of longevitywithin European populations to those obtained by the BeijingGenomics Institute (BGI) on a large collection of DNA and clinicaldata regarding a totally different ethnic group such as the HanChinese population;

(iv) subgroup comparisons with respect to social and environmentalfactors.

Coordinator Prof. Franceschi, Claudio

University of Bologna - CIG

Via Zamboni 33

40126 Bologna, Italy

Phone: + 39 051 2094743

Fax: + 39 051 2094747

E-mail [email protected]

Project web-site: http://www.geha.unibo.it

Key words: healthy ageing, longevity, demography, affect-ed sibpair analysis, linkage disequilibriummapping, mitochondrial DNA,APOE, func-tional genomics, proteomics, gender, geneticethical issue

Partners

2 France

2 Germany

6 Italy

1 The Netherlands

1 Greece

2 Finland

1 Poland

2 United Kingdom

3 Belgium

2 Denmark

1 People’s Republic of China

Acronym: GEHAProject number: LSHM-CT-2004-503270EC contribution: €7 200 000Instrument: Integrated ProjectDuration: 60 monthsStarting date: 01/05/2004


SummaryUnderstanding the cause of female infertility, as well as the molecular

mechanisms of embryo implantation, is important for treating the

former and increasing the success rate of IVF- ET. Discrete molecular

implantation defects might also be the ‘primary lesion’ in pre-eclampsia.

EMBIC will network and structure leading but unlinked European groups

so as to catalyse their efforts and maximise their potential. Recent

advances in genomics and proteomics open the possibility of

understanding what recent KO animal studies and clinical evidence

highlight as being the main events controlling implantation.

ProblemFemale sterility is increasing in Europe and this is partly countered byAssisted Reproductive Technologies. In December 2002, the Europeanin Vitro Fertilisation (IVF) Embryo Transfer (ET) monitoring programmereported in a study from 22 countries some 258 460 cycles of treatment.The success rate is stalled at present around 25% for IVF and 27% forICSI (intra cytoplasmic sperm injection).As a partial consequence of therise in infertility, compared with 1998, the number of cycles increasedby 11%, and projections are for a similar increase in the 2003-2004period. Understanding the cause of such a rise in female infertility istherefore of prime importance. Furthermore, the success rate of ETremains low, which is costly psychologically and financially. In mostEuropean member countries,a single cycle costs of the order of €3 000to €5 000.In addition,as an empirical approach to improve implantationrates,several embryos may be transferred,normally resulting in a multiplepregnancy and delivery rate of 26.3% (most often,but not always,twins).Finally, discrete molecular implantation defects might be the ‘primarylesion’ in pre-eclampsia, a high risk disease frequent in Europe and themajor cause of maternal mortality (1.5 deaths /100 000 pregnancies),causing many associated maternal deaths in developing countries.Limitingfactors to implantation seem to be ‘the implantation window’, theproper formation of a functional decidua basalis with intensive tissueremodelling (uterus), and de novo organogenesis (placentaformation).

AimWe aim to build an European virtual laboratory on majormechanisms of implantation by thoroughly exploring what knockout mice have recently established as cellular-cytokine networks/ keypathways promoting the development of two de novo organs: thedecidua basalis and the mature placenta.

At present, fragmentation of experimental capacity and disparateapproaches result in lack of a comprehensive skills base, and lack ofaccess to very specialised approaches and technological platformssuch as animal experimentation in very strict conditions, genomicsand proteomics facilities or multicentric clinical evaluation. Theserequire being used in a coordinated fashion to maximise their effectin this area.

We will thus:

1. assemble critical talents and approaches, to develop anintegrative, evaluative, capacity to set up EMBIC;

2. integrate EMBIC laboratories using crucial models andcoordination of the joint programme of activities:

2.1. early embryo signalling to ultimately allow selection of only thoseembryos which will effectively implant;

2.2. key events in tissue remodelling;

2.3. homing/ proper activation of Natural Killer (NK) cells;

2.4. role of MHC class I gene products and their recognition by NKcells;

2.5. control of the inflammation complement related pathways;

2.6. cytokine/ chemokines/ profiling;

A murine preimplantation

uterus labellingwith DBA lectinreveals it is com-posed at 80% of activated

lymphocytes ofthe natural killer

cells lineage

The control of embryo implantation. Studies of geneexpression, protein profiles / functions at the uteroembryonic level: Cellular and molecular developmentalevents at the fetomaternal interface

EMBICHUMAN DEVELOPMENTAND AGEING





2.7. invasion and early post-implantation events, Matrix MetalloProtease (MMP) based proteolysis/ adhesion moleculefunctions.

3. constitute a European cohort of infertile women with creation of RTgenerated DNA, sera and micro-biopsy tissue samples banks;

4. establish guidelines for management of infertile women combinedwith diagnosis procedures and ultimately recombinant technologiestherapies for selected pathologies;

5. open the network of validated platforms for education andcooperative experimentation.

EMBIC will contribute and benefit from the creation of integratedplatforms based on animal models, genomic and proteomic facilities,protein intra-net database set-up and integrated clinical set-up.EMBICwill spread excellence by facilitating the exchange of scientists withinthe laboratories,promote recruitment/training of out-network post-docs, organise workshops and satellite meetings in pan-European orregional immunology/fertility meetings and an annual summer school.

Expected resultsWe believe that we will answer the following questions:

1) Which preimplantation embryo signals permit only some embryosto implant in a receptive uterus?

2) Why is there such a high proportion of NK cells in the implantationuterus, a percentage higher even than that seen in lymph nodes?

3) What is their origin?

4) Which embryonic cell surface soluble factors signals induce theproper NK activation vs. an abortogenic one?

5) What are the cellular and molecular determinants of a tolerantuterus?

6) Which molecules/cells control early stroma remodelling and tissuedifferentiation (particularly spiral arteries)?

7) What controls trophoblast invasion and differentiation?

8) Which uterine growth factors permit proper placental dif-ferentiation (essentially at trophoblast level) and growth?

Potential applicationsScreening of the embryos to determine those which will implant,improvement of IVF –ET success rate,determination of new strategiesfor IVF-ET management, identification of genetic defects in sterility,understanding local uterine angiogenesis, insights into the mechanismsof pre-eclampsia. It is also expected that we will identify new geneexpression defects causing female sterility as well as define therapeuticapproaches and diagnostic tools.

Coordinator Dr Chaouat, Gérard

Unité 131 INSERM

Equipe cytokines et relation materno foetale

Maternité Hôpital Antoine Béclére

92141 Clamart CEDEX, France

Phone: + 33 14 537 4450

Fax: +33 14 537 4450


Project web-site: www.embic.org

Key words: embryo, implantation, signals, HLA-G, NKs,inflammation, complement, arteries, spiral

Partners4 France

2 United Kingdom

1 Spain

4 Italy

2 Hungary

2 Germany

1 Belgium

1 Austria

Acronym: EMBICProject number: LSHM-CT-2004-512040EC contribution: €7 400 000 Instrument: Integrated ProjectDuration: 48 monthsStarting date: 01/10/2004


SummaryThis network will elucidate molecular and cellular processes underlying

specification and differentiation of mesodermally derived organ systems.

We integrate developmental genetics and experimental embryology

with modern cell biology and genome scale analysis. These new

technologies will enable us to identify genes which function in building

a specific organ or in a particular aspect of embryogenesis. A major

revelation of developmental biology has been the extent to which

molecular strategies are redeployed,even during regeneration.Thus this

information is the basic knowledge required for organ and tissue

engineering.

ProblemThe development of new approaches to treating disease willrevolutionise health care in the coming decade.Treatment of cancerswill increasingly rely on targeted molecules rather than cytotoxicdrugs. Manipulation of stem cells for cell and tissue replacementtherapies holds great promise for treatment of degenerative diseaseand injury. Both approaches depend critically on detailed knowledgeof the molecular and cellular events governing normal differentiationof the target organs and tissues.This knowledge provides the basisfor organ and tissue engineering.

Many important diseases affect organ systems – such as heart,vascular system,blood,kidneys, skeleton, and musculature - derivingsubstantially or exclusively from mesodermal cells.Heart failure andstrokes resulting from atherosclerosis, kidney failure, musculardystrophy, osteoporosis, tumours and leukaemia are caused eitherby defects in development of these mesoderm containing organsystems or in their function, frequently as a consequence of ageing.Together, these diseases represent principal obstacles to reaching ahealthy old age.

AimThe aim of this network is to integrate the established methodologiesof developmental genetics and experimental embryology with thesophisticated approaches of modern cell biology and the newmethodologies of genome scale analysis made possible by genomesequencing projects.These new technologies will enable us to identifymany of the genes which function in building a specific organ systemor in directing a particular aspect of embryogenesis.Analysing thesegenes, investigating their functions,and placing them in developmentalcascades as well as following the cells which they affect, willundoubtedly reveal new aspects of organ development,extending andcompleting the existing picture. The extent to which molecular

strategies are redeployed, not only at different sites duringembryogenesis, but also during later tissue regeneration, is essentialfor understanding and eventually correcting,by appropriately targetedtherapeutics,any malformation or deregulation which affects the adultorgan and is the basic knowledge required for organ and tissueengineering. It will enable identification of the gene cascades associatedwith deadly or disabling genetic diseases and of suitable target genesfor drug discovery. It will point the way for making specifically tailoredstem cells for a multitude of therapeutic applications and for organdevelopment in vitro.

Expected results - We will sustainably integrate the participating groups into a durable

world force in this area.

- We integrate users and facilities into the network’s Joint TechnologyPlatform.

- We develop a Joint Programme of Research which will generateimportant publications and joint initiatives during the network’slifetime

- We organise a series of network symposia and a series of summerschools.

- At least 20 completed PhDs will emerge from the network over itslifetime, as will a number of new independent groups.

- We expect the network to generate industrial applications/ patentsas saleable technology.

Potential applications Genomic and postgenomic approaches will be applied to understandhuman development and ageing.This will develop the evidence basefor improving public health strategies to promote healthydevelopment and ageing.

Cells into organs: Functional genomics for developmentand disease of mesodermal organ systems

Cells into OrgansHUMAN DEVELOPMENTAND AGEING





Coordinator Dr Durston,Anthony J.

The Netherlands Institute for Developmental Biology

Uppsalalaan 8

3584 CT Utrecht,The Netherlands

Phone: + 31 30 212 1800

Fax: + 31 30 251 6652


Project web-site: www.cellsintoorgans.net

Key words: organogenesis, stem cells, mesodermalorgans

PartnersDr Deschamps, Jacqueline and Dr Korswagen, Rik

The Netherlands Institute for Developmental Biology


Dr Grosveld, F, Dr Dzierzak, Elaine and Charité,Jeroen

Erasmus University Medical Centre

Rotterdam,The Netherlands

Dr Gurdon, John and Dr Smith, Jim

The Wellcome Trust/Cancer Research United Kingdom

Gurdon Institute of Cancer and Developmental Biology

Cambridge, United Kingdom

Dr Ingham, PW, Dr Borycki,Anne-Gaelle and DrRoehl, Henry

The University of Sheffield

Sheffield,, United Kingdom

Dr Stern, C and Dr Wolpert, Lewis

University College London


Dr Buckingham, Margaret and Dr Nicolas, Jean-François

Institute Pasteur

Paris, France

Dr Cossu, Giulio

Fondazione Centro San Raffaele Del Monte Tabor,

Milan, Italy

Dr Jacinto,A, Dr Thorsteinsdottir, Solveig, DrPalmeirim, Isabel and Dr Rodríguez-León, Joaquín

Instituto Gulbenkian de Ciencia/Fundacao CalousteGulbenkian

Oeiras, Portugal

Dr Jaeckle, Herbert

Max-Planck-Gesellschaft zur Foerderung derWissenschaften e.V.

Max Planck Institute for Biophysical Chemistry

Göttingen, Germany

Dr Wagner, Erwin and Dr Hartmann, Christine

Forschungsinstitut fur Molekulare Pathologie Ges. M.b.H.

Research Institute of Molecular Pathology

Vienna, Austria

Dr Affolter, Markus and Dr Gehring,Walter

University of Basel

Basel, Switzerland

Dr Duboule, Denis

University of Geneva

Department of Zoology and Animal Biology

Geneva, Switzerland

Acronym: Cells into OrgansProject number: LSHM-CT-2003-504468EC contribution: €7 200 000 Instrument: Network of ExcellenceDuration: 60 monthsStarting date: 01/04/2004


SummaryCoordination and Consolidation of European Biogerontology will

represent a step forward en route towards the formation of a

European College of Biogerontology. LINK-AGE will be a

Coordination Action building upon, and very significantly extending,

existing European research in this field. Such research is still

fragmented, limiting the ability to progress in an area of great economic

and social importance for the future of Europe.

LINK-AGE will provide an open, transparent mechanism to integrate

research by addressing the following core objectives:

1) To identify common research strategies that will generate critical

mass and added-value from European biogerontology research.

2) To establish a process that will help bring new researchers into the

field from new geographical regions within the wider European

community.

3) To establish a process that will bring new researchers into the field

from other research areas within life sciences and health of

relevance to ageing and longevity.

4) To establish a framework that will allow effective integration of

research on different species to maximise the opportunities for

synergy and interaction between researchers working on such species.

To meet these objectives, LINK-AGE will support a closely

coordinated programme of topic working groups, workshops and

conferences, summer schools, and dissemination activities.Through

its dissemination activities, it will develop effective links with the wider

public and industry, in order that translation into benefit of emerging

knowledge of the underpinning science of healthy ageing can be

exploited as rapidly as possible.

ProblemEurope faces the immense challenge of unprecedented increase inlife expectancy, which will continue into the 21st century.Althoughthis state of affairs is the essentially positive outcome from multipleimprovements in health care and socioeconomic circumstances, itnevertheless presents great strains for all member and associatedstates of the European Union in terms of increasing prevalence ofage-related health problems and the growing financial implicationsfor pensions, etc.There is urgent need for more basic research on

the underpinning science of biological ageing, in order that it shallbe possible to minimise dependency and improve quality oflife for the rapidly growing numbers of older people.

Recent advances indicate that it is possible to intervene positively inthe mechanisms that cause age-related frailty, disability and disease,particularly by developing and exploiting the fields of genomics andbiotechnology for health in old age.These fundamental advances inscience and technology offer exciting opportunities to extend healthspan (period of good quality life and functional \independence) andto develop European industry addressing the challenges of age.

At present, European research capacity in biogerontology is stillfragmented although efforts have been made through theIntegrated Project programme of the European Union. This limitsability to make progress and results from several causes. First, thebiology of ageing is itself inherently complex,with targets for studyat many levels from molecules to cells to tissues to whole organisms,and in many different biomedical contexts (e.g. dementia,osteoporosis, visual impairment, declining immune function, etc).Second, in view of the practical advantages of working with short-lived model organisms, research is currently being conducted on awide range of species (fungi, invertebrates, rodents, other ma-mmals, birds) as well as humans.

Biogerontology intrinsically requires integration of research acrossdifferent biological levels, species, and biomedical contexts (e.g. it islikely that some of the same fundamental mechanisms are shared).Therefore there is need for a new coordination action that aims:

(i) to achieve stronger integration and effectiveness within the field;

(ii) to develop links between basic research and industry,particularlyto help stimulate the success of existing SME's or new SMEs;

(iii) to include and to support the participation of scientists acrossthe full geographical span within Europe, particularly includingscientists from candidate and associate states of the EU.

AimScientific coordination

The objectives of LINK-AGE in terms of scientific coordination are:

a) To identify and help implement common research strategies thatwill generate critical mass and added-value from Europeanbiogerontology research.

b) To establish a process that will help bring new researchers into thefield from new geographical regions within the wider Europeancommunity.

c) To establish a process that will bring new researchers into the fieldfrom other research areas within life sciences and health ofrelevance to ageing and longevity.

Coordination and consolidation of EuropeanBiogerontology: en route towards formation of a European College of Biogerontology

LINK-AGEHUMAN DEVELOPMENTAND AGEING





d) To establish a framework that will allow effective integration ofresearch on different species to maximise the opportunities forsynergy and interaction between researchers working on such species.

Technical coordination

The objectives of LINK-AGE in terms of technical coordination are:

a) To establish a category of associate membership of LINK-AGE forthose wishing to make connections with the field, but whose workdoes not yet meet the criteria for quality and relevance.

b) To use the membership structure to draw into the membership ofLINK-AGE researchers from diverse geographical regions withinEurope, particularly those previously disadvantaged in access toscientific research support.

c) To develop and support a series of LINK-AGE, conferences, andsummer courses to address the scientific objectives.

d) To establish an organizational framework for LINK-AGE to meetits scientific and technical objectives and to validate the conceptof a distributed network of excellence in biogerontology researchacross Europe.

Potential impact Research that can lead to novel intervention to extend the healthspan and improve quality of life at older age has the potential forenormous impact in an ever-ageing society. Furthermore, thegrowing anxiety and fiscal threat posed by increased pension costsis founded on biodemographic models of ageing that urgently needupdating by better informed knowledge of the ageing process andprojections for future life expectancy.The scientific impact of theproject will come from integrating the currently fragmented researchactivity within Europe.The diversity of European research traditionsis potentially a rich resource for a topic as multi-faceted asbiogerontology,but only if these diverse elements communicate witheach other and develop ways of working together.

It is only recently that researchers in other fields of biomedicalresearch related to middle and late life degenerative conditions (e.g.dementia, cancer, cutaneous biology) have begun to recognise thatsince age tends to be the single biggest risk factor for the conditionthey are studying, understanding why the aged cell or organ is morevulnerable to pathology is likely to enable major breakthroughs.LINK-AGE will impact on this hitherto under-recognised need byencouraging many more researchers to participate in coordinatedwork that connects the study of age-related conditions with theunderpinning mechanisms of ageing.

It is now clear that ageing itself is the result of progressive, lifelongaccumulation of a variety of molecular and cellular damage. Thisimplies that ageing is a process that operates cumulatively acrossthe life course and therefore events that happen at any age, even inutero, can have a major impact on an individual's expectation oflength of life and of health in old age.LINK-AGE will encourage moreresearchers to address the links between early and late-lifeprocesses.

CoordinatorDr.Toussaint, Olivier

FNRS Research Associate

University of Namur (FUNDP)

Research Unit on Cellular Biology (URBC)

Rue de Bruxelles, 61

B-5000 Namur, Belgium

Phone: + 32 81 724132

Fax: + 32 81 724135


http://www.fundp.ac.be/urbc

PartnersProf.TBL Kirkwood

University of Newcastle upon Tyne, U.K.

Prof. M. Blasco

Spanish National Cancer Centre, Spain

Dr. G. Butler-Browne

Université Pierre et Marie Curie, France

Dr. ES Gonos

National Hellenic Research Foundation, Greece

Prof. E. Slagboom

Leiden University Medical Center,The Netherlands

Prof. J.Vanfleteren

University of Gent, Belgium

Prof. R. Contreras

Flanders Interuniversity Institute for Biotechnology, Belgium

Prof.T. Nystrom

University of Göteborg, Sweden

Prof. CC Zouboulis

Charite Universitaetsmedizin, Germany

Prof. HD Osiewacz

Johann Wolfgang Goethe-Universität,Germany

Dr. M Salmon

Straticell Screening Technologies, Belgium

Prof. C. Franceschi

University of Bologna, Italy

Prof BFC Clark

University of Aarhus, Denmark

Acronym: LINK-AGEProject number: LSHM-CT-2005-513866EC contribution: €1 100 000 Instrument: Coordination ActionDuration: 48 monthsStarting date: 01/12/2005


SummaryDrug treatments which enhance bone formation are likely to be more

effective than antiresorptive treatments in the treatment of patients

with established osteoporosis.With this in mind, the present project

aims to advance understanding of the mechanisms responsible for bone

formation, with the long-term aim of harnessing this knowledge to

develop new anabolic agents for osteoporosis. We will define

downstream effectors of molecules that regulate bone formation in

experimental models and identify the signalling pathways that are

activated in human genetic diseases characterised by increased bone

formation. The mechanisms of action of drugs with known anabolic

effects will be investigated and novel genes that regulate bone formation

will be uncovered by ENU mutagenesis and genetic mapping studies.

The project will lead to a greater understanding of how bone formation

is regulated and will underpin the development of new therapeutic

strategies for the prevention and treatment of osteoporosis.

ProblemOsteoporosis represents a major disease burden in Europe and occursbecause there is relative uncoupling between the amount of boneremoved by osteoclastic bone resorption and that which is replacedby new bone formation. Most of the drugs that are used to treatosteoporosis act by inhibiting bone resorption and there is only onetreatment available (the 1-34 fragment of parathyroid hormone) thatworks by stimulating bone formation. Antiresorptive therapies arehighly effective agents for the prevention of osteoporosis, and alsoreduce the risk of fracture in patients with established osteoporosis.They work less well in patients with more advanced disease,however,because they are incapable of replacing bone tissue that has been lostas the result of the osteoporosis.

AimThe aim of the project is to gain better understanding of themechanisms by which bone formation is regulated with the aim ofidentifying new molecular targets that will form the focus for newtherapeutic strategies for the management of osteoporosis.This willbe achieved by investigating the transcriptional regulation of key targetgenes that play a role in regulating bone formation; by defining theeffector molecules that are transcriptionally regulated by drugs andendogenous signaling factors that stimulate osteoblast activity and bydefining the signalling pathways that are activated in human geneticdiseases characterised by increased bone formation.Novel genes thatregulate bone formation will be identified by positional cloning studiesin experimental models which show a bone phenotype as the resultof ENU mutagenesis.

Expected results 1. Better understanding of the mechanisms by which genes that

promote bone formation are regulated at a transcriptional level.

2. Identification of a common set of target genes that are regulatedby potentially anabolic drugs and endogenous factors that promotebone formation.

3. Generation of experimental models that will provide proof ofconcept that genetic manipulation of putative anabolic moleculescan promote bone formation in vivo.

4. Identification of novel genes that regulate bone formation byclassical positional cloning studies.

Potential applications The molecules and target genes that are identified by this project willrepresent a new generation of molecular targets that can potentiallyact as anabolic drugs themselves, or can act as targets for the designof new drugs that enhance bone formation.The project will thereforebe of value in helping to develop new treatments for osteoporosiswith associated benefits for citizens who suffer from this disablingdisease, in the European Community and beyond. It is also anticipatedthat new intellectual property will be developed during the projectwhich could have positive implications for generating income for thehigher educational institutions and commercial companies that aretaking part in this project.

Molecular Mechanisms of Bone Formation and Anabolism

ANABONOSHUMAN DEVELOPMENTAND AGEING





CoordinatorProf. Stuart, H Ralston MR FRCP FmedSci

ARC Professor of Rheumatology

Rheumatic Diseases Unit


Western General Hospital

Edinburgh EH2 2XU, United Kingdom

Phone: +44 131 537 1088

Fax: +44 7714 266 616


Project web-site: http://www.abdn.ac.uk/anabonos

Key words: osteoporosis, bone formation, anabolic,parathyroid hormone, osteoblast

PartnersDr van Hul,Wim


University of Antwerp

Antwerp, Belgium

Dr Charnay, P

INSERM U368

Ecole Normale Superieure

Paris, France

Prof. de Vernejoul, Marie-Christine

INSERM U606

Hôpital Lariboisièré

Centre Viggo Petersen

Paris, France

Dr Levi, Giovanni

CNRS UMR5166 - MNHN

Evolution des Régulations Endocriniennes

Paris, France

Dr Löwik, Clemens

Department of Endocrinology C4R



Dr Garcia,Teresa

Proskelia Pharmaceuticals

Romainville

Paris, France

Dr Grigoriadis,Agi

Department of Craniofacial Development

Kings College London

Guy’s Hospital


Dr Gannon, Frank

EMBL Heidelberg

Heidelberg, Germany

Dr Wagner, Erwin

Research Institute of Molecular Pathology IMP

Vienna,Austria

Dr Sedlmeier, Reinhard

Ingenium Pharmaceuticals AG

Martinsried, Germany

Dr Ferrari, Serge

Geneva University Hospital

Geneva, Switzerland

Dr Mundlos, Stefan

Research Group Development & Disease

Max Planck Institute for Molecular Genetics

Berlin, Germany

Dr Hrabé de Angelis, Martin

GSF National Research Centre

Munich, Germany

Acronym: ANABONOSProject number: LSHM-CT-2003-503020EC contribution: €3 000 000 Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/03/2004


SummaryOsteoporosis (OP) is a metabolic bone disease characterised by loss

of bone mass and disturbed bone microarchitecture compromising

bone strength and thereby pre-disposing for fractures.OP is a major

health problem and of increasing concern in the European

Community.The disease shows a strong gender bias in which genetic

predisposition is important and a major predictor of our ability to

reach and sustain optimal bone mass.The current project is focused

on improving the understanding of the molecular mechanisms

involved in bone homeostasis, and a main emphasis will be on the

anabolic aspects. New knowledge is sought using contemporary

array technology and functional genomics building on the recently

definition of the human genome.A major target will be identification

of the mRNAs and proteins that exercise a central role in the

building (anabolic) phases of bone metabolism, including but not

limited to those regulated by parathyroid hormone. Selective

stimulation of anabolic effectors will, it is argued, form the basis for

new treatment modalities that will increase new and fully-functional

bone formation. This approach contrasts

with many contemporary regimes of

treatment that primarily inhibit bone

resorption, thus increasing the amount of

more or less worn tissue.A special attempt

will be made to identify genetic markers

that can be used for early identification of

people at risk for later development of

osteoporosis.

ProblemBone is a dynamic tissue that is continuallyremodelling throughout life. In all ageingpeople this profit and loss process favoursloss of bone mass. Consequently, many de-velop osteoporosis with considerablyenhanced susceptibility to fractures with upto 30% mortality and massive, lastingmorbidity. In fact, OP represents the mostprevalent and incapacitating disease ofwomen after 50 years of age and theincreased incidence of the disease alsoamong men has made it a serious threat tohealthy ageing of both genders in Europe.

Primary OP is a disease of unknown aetiology that is usually dividedinto postmenopausal and age-related OP although there are unifyingfeatures.The broad argument is that the dynamic processes of boneremodelling that comprise bone homeostasis have somehow failed.The conventional view is that the balance of production of bone bymeans of osteoblasts cannot compensate for bone resorption due tothe activities of osteoclasts. These overall facts are clear andparathyroid hormone (PTH) has been recognised as not only apotential catabolic influence but also therapeutically available as ananabolic influence.

The molecular composition of the bone extracellular matrix in OPis considered largely unaltered,but surprisingly little attention has beenpaid to this aspect.

AimThe driving force for this project is that the molecular mechanismscausing or leading to OP are not sufficiently known to createsubstantial evidence-based knowledge for early diagnosis, preventionor causal treatment of the disease.Thus a main aim of the project isto combine genomic data (sequence and microarray expression data)with functional genome research and proteomics directed atidentifying anabolic target genes in the skeleton. In this way theOSTEOGENE initiative seeks to provide a link between gene function

Molecular mechanisms of bone homeostasis

OSTEOGENEHUMAN DEVELOPMENTAND AGEING





and disease as a frame-work for stimulating biomedical commercialactivities in the areas of early diagnosis, prevention and treatment ofOP. The project will be undertaken by a multidisciplinary teamincluding medical practitioners, molecular and cellular biologists andbiochemists, all with an inter-national track record.

The long-term aim will be a reduction in the impact of OP in Europebrought about by application of appropriate evidence-based thera-peutic and preventive medicine.

Expected resultsThe results of this project will substantially add to the existingknowledge base regarding:

1. association between genetic polymorphism and development of OPin humans;

2. possible identification of OP disease genes through genetic andpost-genomic studies in man and animals;

3. improvement of basic insight into osteoblast and osteoclastregulation and their matrix interactions, and intra-/intercellularmolecular signalling as it relates to bone remodelling;

4. the chemical nature and significance of bone matrix proteins andtheir molecular interaction in the bone remodelling process;

5. the bone remodelling process and its regulation by key anaboliceffectors including PTH;

6. genes and gene products that are associated with or causally linkedto bone formation.

Potential applications The project describes how to obtain for the first time an overviewof OP-associated and -related genes and gene products defininga risk profile or genetic susceptibility. This strategy will form thebasis for developing a diagnostic genetic test for the earlydetection of OP carried out on the mRNA or protein level.Theprojected objectives and deliverables represent majorcontributions to the medical diagnosis, care and treatment of OPcompared to the present state-of-the-art where OP is under-diagnosed and detected late in the disease, frequently not until thefirst fracture. An expected outcome after compiling, analyses andverification of the data, is the capacity to move towardsdevelopment of a genetic test for the early diagnosis or detectionof patients at risk for developing osteoporosis. The novelknowledge generated in these studies will found the basis of newtreatment modalities aiming at increasing bone formation ratherthan reducing bone resorption.

Coordinator Prof. Gautvik, Kaare M

Department of Clinical Biochemistry,

Division of Laboratory Medicine

Ullevål University Hospital

Kirkeveien 166

0407 Oslo, Norway

Phone: + 47 957 42 125

Fax: + 47 22118189


Project web-site: Not yet operative

Key words: osteoporosis, gene profiling, bone anaboliceffectors, genetic polymorphism

PartnersInstitute of Pathology, University of Oslo, RikshospitaletUniversity Hospital, Norway

Endocrine Section, Department of Medicine,Rikshospitalet University Hospital, Norway

Department of Cell and Molecular Biology, Section forConnective Tissue Biology, Biomedical Centre, LundUniversity, Sweden

Division of Bone Disease, University Hospital, Geneva,Switzerland

School of Clinical Laboratory Sciences, University ofNewcastle,The Medical School, United Kingdom

Department of Experimental Medicine, School ofMedicine, Bone Biopathology Laboratory, L’Aquila, Italy

Immunodiagnostic System, Boldon, United Kingdom

Acronym: OSTEOGENEProject number: LSHM-CT-2003-502941EC contribution: €2 000 000 Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/01/2004


SummaryAGEACTION aims to structure a process to: (i) develop a stronger

sense of common purpose to deliver the knowledge base that will

extend health, reduce dependency, and improve quality of life for

Europe’s older people; (ii) identify the links between biological ageing

research and the underpinning mechanisms of a very wide range of

medical conditions (disability, frailty, disease) for which age is the single

biggest risk factor; (iii) identify links between biological ageing research

and social factors such as nutrition,education,lifestyle,housing,transport

and culture that will help to exploit synergies that can lead to extended

health, reduced dependency, and improved quality of life for older

people; (iv) stimulate new interactions between biological ageing

research and technological innovation that can lead to extended health,

reduced dependency, and improved quality of life for older people; (v)

stimulate closer engagement between biological ageing research and

industry across a range of activities leading to creation of new business

opportunities,particularly the formation of SMEs to exploit and develop

Europe’s growing research capability in biological ageing research; (vi)

create closer interactions between biological ageing research and those

involved in financial planning in order to take better account of new

insights into factors that affect life expectancy, health expectancy, and

projected financial needs (including health and social support) for older

people; (vii) provide for Europe’s older people (and younger people –

the future old) opportunities for greater awareness and more accurate

reporting of advances in biological understanding of the ageing process

that can lead to informed decision-making and empowerment to

maximise opportunities for healthy old age; (viii) give Europe’s policy-

makers a clearer understanding of the nature of the ageing process and

of the potential arising from the above activities.

ProblemEurope faces the immense challenge of unprecedented increase inlife expectancy, which will continue into the 21st century.Althoughthis state of affairs is the essentially positive outcome from multipleimprovements in health care and socioeconomic circumstances, itnevertheless presents great strains for all member and associatedstates of the European Union in terms of increasing prevalence ofage-related health problems and the growing financial implicationsfor pensions, etc. It is widely recognised that in order to meet thischallenge there needs to be multidisciplinary coordination ofresearch and development effort. However, to date there has been

little effective linkage between other areas of activity (social,medical,economic, engineering) and biological ageing research, which aimsto understand the nature of the ageing process itself – what causesageing, what can modify it, what underlies the continuing increasesin life expectancy and declines in mortality of the oldest-old acrossEurope, and how biological ageing interacts with other factors thatinfluence the lives of older people. This lack of interaction hasresulted in a failure so far to exploit important linkages and to makethe most of the enormous opportunities which exist to harness thegrowing understanding of the biological nature of the ageing processto help improve the health (understood in the WHO sense ofcomplete mental, physical, and social well-being) and quality of lifeof Europe’s older people.The reasons for the present situation areeasily understood. First, biological ageing research is relatively newand is itself still fragmented. Second, recent advances in biologicalageing research have overturned many of the traditionalconceptions about ageing, but awareness of this has yet to influenceother spheres of activity.Third,no suitable action has yet taken placeto bring together the various groups that need to engage with thedifficult but essential task of building the necessary bridges betweenbiological ageing research and other domains.

AimThe main aim of the AGEACTION SSA is to structure a processculminating in a high-level conference that will provide a uniqueopportunity to realise the potential of biological ageing research inEurope, in the two senses of coming to awareness, and makingsomething happen or real.Specifically,AGEACTION has the followingobjectives:

1.To set in motion a process that will enable biological ageingresearchers to develop a stronger sense of common purpose andshared potential to deliver the knowledge base that will extendhealth, reduce dependency, and improve quality of life for Europe’solder people.

2.To set in motion a process that will identify the links betweenbiological ageing research and the underpinning mechanisms of avery wide range of medical conditions (disability, frailty,disease) forwhich age is the single biggest risk factor.

3.To set in motion a process that will identify links between biologicalageing research and social factors such as nutrition, education,lifestyle, housing, transport and culture that will help to exploitsynergies that can lead to extended health, reduced dependency,and improved quality of life for older people.

4.To stimulate new interactions between biological ageing researchand technological innovation, including information technology,nanotechnology and assistive technologies across a wide range thatcan lead to extended health, reduced dependency, and improvedquality of life for older people.

Realising the potential of biological ageing research

AGEACTIONHUMAN DEVELOPMENTAND AGEING





5.To stimulate closer engagement between biological ageing researchand industry across a range of activity – including pharmaceuticals,nutraceuticals,diagnostics,nutrition,and lifestyle products – leadingto creation of new business opportunities and particularly theformation of SMEs to exploit and develop Europe’s growing researchcapability in biological ageing research.

6.To create closer interactions between biological ageing researchand those involved in financial planning (actuaries, insurancecompanies, pension providers, etc) in order to take better accountof new insights into factors that affect life expectancy, healthexpectancy,and projected financial needs (including health and socialsupport) for older people.

7.To provide for Europe’s older people (and younger people – thefuture old) opportunities for greater awareness and more accuratereporting of advances in biological understanding of the ageingprocess that can lead to informed decision-making andempowerment to maximise opportunities for healthy old age.

8.To provide for Europe’s policy-makers a clearer understanding ofthe nature of the ageing process and of the potential arising fromthese activities.

Expected resultsThe main result will be the organisation of a high-level conferenceaddressing the aims of the project.

To achieve this result a number of enabling results will be required,including:

(i) the establishment of relevant sector panels to define the agenda;

(ii) the identification of venue, dates and participant lists;

(iii) the preparation of background and supporting materials;

(iv) the organisation of appropriate dissemination activities;

(v) and the establishment and operation of procedures to maximiseeffective follow-through of the conference outputs.

Potential applicationsThe project has a wide range of potential applications which aredirectly related to its aims.

Coordinator Prof. Kirkwood,Thomas B L

University of Newcastle upon Tyne

Henry Wellcome Laboratory for Biogerontology

Institute for Ageing and Health

Newcastle upon Tyne NE4 6BE, United Kingdom

Phone: +44 191 256 3319

Fax: +44 191 256 3445


Project web-site: To be developed

Key words: ageing, longevity, health, age-related diseases,quality of life, interdisciplinary research,technology, genetics, nutrition.

Acronym: AGEACTIONProject number: LSHM-CT-2005-512053EC contribution: €170 000 Instrument: Specific Support ActionDuration: 24 monthsStarting date: 01/11/2005



• INTACT 162• BIOCARE 164• Angiotargeting 166• PRIMA 168• Active p53 170• EMIL 173• TRANSFOG 176• FIRST 179• CANCERDEGRADOME 182• STROMA 185• Mutp53 187• MOL CANCER MED 191• EUROXY 194• MAESTRO 195• CCPRB 196• eTUMOUR 198• TRANSBIG 200• European LeukaemiaNet 202• DNA METHYLATION 206• European MCL Network 209• BRECOSM 212• MetaBre 214• ENACT 217• PROTHETS 219• P-MARK 221• EUSTIR 223• EUROCAN +PLUS 225

Cancer


1st Call:

FP6-2004-LIFESCIHEALTH

LSH-2002-2.2.0-1 Translating basicknowledge of functional oncogenomicsinto cancer diagnoses and treatment

- INTACT 162

- Active p53 170

- TRANSFOG 176

LSH-2002-2.2.0-2 Multidisciplinaryresearch to explore and validatemolecular targets for innovativetreatment

- Angiotargeting 166

- PRIMA 168

- CANCERDEGRADOME 182

- STROMA 185

- Mutp53 187

- MOL CANCER MED 191

- EUROXY 194

LSH-2002-2.2.0-3 Networking fortreatment and/or prevention clinicaltrials (phase I and II) aimed at improvingclinical practice in the light of newmolecular knowledge

- TRANSBIG 200

- European LeukaemiaNet 202

LSH-2002-2.2.0-4 Innovative research inradiation therapy

- FIRST 179

- MAESTRO 195

LSH-2002-2.2.0-5 Molecular imaging forearly detection of tumours andmonitoring of treatment

- EMIL 173

- eTUMOUR 198

- BIOCARE 164


CANCER Introduction


LSH-2002-2.2.0-6 Networking of qualitycontrolled cancer registries andrepositories for molecular epidemiologyand quality assessment

- CCPRB 196

LSH-2002-2.2.0-7 Molecular mechanismsinvolved in organ-specific metastaticgrowth processes in breast cancer

- BRECOSM 212

- MetaBre 214

LSH-2002-2.2.0-8 Translational researchon promising predictive and prognosticmarkers

- DNA METHYLATION 206

- European MCL Network 209

- ENACT 217

- PROTHETS 219

- P-MARK 221

LSH-2002-2.2.0-9 Molecular mechanismsof cancer-related pain

LSH-2002-2.2.0-10 Workshop oncorrelative laboratory studies relevant totherapeutic clinical studies

3rd Call:

FP6-2004-LIFESCIHEALTH-4

LSH-2004-2.2.0-9: Feasibility Study forthe coordination of national Cancerresearch activities.

- EUSTIR 223

- EUROCAN +PLUS 225


CANCER


SummaryDespite intensive worldwide research efforts, cancer remains a

devastating,often poorly treatable disease.We propose to develop and

apply new functional genomics technologies that will provide unique

approaches to the design of new pathway-specific cancer therapies.Our

specific objectives are:

1. to develop large-scale functional genomic analysis to identify novel

mechanisms involved in cancer development; specifically, we will

generate the tools and technologies to carry out genome-wide loss-

of-function screens in mammalian cells.

2. to apply these technologies to specific models of major human cancer-

causing pathways to define novel targets for therapy.

3. to use existing and generate novel mouse models and non-invasive

tumour imaging to validate and assay cancer gene function in vivo and

to develop new treatment modalities.

4. to develop cell-based assays for cancer-relevant genes and pathways

that will serve as readout for the identification of anticancer agents

through the screening of chemical compound libraries.

5. to distribute and disseminate the novel technologies for the study of

gene function in vitro and in vivo within the consortium and to

researchers in the European Community.

To reach these objectives we have formed a multidisciplinary

research consortium, including top scientists with extensive

experience in developing innovative genomics technologies and

with an excellent track record in identifying key signaling molecules

involved in cancer, as well as SMEs with experience in identifying

cancer-relevant genes and in screening chemical compound

libraries.The location of most of the partners at leading European

cancer centres will ensure optimal conditions for the development

of novel cancer-specific treatments.

Scientific and technological objectives 1. Use large-scale functional genomics, in particular genome-wide loss-

of-function screens, to identify novel mechanisms, including noveloncogenes and tumour suppressor genes, involved in thedevelopment of human cancer.

2.To generate novel tools in the form of RNAi retroviral libraries(mouse and human), cell-based assays, mouse models and reagentsthat will be distributed on a non-profit cost-charge to academicresearchers in the European Community.

3.To develop novel technologies for target validation in mouse andto develop mouse models to validate the role of the identified genesin the development of cancer.

4.To develop cell-based assays for cancer-relevant genes that willserve as a starting point for the identification of anticancer agentsthrough the screening of chemical compound libraries.At the endof the four-year programme, collaboration with largepharmaceutical companies will lead to further refinement of lead-compounds and the possible introduction of novel anti-canceragents into clinical trials.

5.To develop novel technologies to study gene function in vitro andvivo, and to distribute these technologies within the consortiumand subsequently to researchers in the European Community.

Specific phases of the project 1. Establishment of the technology platforms:

a. development of bar-code screen for the human siRNA library

b. generation of mouse siRNA library

c. development of protocols for high-efficient reverse infection of primarycells

d. development of ERM-tag screen

e. development of lentivirus vectors and protocols for making transgenicmice.

Identification of novel targets for cancer therapy


CANCER INTACT

A. Schematic drawing of the pSUPER vector and the predicted stem-loopprecursor transcript that is processed by intracellular RNases to siRNA-like molecules. B. Schematic drawing of a gene-specific pSUPER insert,

consisting of two 59-mer oligonucleotides that contain a 19 nt gene-spe-cific insert, a loop sequence, followed by the reverse-complement of the

same 19 nt gene-specific insert and a termination signal (5xT).


2. Establishment of cellular models for performing ERM-tag and siRNAlibrary screens.

3. Determination of cancer relevance of identified genes throughassessment of their expression level in primary human tumors,characterisation of their biological function, and generation ofmouse models.

4. Development of cell-based assays for newly identified cancerrelevant genes for the use of screening of compound libraries.


CANCER

Stable siRNA expression vector contains a gene specific identifier.Expression vectors for siRNAs encode a short hairpin RNA molecule

(RNA hairpin) (Brummelkamp et al., 2002b).

Bar code screen. Schematic outline of bar code siRNA hybridisa-tion screen to identify genes that increase cellular fitness after

stress or decrease cellular fitness after stress.

Coordinator Prof. Helin, KristianBiotech Research & Innovation Centre (BRIC)Fruebjergvej 32100 Copenhagen, Denmark Phone: + 45 39 17 96 66 Fax: + 45 39 17 96 69 E-mail: [email protected] Project web-site: http://www.imt.uni-marburg.de/intact/Key words: RNAI Libraries, Oncogenes,Tumour suppres-sors, Signaling, Mouse models, Compound medical libraries.

PartnersProf. Pelicci, Pier Giuseppe,European Institute of Oncology,Milan, Italy Berns,Anton ,Cancer Institute,Amsterdam,The Netherlands Bernards, René,Cancer Institute,Amsterdam,The Netherlands Van Lohuizen, Maarten,Cancer Institute,Amsterdam,The Netherlands Blasco, Maria,Spanish National Cancer Center,Madrid, SpainSerrano, Manuel,Spanish National Cancer Center,Madrid, SpainBaccarini, Manuela,Vienna Biocenter,Vienna,Austria Schmitt, Clemens,Max-Delbrück-Center,Berlin, Germany Eilers, Martin,University of Marburg,Marburg, Germany Trumpp,Andreas,ISREC,Lausanne, Switzerland Auguet, Michel,ISREC, Lausanne Karen Vousden,Beatson, CR-UK, Glasgow, United Kingdom Dejean,Anne,Pasteur,Paris, France Morphochem,Munich, Germany Agendia,Amsterdam,The Netherlands

Acronym: INTACTProject number: LSHC-CT-2003-506803EC contribution: €8 200 000 Instrument: Network of ExcellenceDuration: 48 monthsStarting date: 01/01/2004


SummaryEarly tumour detection and response monitoring require maximum

sensitivity and specificity of the imaging method. During the 1970s

and early 1980s,Computed Tomography (CT) with diagnostic X-rays

made a revolution in accurate delineation of normal tissue anatomy

as well as gross tumour growth. In the mid 1980s and 1990s,magnetic

resonance imaging and spectroscopy allowed even more accurate

differential diagnostics of soft tissue malignancies with the possibility

of distinguishing between tumour tissues,oedema and normal tissues.

The integration of positron emission and X-Ray computed

tomography in one unit is bringing another diagnostic revolution to

tumour imaging. By combining these two imaging modalities, an

unprecedented accuracy in the delineation of the tumour on a

background of normal tissue anatomy is achieved.

Although significant progress in cancer cure rates have been achieved

in the past,approximately 45% of patients still succumb to their disease

due to local (~25%) and/or distant (20–25%) tumour recurrence.Early

detection of small tumour deposits may allow successful treatment.

Moreover, lack of individualised tumour characteristics leads to

erroneous over - and under-treatment and precludes individualised

therapy selection. Molecular tumour imaging is an active area of

development and may provide a non-invasive tool to tackle some of

these problems as it has benefited substantially from the recent

development of our knowledge about molecular genomics and

proteomics pathways.The development is very rapid and many new

approaches are likely to be developed in the coming years.

The most commonly used radiotracer used; fluorodeoxyglucose

(FDG), is not tumour-specific, as all regions with an increased

metabolic rate will show an elevated glucose uptake. More specific

tumour markers allowing an even more accurate imaging of the

tumour clonogen density are therefore of importance as they may

image e.g. perfusion, hypoxia, amino acid and receptor status.

Methionine and other amino acids are already available as tracers

and, although they may be better than FDG, they may still not be

sufficiently specific, since they are incorporated in all tissues that

are being renewed. For some tumours, there are more specific

markers such as 11C-Choline, and FHBC or FDHT (Fluorodihydro-

testosterone) for imaging androgen receptors in prostate cancer.

Vasculature could be visualised by known tracers such as ammonia

( 11CH3) or water (H215O).

Project objective BioCare is focused on developing new techniques and approaches toincrease the sensitivity and specificity of existing tumour imagingtechniques as well as introducing more systematic and adaptiveapproaches based on high-quality tumour imaging.The objective ofthe project is to:

• improve and speed up the implementation of PET-CT imaging incancer management

• develop new European intellectual property to improve tumourimaging by more specific tumour tracers. They will result inconsiderably increased resolution, sensitivity and specificity intumour detection.

BioCare is subdivided into four major activities addressed throughnine work packages.The areas are namely: PET camera development,development of new tracers, experimental and clinical validation andimplementation of the techniques above in medical oncology.

Work package 1

Design of detectors for whole body PET systems with a high intrinsicresolution. Investigation of the possibility of integrating a PET-CTdevice with a radiation therapy unit with an ergonomic design bothfor patients and personnel to simulate imaging of the tumour responseand responsiveness as well as dose delivery in vivo.

Work package 2

Methods for real-time monitoring of the apoptotic response to radiotherapy and to predict early responses during the course of therapyfor optimising therapy planning and making prognostic evaluations.

Work package 3

To promote understanding of the complex processes induced bycancer therapy,especially radiation therapy, through a comprehensiveevaluation of established (e.g. FDG, FLT) and new tracers for therapyresponse assessment in human tumour models.

Work package 4

Development of radiolabelled aptamers, small tailor-madeoligonucleotides aimed at tumour-specific target structures forindividually optimised cancer treatment.

Work package 5

Development of molecular imaging methods that can vissualize andquantify temporal and spatial changes in hypoxia in human tumours.

Work package 6

To investigate the use of state-of-the-art Positron EmissionTomography with Molecular Imaging and X-Ray CT-based anatomicalimaging to monitor the radio- and chemotherapy of cancer and totrace the early response of the tumour of interest by quantifying thesensitivity of the tumour in three dimensions in vivo.

Molecular imaging for biologically optimised cancer therapy


CANCER BIOCARE


Work packages 7 & 9

PET-CT-SIM molecular tumour imaging and treatment simulation withconformal RT to make the concept of a ‘biological target volume’reality leading to biologically optimised molecular tumour imaging andradiation treatment planning.

Work package 8

To examine molecular targets involved in tumour angiogenesis usinganti--angiogenetic probes and to investigate the value of function-related indices of response (e.g. blood volume, flow, permeability,metabolism, etc.) to non--invasively monitor the effects of therapy.


CANCER

Coordinator Prof. Brahme,Anders

Department of Medical Radiation Physics


171 77 Stockholm, Sweden

Phone: + 46 8 517 724 96


Key words: Tumour imaging, PET, PET-CT, MRSI, Optictumour imaging,Tumour response monitoring.

PartnersDresden University of Technology, Germany

The Victoria University of Manchester; United Kingdom

Forschungszentrum Rossendorf e.V., Germany

University of Maastricht, The Netherlands

Katholieke Stichting UMC St. Radboud,The Netherlands

Aarhus University Hospital, Denmark

Institut Gustave-Roussy, France

Universität Hamburg, Germany

Université Catholique de Louvain, Belgium

Universitair Ziekenhuis Gasthuisberg, Belgium

The Netherlands Cancer Institute,The Netherlands

Soltan Institute for Nuclear Studies, Poland

University of Turku, Finland

PencilBeam Technologies AB, Sweden

PEVIVA AB, Sweden

RayClinic AB, Sweden

European Society for Therapeutic Radiology and Oncology, Belgium

European Organization for Nuclear Research,Switzerland

RayTherapy Imaging AB, Sweden

RaySearch MedicalAB, Sweden

Acronym: BIOCAREProject number: LSHC-CT-2004-505785EC contribution: €6 000 000Instrument: Integrated ProjectDuration: 54 monthsStarting date: 01/03/04


SummarySolid tumour growth depends on a continuous supply of nutrients by

new blood vessels that grow into the tumour. This process, termed

‘tumour angiogenesis’, is regulated by a number of complex factors

involving both tumour and host cells. How the tumours communicate

with the normal cells to produce blood vessels has during the last years

gained increasing attention and it has recently been shown that targeting

the host vasculature has a therapeutic potential for certain tumours.

The Integrated Project Angiotargeting focuses on the identification of

novel genes and gene products that regulate tumour angiogenesis and

on validating such products as therapeutic targets. In addition, novel

therapeutic strategies will be evaluated in preclinical models as well as

in the clinic.Angiotargeting will therefore open new avenues in the search

for new therapeutic compounds towards malignant disease.

Angiotargeting focus on the identification and validation of novel

therapeutic targets on tumour blood vessels. Such targets will be used

in the development of novel therapeutic strategies towards tumour blood

vessels growth.

The concept of treating genetically stable vascular cells, rather than

drifting tumour cells, has gained increasing acceptance in the scientific

community. It is essential that European research centres co-ordinate

their research efforts within this promising area of science and that

innovations within the field of angiogenesis are supported at European

level.The Angiotargeting consortium is contributing particularly to the

knowledge base for the development of the European biotechnology

industry within the field of angiogenesis.

Angiotargeting represents an added value on a range of aspects related

to integration of research in Europe by combining some of the most

qualified research groups and establishing a European-based strategy for

treatment of cancer targeting the tumour vascular supply.

Angiotargeting combines front-line knowledge of basic and clinical

research involving global gene and protein analyses, stem cell research,

physiological mechanisms, advanced animal model systems, molecular

imaging and clinical research. The consortium exploits the research

expertise accumulated at six European universities,six European research

institutions and two biotechnology companies with a common goal of

finding new therapeutic targets,that cannot be achieved at national level.

Scientific objectives 1.To co-ordinate multidisciplinary research and basic knowledge

within the field of tumour cell matrix interactions, to provide thebasis for novel therapeutic strategies against tumour progression.

2.To get a comprehensive understanding of how tumours generatevascular supply by using advanced genetic model systems.

3.To forward new technological approaches, including highthroughput screening technologies within the field of tumour cell-matrix interactions,to define and validate key molecular targets thatcontrol tumour angiogenesis.

4.To assess and validate strategies that disrupt and abrogate tumourangiogenesis and invasion.This includes the validation of novel aswell as described potential therapeutic targets towards the tumourvascular and invasive transcriptome and proteome.

5.To establish comprehensive bioinformatics tools for the analysis ofhigh throughput gene and protein data, from defined cell populationswithin tumours, with the aim of validating targets by assessingtherapeutic efficacy in preclinical as well as clinical models.

6.To implement state of the art platforms for preclinical and clinicalassessment of newly developed compounds.

Multidisciplinary research to explore and validate molecular targets for innovative treatments


CANCER Angiotargeting



CANCER

Acronym: AngiotargetingProject number: LSHC-CT-2004-504743EC contribution: €6 000 000Instrument: Integrated ProjectDuration: 48 monthsStarting date: 01/11/2004

Coordinator Prof. Bjerkvig, Rolf

University of Bergen

Muséplass 1

5020 Bergen, Norway

Phone: + 47 55 58 63 52

Fax: +47 55 58 63 60


Key words: Tumour Targetting,Angiogenesis

PartnersUniversity of Bergen, Norway

European Institute of Oncology, Milan, Italy

University of Uppsala, Sweden

Netherlands Cancer Institute,The Netherlands

Xantos Biomedicine AG, Germany

Maastricht University,The Netherlands

University of Oxford, United Kingdom

Vrije Universiteit Medical Centre, Amsterdam,The Netherlands

University of Oulu, Finland

Institute of Experimental Medicine, Academy of Sciencesof the Czech Republic

Centre Recherche de Public Santé, Luxembourg

The Karolinska Institute, Sweden


SummaryProstate cancer is one of the most common malignancies in the

western male population. In Europe, approximately 40 000 men die

of prostate cancer each year and that number is likely to increase,

due to the ageing population,to roughly 60 000 men in 2020.Therefore

prostate cancer is a significant medical problem with which the

European Community will be confronted increasingly in the oncoming

decades. For localised prostate cancer, radical therapies aiming at

eradicating all malignant processes in the prostate gland are available

that can cure the patient.However, if the malignant process has locally

or distantly spread, no curative medical intervention is currently

available. Since the early 1940s androgen ablation therapy has been

the mainstay in an attempt to control prostate neoplasms, but

unfortunately this is only of a palliative nature and tumour progression

due to the expansive growth of cancer cells that are unresponsive to

currently available hormone therapies is inevitable. Furthermore,

prostate cancer cells have a strong tendency to spread to the bone,

a site where metastases cause great morbidity, ultimately leading to

a painful death.

Research plan In the PRIMA project a multidisciplinary effort is proposed toexplore the pathways that lead to the most lethal aspect of prostatecancer, i.e., hormone-therapy-unresponsive bone metastaticlesions. It has become clear that in the majority of advancedprostate cancers the androgen receptor signalling pathway is activeeven in the absence of androgens. European research teams witha leading role in androgen receptor research will integrate theirefforts to exploit androgen receptor mediated signaling as atherapeutic target. This should be achieved by: 1) targeting theandrogen receptor itself; 2) interfering with androgen receptoractivation by non-steroids;3) studying non-transcriptional functionsof the androgen receptor; 4) targeting essential androgen receptorco-factors over-expressed in prostate cancer; and 5) inhibiting thoseandrogen receptor target genes which regulate prostate cancer cellgrowth, survival and differentiation.The androgen receptor teamswill join forces with European investigators that study theinteraction between prostate cancer cells and the bone micro-environment. Expression profiling of members of the TGF-‚ superfamily and signal transduction molecules in cell lines, animal modelsand clinical specimens should provide more insight in the role ofthese molecules in the development of bone metastatic lesions.Furthermore,epithelium-mesenchymal transition will be extensivelystudied. The exploration of the pathways leading to hormone-

therapy-unresponsive bone metastatic disease will use functionalgenomics and expression profiling as technology platforms.Thesetechnology platforms will also be used to identify novel candidatetargets for treatment. A specific bioinformatics platform will bedeveloped to analyse all collected data. In the targeted discoveryphase, a great number of candidate target genes will be identifiedthat, in addition to already available targets from earlier co-llaborative programmes, need to be phenotypically and/orfunctionally validated. Phenotypical validation will be performed inarchival material of patients with a well documented follow-up, inall stages of the disease process. In addition, high-throughputfunctional, cell-based analysis and molecular target validation willbe performed by knocking down genes that are over-expressed inhormone refractory or metastatic prostate cancers using RNAinterference.The knowledge obtained from the targeted discoveryphase and validation phase will be used to establish assays whichwill in turn be used for high throughput screening of low molecularweight compounds (i.e., more than 25 000 compounds).The assayswill use easy-to-upscale formats and reporters that can be easilyread out.

The final phase of the project will be the testing of interestingcompounds for their ability to efficiently interfere with cancer cellproliferation and/or survival in a bone environment in the absenceof androgens.The lead compounds will be tested for their efficacyin models for bone metastatic prostate cancer. Hence translationof the obtained knowledge into therapeutic strategies is anintegrated part of the project.

ConsortiumThe PRIMA consortium is organised in a kind of matrix structure,in which the top European research laboratories in the field ofurological oncological research, particularly prostate cancer, havejoined forces with strong disciplinary teams in the field of molecularlife sciences. The experimental urology laboratories have theadvantage of covering the distance from the clinical need to theexperimental research approach and vice versa. Research plans areaimed at clinical questions, in the case of this project the treatmentof hormone unresponsive prostate cancer.The ‘clinical applicability’-driven research efforts of these typical experimental urologyresearch teams does not allow in-depth investment in platformtechnologies, such as genomics, transcriptomics and bio-informatics.Therefore, the efforts are integrated with expert European teamsin molecular endocrinology, bioinformatics, functional genomics,expression profiling and design and establishment of (screening)models. This has resulted in an integrated consortium aimed atsolving a major clinical issue, i.e., an effective treatment for prostatecancer.


CANCER PRIMA


Related projects Currently, two other FP6-projects dealing with prostate cancer arein contract negotiation phase for funding by the EC.The project P-MARK,a STREP,concentrates on the identification and developmentof new prognostic markers for prostate cancer, and GIANT, an IP,aims at the development of viral and non-viral vectors for thetargeted treatment of prostate cancer. The three consortia areclosely related and have many existing collaborations. In order toadequately inform scientists and urologists about the knowledgegenerated by the projects and to get as many clinicians as possibleinvolved in the projects, a team of six urologists and scientists isresponsible for external communication and representation of thethree consortia.This team includes the three coordinators as wellas people involved in at least two of the projects. Integrated effortswill be made to inform, educate and discuss the progress of theprojects with the European Urology community through theEuropean Association of Urology (EAU).


CANCER

Coordinator Prof. Schalken, J A

University Medical Centre St. Radboud

Dept. of Experimental Urology

PO Box 9101

6500 HB Nijmegen,The Netherlands

Phone: + 31 24 361 4146

Fax: + 31 24 354 1222


Project web-site: www.primaproject.org

Key words: Prostate Cancer,Androgen Receptor, BoneMetastasis

PartnersErasmus Medical Center Rotterdam,The Netherlands

Centre Eurpéen de Recherche en Biologie et Médecine,France

University of Sheffield, United Kingdom

Turun Yliopisto, Finland

Speciality Chemical Services Holding B.V.,The Netherlands

Medizin Universitaet Innsbruck,Austria

University of New Castle upon Tyne, United Kingdom

Forschungszentrum Karlsruhe GMBH, Germany

Universitaet Bern, Switzerland

University of York, United Kingdom

Centre de Recherche pour les pathologies prostatiques,France

Leiden University Medical Centre,The Netherlands

University of Tampere, Finand

Weizmann Institute of Science, Israel

The Chancellor , Master and Scholars of the University of Cambridge, United Kingdom

Acronym: PRIMAProject number: LSHC-CT-2004-504587EC contribution: €6 000 000Instrument: Integrated ProjectDuration: 60 monthsStarting date: 01/07/2004


SummaryThe prevention of human cancer development

depends on the integrity of a complex network of

defence mechanisms that help cells to respond to

various stress conditions. A key player in this

network is the p53 tumour suppressor protein. By

inducing efficient growth inhibition, p53 eliminates

cancer cells thereby preventing the development of

human malignancies.These functions of p53 often

determine the efficacy of anti-cancer therapies.

Although p53 is frequently mutated in some

cancers, in about 50% of all human cancers p53 is

non-mutated and could, in principle,be activated to

prevent tumour progression.This situation is prevalent among a wide

range of cancers, notably breast carcinoma. However, p53 activity is

hampered by malfunction of its many modulators, such as Mdm2 or

p73,which govern p53 tumour suppressive activity by acting upstream

and/or downstream of p53. There is therefore a crucial need to

understand how p53 modulators contribute to human malignancies.

Based on this information,we propose to develop rational therapeutic

approaches to manipulate p53 modulators, thereby wakening the

sleeping tumour suppression activities of p53, allowing it to eliminate

cancer cells.A carefully structured consortium comprises 19 academic

research centres and SMEs (see diagram). It will interactively build a

technology platform to comparatively identify,characterise and evaluate

the regulatory roles of p53 modulators and define the mechanisms of

their action. Large-scale gene functional analyses will be conducted to

identify relevant signalling pathways that impair or mediate tumour

suppression by p53. These analyses will include p53 activators and

inhibitors,p53 homologues p73/p63,and dissection of p53 target genes

mediating apoptosis and growth arrest. Our links with highly profiled

clinical partners and our access to large,well-characterised and clinically

documented sample collections will enable the evaluation of diagnostic

expression profiles, and their potential prognosis value in cancer.

Particular emphasis will be directed towards translating the

information on p53 regulation into the development of new anti-cancer

therapies. p53 regulatory proteins will be used for the identification of

new molecular targets for drug discovery.

ProblemCancer is the second leading cause of death in European countries,and one of the most imminent health problems in the developed world.The p53 protein is generally recognized as the key determinant oftumour suppression. It has been declared by the European Union that“a large co-operative effort is needed to ensure that every Europeancitizen will rapidly profit from the revolution of knowledge in cancermanagement” (Philippe Busquin). The presence of wild type p53 isparticularly prevalent in breast cancer, the type of cancer that standsat the centre of the European cancer policy.Since breast cancer affectsmostly (though not exclusively) women,breast cancer research is alsoan important task to implement the gender dimension into basicresearch. For these reasons, we will choose breast cancer as one ofour focuses in this block of work.Moreover,a non-mutated but inactivep53 is also found in a high percentage of the most frequent intracranialtumour of children, neuroblastoma. Since paediatric tumours areparticularly dramatic events for patients and their families, it appearsappropriate to put another focus on this tumour species.

AimThe principal aim of this proposal is to ease both diagnosis and prognosticclassification, as well as the efforts towards novel therapy regimens totreat patients suffering from breast cancer and neuroblastoma.Overall,the integrated action of our consortium is aiming at re-establishingtumour suppressor activity in cancer, thereby translating basic knowledgeof functional oncogenomics into cancer diagnoses and treatment, andcontributing to leadership in European health technology.

Outline of the consortium

Manipulating tumour suppression:a key to improve cancer treatment


CANCER Active p53


Expected resultsThe overall goals of this integrated effort are to understand:

1. which modulators determine the tumour-suppressive activities ofthe p53 family members

2. by what mechanisms these modulators affect the tumoursuppression activities

3. how the expression and activity of p53 modulators is regulated

4. whether p53 modulators affect the biological characteristics oftumour cells

5. whether the status of p53 modulators correlates with the clinicaloutcome and can be used to determine the individual prognosis

6. whether and how p53 modulators can be targeted by therapeuticstrategies, and be manipulated towards regaining tumoursuppression.

7. disseminate the knowledge that will be produced to practically allthe interested parties including medical doctors,and managerial staffin the industries

8. familiarise SMEs with scientific research work and state-of-the-arttechnology that will provide the necessary know-how for theimprovement of their services and competitiveness.

Potential applicationsThe ultimate general objective of this research proposal is to providea basis for the re-activation of tumour suppression and the design ofnovel therapeutic approaches to combat cancer. In particular, we areaiming at modulating p53 family activities to decrease resistance oftumour cells to anti-cancer treatments.Thus, the ultimate goal of thisresearch proposal is the identification of novel drug targets andstrategies for induction of p53-mediated apoptosis in therapy-resistantcancer cells.The participation of the SMEs is expected to play a keyrole to the practical application of the knowledge that will be produced.

The four blocks are linked as outlined.These links are formedaccording to the biological activities governing p53, and therefore,the scheme simultaneously depicts biological dependencies as wellas the mode of collaboration within the consortium.Activators ofp53 frequently act by antagonizing p53 inhibitors, and vice versa,this will be taken into account by networking accordingly betweenthe blocks 1 and 2.Activators and inhibitors of p53 may act on

p73 and p63 as well, and this was shown to be true in a numberof cases.Therefore, each regulator of p53 will be assessed regard-ing its impact on p53-homologues as well, by collaborative effortsbetween Block of work 3 with blocks 1 and 2. Finally, the assess-ment of p53 downstream activities, and the development of cut-

ting-edge technologies to analyze them, will be used throughout theconsortium.Therefore, Block of work 4 forms a basis not only toreach excellence on its own, but also to effectively advance the

progress of blocks 1, 2 and 3


CANCER

The members of our consortium have identified a number of p53-mod-ulators (stage 1), and in some cases, have begun to understand theirmechanisms of action.We are now pursuing an integrated strategy toadvance our knowledge on the nature of these modulators through

stages 2-5, and ultimately to evaluate their potential as candidate drugtargets (stage 6).We are starting from the scenario outlined below.


CANCER


Coordinator Dr Blandino, GiovanniDepartment of Experimental OncologyRegina Elena Cancer InstituteVia delle Messi D’Oro 156Rome, ItalyPhone: + 39 06 52662522Fax: + 39 06 52662505E-mail: [email protected] Project web-site:http://www.europeire.it/Activep53/intro.htmlKey words: tumour suppression, p53, p73, p63,

inhibitors, activators, technology

PartnersDr Dobbelstein, MatthiasCentre of Medical Biotechnology University of Southern Denmark Odense Denmark Dr Haupt,Ygal The Lautenberg Center for General and TumourImmunologyThe Hebrew University - Hadassah Medical School,Jeruslem, IsraelDr Kroemer, GuidoCentre National de la Recherche ScientifiqueLaboratoire de Génétique Oncologique – UMR8125 – Institut Gustave RoussyVillejuif, FranceDr Lu, XinLudwig Institut Fur KrebforschungTumour Suppressor GroupLudwig Institute For Cancer ResearchLondon, United KingdomDr Voudsen, KarenThe Beatson Institute For Cancer ResearchTumour Suppressor Laboratory,Glasgow, United KingdomDr Rotter,VardaWeizmann Institute of ScienceMolecular Cell Biology / BiologyRehovot, IsraelDr La Thangue, Nicholas BUniversity of GlasgowBiochemistry and Molecular BiologyInstitute of Biomedical and Life Sciences, Cathcart LabGlasgow, United KingdomDr Melino, GerryMedical Research Council Leicester, United Kingdom

Dr Bartèk, JiryDanish Cancer SocietyDept. of Cell Cycle and CancerInstitute of Cancer Biology Danish Cancer SocietyCopenhagen, DenmarkDr Levrero, MassimoFondazione Andrea CesalpinoLaboratory of Gene ExpressionRome, ItalyDr Jochemsen,Aart GerritDept. Molecular and Cell Biology,Tumour SuppressorGroupLeiden University Medical CenterLeiden,The NetherlandsDr Selivanova, GalinaKarolinska Institute Department of Laboratory Medicine, Stokholm, SwedenDr Del Sal, GianninoUniversità Degli Studi Di Trieste Dipartimento di BiochimicaBiofisica E Chimica Delle MacromolecoleTrieste, ItalyDr Iggo, RichardSwiss Institute for Experimental Cancer ResearchOncogene GroupDr Deppert,WolfgangHeinrich-Pette-Institut für Experimentelle Virologie undImmunolgie an der Universität HamburgDepartment of Tumour VirologyHamburg, GermanyDr Lane, DavidUniversity of DundeeDepartment of Surgery and Molecular OncologyNethergate, Dundee, United KingdomBiotecgen s.r.l.Department of Biological SciencesInstitute of PhysiologyLecce, ItalyDr Moarefi, Ismail SiREEN AGMartinsried, Germany

Acronym: Active p53Project number: LSHC-CT-2004-503576EC contribution: €6 000 000 Instrument: Integrated ProjectDuration: 60 monthsStarting date: 01/12/2004


SummaryThe general objective of the EMIL Network of Excellence is to merge

the leading European research teams in molecular imaging, in

universities, research centres and small and medium enterprises, to

focus on early diagnosis, prognosis and therapeutic evaluation of

cancer.

The EMIL network brings together 58 partners representing 43 bodies

in 13 European countries, and integrates six technological facilities:

Orsay (France), Turin (Italy), Cologne (Germany), Leiden

(Netherlands), Milan (Italy) and Antwerp (Belgium) around a

common activity programme including:

• integration activities: creation of a network of technological and

training facilities favouring the mobility of researchers and the

integration of small and medium sized enterprises into the EMIL

network

• dissemination of expertise activities: training, communication,

common knowledge management and intellectual property rights

• research activities:a common research programme with a horizontal

dimension, making use of methodological tools of physics, biology

and chemistry necessary for the further development of molecular

imaging (instrument techniques, molecular probes, biological

engineering), and a vertical integrative dimension, bringing together

cancer imaging applications (early diagnostic imaging, development

of new therapies, imaging for drug development).

ProblemCancer is characterised by an uncontrolled proliferation of cells thatescape the rules of the organism they originate from. For normalcells, these rules are both spatial (a cell’s location is defined by itsintegration in an organised tissue) and temporal (a cell obeys thelaws of controlled division and death corresponding to itsprogrammed life cycle). Cancer cells disobey the laws of time andspace, proliferate and invade.

The last two decades have witnessed enormous advances in ourunderstanding of cancer at molecular level and have demonstratedthat it results from abnormal gene expression in cell clones. Geneexpression analysis techniques are now witnessing systematiccompilation of molecular data that can be used to provide accuratediagnosis and prognosis.These techniques are well-established andwidely applied to in vitro biological samples, but they destroy the

sample during analysis and are not applicable to whole body andlongitudinal explorations. Hence they fail to recognise the essentialcharacter of cancer, development across time and space.

On the other hand, in vivo imaging is a repeatable and non-invasivelocalisation technology with the potential to become the preferredmeans for cancer diagnostics and follow-up. However, imaging isbased on evidencing a contrast between cancer and normal tissue,and this is quite challenging to perform in vivo in view of the factthat cancer cells are a clone of normal cells. Even though anatomicimaging can occur in vivo at sub-millimetre resolution, imagingtechniques based on gross physical differences such as density orwater content perform poorly in producing a contrast which mustbe based on specific imaging agents targeting tumour cells.

Molecular imaging is a new science bridging together molecularbiology and in vivo imaging with the aim to detect the expression ofspecific genes. Imaging science has made sufficient progress in thelast decade to bridge the gap between physiology and molecularbiology, and is now at the stage where it can perform molecularimaging of gene expression in vivo. Significant advances have occurredin molecular imaging modalities, including the nuclear medicinetechniques of SPECT and PET, MRI and spectroscopy which haveattained resolution sufficient for small animal imaging, and opticalimaging, which can now reach unprecedented sensitivities.

AimThe potential of molecular imaging is considerable.

• In fundamental research, it allows the visualisation of cell functionand molecular processes in living organisms, in particular themonitoring of the stages of growth and ageing, the response toenvironmental factors, the exploration of cell movements, etc.

• In experimental medicine it identifies the molecular determinantsof pathological processes in situ,evaluates new molecular therapiessuch as gene therapy, and accelerates drug development (deliveryof active compounds, efficacy of vectors, etc.).

With the evolution of imaging techniques and the capacity to transferanimal data directly into clinical applications, molecular imaging is amost promising technique to tackle cancer detection, following therule of the three Ps: Precocious, Precise and Predictive.

- Precocious: several successive mutations are necessary to makea cell cancerous. By detecting genetic anomalies at the very firstmutation, molecular imaging could permit early diagnosis andprompt intervention right at the start of the cancer-formingprocess.

- Precise: molecular imaging makes it possible to detect precisely,in space and time, the gene or genes that are dis-regulated in thecancer cell. The tumour can then be characterised with all therequired molecular precision.

Molecular imaging of cancer

CANCEREMIL



- Predictive: the fineness of the information obtained by molecularimaging makes it possible not only to determine the tumour type,but also to predict its evolution, adapt the treatment and monitorits efficacy.

This is essential to:

• validate in the context of living organisms the targets and drugsdesigned by genome data mining and in vitro gene expressionanalysis through methods that are both non-invasive and repeatable

• acquire fundamental knowledge about the patterns of geneexpression in normal tissues and define the changes in specific geneexpression in cancer

• design and develop drugs targeting cancer-related gene expression

• allow precise evaluation of new treatments and new anticancer drugsthat are required for progress in cancer management, throughreliable measures of the cancer burden.

Expected results The present initiative is taken to capitalise on the extraordinaryopportunity for studying non-invasively gene expression andfunction in cancer, due to recent advances in molecular imagingmodalities. Because molecular imaging is fundamentally multi-disciplinary by nature, the instrument for this goal is a Network ofExcellence bringing together genome-oriented scientists with thevarious actors of imaging science and the clinicians dedicated toformulating novel diagnostic methods based on imaging.The generalobjectives of EMIL are to:

1. coordinate the current effort in EMIL by merging 43 groups fromuniversities, research centres and SMEs coming from differentscientific and technical fields into one virtual excellence centrewith dedicated technological training platforms and integrateddissemination and management activities

2. advance EMIL to the scientific, technical and economical statusthat should be expected from its value for European citizens, inorder to improve cancer diagnosis follow-up, to promote andassist in the development of new targeted therapies, and translatescience and technology progress into economical benefits

3. act as leverage for a strong technological development that canbe fuelled through specific research and development projects.

And more precisely:

4. to optimise hardware and software technologies for the integrationof radiotracer, magnetic resonance and optical imaging data.Thiswill require specific instrumental development and validation forcancer research, as well as software tools for the co-registration,quantitation and processing of multimodal data

5. to develop so called ‘smart’ imaging probes which are specific fora given molecular process and which can be detected and localisedby at least one imaging modality

6. to use further developments of mouse models of human cancerto: (i) improve the early detection of small cancers by advanced

imaging, (ii) directly study alteration of gene expression, tumourcell proliferation and migration in vivo over an extended periodof time in the same animal

7. to identify in vivo molecular targets of cancer and metastasisenabling an early diagnosis, assessment of disease progression andresponse to therapy

8. to establish imaging-guided patient-tailored therapies

9. to develop imaging technologies for in vivo drug screening usinganimal models predictive for human disease and applications tohuman clinical trials

10. to do molecular imaging of apoptosis in cancer.

Potential applications 1.Tumour diagnosis

2. Follow up of tumour progression

3.Therapeutic evaluation


CANCER

Coordinator Tavitian, Bertrand

CEA - SHFJ

Unité d’imagerie « in vivo » de l’expression des gènes

4 place du Général Leclerc

91401 Orsay, France


Project web-site: www.emilnet.org

Key words: EMIL, molecular imaging, cancer, drug devel-opment, guided therapies, tumour diagnosis,in vivo imaging of gene expression

PartnersDipartimento di Chimica I.F.M., Università degli di Studi diTorino,Turin, Italy

Dept. of Neurology, Lab for Gene Therapy and MolecularImaging, Klinikum at the University of Cologne (MEK),Germany

Department of Endocrinology and Metabolic Diseases,Leiden University Medical Centre, The Netherlands

Centre of Excellence on Neurodegenerative Diseases,Università degli Studi di Milano, Milan, Italy

Biospace Mesures, Paris, France

Department of Biomedical Sciences and Dept Physics -RUCA - Bio-Imaging Lab, Universiteit Antwerpen, Belgium


MPI for Neurological Research, MRI Laboratory, MaxPlanck Society, Cologne, Germany

CNRS- ICSN, Gif sur Yvette, France

INSERM,ADR de Lyon, France

Dept. of Medical Biochemistry and Genetics,The PanumInstitute, University of Copenhagen, Faculty of Health,Denmark

Department of Biological Chemistry, Group ofOligonucleotides, IOCB-AS of the Czech Republic

Lab. of Oncogene Regulation, Institute of CarcinoGenesis,Moscow, Russian Federation

Dept. of Organic Chemistry - NMR Laboratory, Universityof Mons-Hainaut, Belgium

Laboratory de Méthodologie RMN, Fac des Sciences,Université Henri Poincaré, Nancy, France

Faculté des Sciences de Base (FSB), Institut de ChimieMoléculaire et Biologique (ICMB) – LCIB, EcolePolytechnique Fédérale de Lausanne, Switzerland

Department of Radiopathology & Medical Isotope Use,NCPH-National "FJC" Research Institute for Radiobiology& Radiohygiene, Budapest, Hungary

Institute of Nuclear Chemistry, University of Mainz,Germany

Coordination & Radiochemistry, Université de Liège,Belgium

Laboratory of Bioinorganic Chemistry & Biomedical NMR,Department of Biochemistry, Centro de Neurociências deCoimbra e Biologia Celular, Coimbra, Portugal

BRACCO Imaging S.P.A., Milan, Italy

Radiology & Radiological Chemistry Division, University ofBasel, Switzerland

Consiglio Nazionale delle Ricerche, Istituto di Biostrutturee Bioimmagini, Naples, Italy

Department of Inorganic Chemistry, Prague, CzechRepublic

Chemistry Laboratory, Durham University, United Kingdom

Laboratory of Applied Organic Chemistry and Catalysis,Technische Universiteit Delft, The Netherlands

Dept. of Inorganic and Analytical Chemistry, Laboratory ofRare Earths, University of Debrecen, Hungary

Radiopharmaceutical Chemistry Laboratory, DeutschesKrebsForschungsZentrum Heidelberg, Germany

SKYSCAN, Aartselaar, Belgium

Mauna Kea Technologies, Paris, France

MR Solution Ltd, Guildford, United Kingdom

Wolfson Molecular Imaging Centre,Academic Dept ofRadiation Oncology,The Victoria University of Manchester,United Kingdom

Gastroenterology Department, Hospital Clinic Provincialde Barcelona, Spain

Department of Dermatology and Rudolf-Virchow, Centrefor Experimental Biomedicine, Julius-Maximilians-UniversitätWürzburg, Germany

Dept. of Radiology, Stichting Katholieke Universiteit,University Medical Centre Nijmegen, The Netherlands

Department Ingenieria Electronica / E.T.S.I.Telecomunication, Universidad Politécnica de Madrid, Spain

Department of Urology & Department of ClinicalResearch, Faculty of Medicine, University of Bern,Switzerland

Department of Physics "E. Fermi", University of Pisa, Italy

ForschungsZentrum Juelich GmbH, Zentrallabor furElektronik (ZEL), Juelich, Germany

Department of Biochemistry, University of Cambridge,United Kingdom

Centro Ciclotrone PET, Fondazione Centro San Raffaeledel Monte Tabor, Milan, Italy

Medres Medical Research GmbH iGR, Cologne, Germany

Department of Nuclear Medicine, Radiochemistry &Radiopharmaceutical,Technical University, Munich, Germany


CANCER

Acronym: EMILProject number: LSHC-CT-2004-503569EC contribution: €5 800 000 Instrument: Network of ExcellenceDuration: 60 monthsStarting date: 01/07/2004


Summary

The TRANSFOG project aims at the systematic identification and

functional characterization of novel cancer genes with high potential

diagnostic and therapeutic value in breast, colon and lung cancer.

The TRANSFOG partners will bring together world recognised

competences and resources to reach the following, integrated

research objectives:

I. Identification of novel cancer-related genes of high clinical-

diagnostic potential, with a specific focus on progression and

metastasis of colon, breast, lung cancer.This will be achieved mainly

through extensive gene expression profiling of tumour/metastasis

samples and of cell-based models of cancer progression.To extend

the exploration range,differential proteomics and epigenetic analysis

are also planned. The foreseen outcome is a ranked list of novel

candidate cancer genes emerging from integration of the screening

results, that will undergo functional characterisation and/or

diagnostic validation.

II. Set-up of technologies for systematic cancer gene functional

analysis and for identification of new molecular targets. Gene

functional analysis will be enabled by assembling collections of full-

length cDNAs (FL-cDNAs) and of short interfering RNAs (siRNAs)

subcloned in expression plasmids, to assess the consequences of

gene gain-or loss-of-function in cell-based and preclinical models.

III. Systematic exploration of oncogenic/antioncogenic signalling

pathways,epigenetic regulatory mechanisms.Taking advantage of the

FL-cDNA and siRNA collections made available by the project, cell-

based experimental systems to study protein-protein interaction,

reporter gene expression and epigenetic modifications will be

exploited for systematic analysis of the candidate genes. This will

result in datasets of protein-protein interaction, transcriptional and

epigenetic regulation allowing a comprehensive overview of the

alterations in signalling and regulatory networks involved in cancer

progression.

IV. Development of tools for diagnostic validation of molecular

signatures for cancers of high population impact,namely:colon,breast

and lung. This will enable translation into clinical use of signatures

obtained through the cancer-oriented genomic screenings performed

by the participating units. In particular,the project is expected to define

and validate prognostic signatures associated with the tendency of

the above mentioned cancers to give rise to metastasis.

V. Establishment of a shared bioinformatic platform for functional onco-

genomics data handling and standardisation.This will require a concerted

effort towards codification of the various biological assays according to

specific functional features analysed by each assay,using for example the

Gene Ontology as a template (www.geneontology.org),and the sharing

of analysis software and tools.Towards the same aim, a web-accessible

platform based on the Distributed Annotation System (www.biodas.org)

will be implemented.

The TRANSFOG project will deliver a consistent and integrated

amount of functional data on genes of as yet unknown activity and

biological role. In the process of reaching this objective, the

participating units will be enabled to set up truly post-genomic efforts

toward systematic gene functional characterisation.New technologies

will be developed that will allow exploration of gene regulatory

networks,protein-protein interactions and high-throughput cell-based

evaluation of basic biological functions such as motility, growth,

apoptosis, invasion, adhesion, polarisation and more complex

processes as in vitro epithelial morphogenesis and angiogenesis.The

technologies for systematic gene functional characterisation

developed here will be useful for functional studies involving a variety

of physiological and pathological processes,and will be made available

to the scientific community in the frame of a collaborative research

network.The bioinformatic networking endowed with the project will

enable participating units to share tools for data handling, database

exploration and functional gene annotation. It will also facilitate

integration of the present network with other EC-funded networks

and with the European and global post-genomic community.

Translational and functional onco-genomics: from cancer-oriented genomic screenings to new diagnostictools and improved cancer treatment


CANCER TRANSFOG


Research activities To reach the proposed goals, TRANSFOG is structured in sevenresearch activities, here briefly outlined.

1. Cancer-oriented genomic screenings in tumours and cell lines

Genome-wide screenings by DNA microarrays, array-CGH,epigeneticand proteomics will be carried out on tumour samples selected formetastatic progression of breast, colon and lung carcinomas, as well ason cancer-oriented experimental models,like serine and tyrosine kinasereceptor-driven transcriptional responses,ligand-induced in vitro epithelialmorphogenesis and invasive growth, in vitro angiogenesis of endothelialcells.The results of the screenings will be integrated to generate a widepanel of previously uncharacterised genes that are potentially involvedin basic biological functions underlying cancer progression, such as cellgrowth, apoptosis, motility, invasion, morphogenesis and others.

2. Development of enabling technologies for systematic gene gain-of-function

Among the possible approaches to functional characterisation ofcandidate genes identified by Activity 1, one is based on enabling theexpression of their full-length (FL)-cDNAs in cells of interest or inbacteria for recombinant protein production. This will require theassembly of a core FL-cDNA collection, which is a strategic deliveryof TRANSFOG.

3.Generation of a siRNA vector collection to enable systematic gene loss-of-function analysis

A second way to analyse the function of genes is by inducing loss-of-function.This can be achieved also in mammalian cells by RNAsilencing technologies (Science 296:550-553, 2002). Some of theparticipating groups have already set up these technologies. Thisknow-how will be exploited for a key effort of the present project,that is the generation of a shared collection of thousands of humansiRNA constructs in a plasmid/retroviral expression system (whichallows easy further transfer of the construct in the target cells ofchoice), mainly targeting genes of unknown function that gain highpriority for TRANSFOG partners through their cancer-orientedgenomic explorations described in Activity 1.The use of single-genesilencing RNA species will allow the identification of individual genefunctions whereas combinatorial approaches will allow thecharacterisation of polypeptides active in the same cellular pathways.

4. Development of high-throughput functional assays

Many of the participants have previously developed and employedsimple assays on cultured cells to evaluate growth,motility, survival,invasion,adhesion,morphogenesis, transformation,angiogenesis andother basic biological functions altered during tumour progressionand metastasis.

Modulation of these functions by the candidate genes will beassessed by systematic transduction of cultured cells with FL-cDNAsor siRNAs subcloned in expression vectors. Some of the proposed

assays will reach an adequate throughput for studying all identifiedcandidates, while other assays, exploring more complex processes,will most likely require additional candidate prioritisation. Large-scale siRNA analysis will also be carried out on Drosophila cells toidentify genes relevant to cell motility. Mouse transgenic andknockout approaches will provide information on the in vivo role ofthe identified candidates in cancer progression and provide the finalvalidation of new molecular targets for cancer therapy.

5. Proteomic approaches to the study of signal transduction and protein-protein interactions

Protein-protein interactions play a key role in a wide range ofbiological processes related to cancer progression. TRANSFOGpartners will set up procedures for high-throughput analysis ofmultiprotein complexes by mass spectrometry,protein microarrays,Biacore biosensor analysis and cell-based protein-protein interactionsystems. Some of these procedures will take advantage of the FL-cDNA collection, which will provide the basis for highly parallelprotein synthesis and purification.

6. Preliminary diagnostic validation of molecular cancer signatures

Converting a molecular signature emerged from a cancer genomicscreening into a validated tool for clinical use is a demanding task.For instance, the platform originally used to define the signature (e.g.a certain type of microarray) may not be the most adequate forsubsequent capillary diffusion of the signature assay.A translationalresearch phase is therefore required in which the signature ofinterest is re-assessed on new tumour samples and with otherplatforms (e.g. realtime PCR, tissue microarrays,immunohistochemistry), and cross-comparisons are made betweenplatforms available at different sites. Standardised procedure will bedefined for the various platforms, and for the management of dataof both clinical and experimental nature. The main diagnosticproblem that the TRANSFOG project plans to address is theprediction of the probability with which a primary carcinoma of thecolon, lung and breast will give rise to metastasis.

7.Generation of a common platform for data handling and gene functionalannotation

Efficient handling and sharing of genomic profiles and gene functionalannotation will be achieved by development of an integrated, web-accessible data handling system with annotation tools for analysisof gene expression and function.The partner EMBL-EBI will providethe necessary expertise in collaboration with bioinformaticpersonnel of the other partners.


CANCER


Coordinator Prof. Storme, Guy

GEIE-LINC (Groupement Européen d’Intérêt Economique- Liaison Network for Cancer)

c/o AZ-VUB Cancer Centre

Laarbeeklaan 101

1090 Brussels, Belgium

Phone: + 32 2 477 61 47

Fax: + 32 2 477 62 12

Project web-site: http://transfog.org

Prof. Medico, Enzio

The Oncogenomics Center

Institute for Cancer Research and Treatment S.P.

142 km 3.95

10060 Candiolo (TO), Italy

Phone: + 39 011 993 3234

Fax: + 39 011 993 3225


Keywords: Oncology, Genomics, Proteomics.

PartnersCNIO, Spain

DKFZ, Germany

NKI,The Netherlands

IRCC, Italy

UMCU,The Netherlands

IFOM, Italy

EMBL-EBI, United Kingdom.

CANCER


Acronym: TRANSFOGProject number: LSHC-CT-2004-503438EC contribution: €6 000 000Instrument: Integrated ProjectDuration: 48 monthsStarting date: 01/06/2004


SummaryRadiotherapy is the second most important

treatment modality after surgery in the

treatment of cancer.At present over 50% of

all cancer patients receive radiotherapy at

one stage in their course. Inevitably normal

tissues are also exposed to ionising radiation

during radiotherapy of tumours. This can

result in organ failure and hence can

seriously limit the treatment dose.

Reduction of the side-effects of

radiotherapy will not only increase the

quality of life after the treatment but may

also result in increased survival of cancer

patients as it will allow dose escalation to

the tumour. This is true even if the most

optimal physical dose delivery (conformal

therapy, protons) of radiation is applied.

Radiation-induced organ failure is mainly

caused by stem cell sterilisation, leading to

a reduced reconstitution of functional cells.The innovative vision of

this project is to reduce radiation-induced complications through

stem cell therapy. Replenishment of the depleted stem cell

compartment should allow regeneration of irradiated tissues. A

successful replacement of stem cells and subsequent amelioration

of radiation-induced complications may open the road to completely

new strategies in radiotherapy and help combat cancer.

ProblemMany attempts have been made to attenuate radiation-induced damageto normal tissues.Although much knowledge has been obtained on themechanism of radiosensitivity of normal tissue, and the pathogenicpathways that eventually result in loss of function, the vast majority ofremedies are either inadequate,diminish in time or have not been shownto be selective for normal tissue only. Therefore a completely newapproach is needed.Today bone marrow transplantation is commonclinical practice.Due to new scientific knowledge and biotechnologicaldevelopments,only recently it has become apparent that bone marrowtransplantation may rescue other organs. Moreover, cells from certaintissues may even repopulate the haematopoietic system.Similar findingshave been reported for stem cells derived from other tissues than bone

marrow.However,tissue specific cells are only available in small numbers.Therefore, bone marrow stem cells have the largest clinical potentialto be used for transplantation into irradiated organisms or individualnormal tissues to provide the organ with sufficient numbers of cellsnecessary for regeneration.

AimThe aim of the project is to develop and optimise techniques toprevent radiation-induced normal tissue complications using adultstem cell therapy. The tissues of interest will be oral mucosa, skin,gut and salivary gland tissues.The first step will be to provide proofof principle for the impact of stem cells on the repair of irradiatedtissues.

To this end protocols for the isolation, mobilisation, andcharacterisation of bone marrow derived stem cells will beperformed and developed. Specific targeted approaches fortransplantation of bone marrow derived stem cells will be designedand tested.

CANCERFIRST


The FIRST project consists of two blocks of works (BOW). In BOW1 normal tissue radiobiol-ogists are brought together to use established animal models to study the effects of celltherapy after radiotherapy.The cell therapy protocols are delivered by stem cell biologist

working in BOW2.

Further improvement of radiotherapy of cancer through side-effect reduction by application of adult stem cell therapy


Expected results:1. optimised protocols for isolation, generation, mobilisation,

characterisation and expansion of stem cells from bone marrow

2. demonstration of proof of principle for the use of bone marrow-derived stem cells to modificate radiation-induced normal tissuedamage in animal models.

Potential applications:The resulting scientific and (bio)technological knowledge and a successfulreplacement of stem cells and subsequent amelioration of radiation-induced complications may eventually lead to new and improved cancertreatment strategies which will profoundly increase radiotherapytreatment success.


CANCER

The blocks of work (BOW) are divided into workpackages (wp).Workpackage 1-4 are the normal tissues studied.They use together withother partners the methods described to determine the success of transplantation.WP 5-8 concerns the different stem cell types and pro-

tocols, common techniques are shared and are distributed to BOW1.TUD (P5): Medical Faculty Carl Gustav Carus, Radiobiology Laboratory,Prof. Dr.Wolfgang Dörr (D). CEA (P3): CEA- Service de Génomique Fonctionnelle, Dr. Michèle Martin (F). University of Groningen, RSCB (P1)Radiation and Stress Cell Biology, Dr. Robert Coppes (Co-ordinator, NL), IRSN (P3) IRSN, Département de Radioprotection de la Sante del'Homme et de Dosimetrie, Dr. Dominique Thierry (F). SCB (P2), University of Groningen, Stem Cell Biology Prof. Dr. Gerald de Haan (NL),LH (P7) Université François Rabelais, Faculté de Médecine, Laboratoire d'Hématopoïèse. Dr. Pierre Charbord (F). 7TM, 7TM Pharma A/S,

Hørsholm, Prof. Dr.Thue Schwartz (DK).



CANCER

Coordinator Dr Coppes, Rob

Department of Radiation and Stress Cell Biology

Faculty of Medical Sciences

University of Groningen

A. Deusinglaan 1

9713 AV Groningen,The Netherlands

Phone: + 31 50 3632709

Fax: + 31 50 3632913


Project web-site:http://www.rug.nl/med/onderzoek/internationalepro-jecten/europeseprojecten/first (in preparation)

Key words: radiation-induced complications, adult stemcell therapy, cancer therapy

Acronym: FIRSTProject number: LSHC-CT-2004-503436EC contribution: €1 500 000 Instrument: Integrated ProjectDuration: 24 monthsStarting date: 01/09/2004


SummaryExtracellular proteases have complex roles with distinct functions at

different stages of tumour development and progression,and may have

conflicting effects on malignancy. The complete repertoire of

extracellular proteases through which cells regulate their local

environment is termed the Degradome. Extracellular proteases

remain an attractive target for intervention against cancer and we

propose to transfer recent insights into their function to pre-clinical

and clinical settings.

ProblemThe critical defining feature of a malignant tumour is the presence ofcells that have broken through tissue boundaries and penetrated intosurrounding normal tissues. It has long been recognised that cellularinvasion of basement membranes and connective tissue stromainvolves the actions of diverse extracellular proteases from multipleenzymatic classes, including the metalloproteinases (MPs) and theserine,threonine,thiol and aspartic proteases,which can be producedeither by cancer cells themselves or by neighbouring host cells.Thesecellular proteases participate also in the formation of new bloodvessels that support the burgeoning energy demands of a rapidlygrowing tumour, and in the ability of cancer cells to metastasize todistant organs. They constitute the Degradome – the completerepertoire of proteases that cells and tissues coordinatively regulatein order to modulate their local environment.

We now understand that pericellular proteolysis is important in theregulation of:

1) growth factor activation, bioavailability and receptor signalling;

2) cell adhesion and motility, 3) apoptosis and survival mechanisms;

4) angiogenesis;

5) specification of cellular identity,and 6) inflammatory responses andimmune surveillance.

In the battle against cancer, the Degradome is important in threeprincipal areas.

1) Cellular proteases and their inhibitors are components of themolecular machinery of malignancy, and thus are attractive astherapeutic targets.

2) Degradome genes are valuable as prognostic and diagnosticmarkers of disease that can improve the accuracy of conventionalclinical and histopathological assessment.

3) Cellular proteases are target molecules for improving tumourdetection and imaging.

The goals in molecular diagnostics are to develop molecular profilingtechnologies and markers of disease status that are broadly applicableto the selection of patients for therapy, or to screening of disease-free individuals who may benefit from prophylactic interventions.

AimThe aim of this project is to define new molecular targets for drugdesign and to develop novel specific interventions that are based onthorough knowledge of the pathophysiological roles of targetproteases and related molecules, and to understand how and whento use them. The identification of new molecular diagnostic andprognostic indicators of patient risk, together with new ways toenhance visualisation of tumours in the clinic,will improve health caredelivery based on an individualised, patient-oriented approach tocancer therapy.

Extracellular proteases and the cancer degradome:Innovative diagnostic markers, therapeutic targets and tumour imaging agents


CANCER CANCERDEGRADOME


Expected results 1.The determination of Degradome gene expression patterns in

human tumour cell lines and mouse models.

2. A detailed analysis of Degradome gene function using tumourprone mouse models.

3.The analysis of protease inhibitor function in combination withother therapies.

4. Elucidation of the interplay between proteases and other keymolecules of intracellular and intercellular signalling.

5. Determination of the regulatory factors that control protease geneexpression in tumours and in the tumour-host dialogue.

6. Characterisation of the cellular expression of Degradome genesfor breast and prostate cancer.

7. Development of active site-directed inhibitors ofmetalloproteinases.

8. Development of ligands able to prevent the formation of protease-substrate, protease-inhibitor, protease-receptor complexes.

9. Production of radiotracers for protease ligands for in vivo imaging,with transfer to clinical paradigms.

Potential applicationsSeveral major pharmaceutical companies have been involved in thedevelopment of synthetic protease inhibitors for cancer therapy overthe past decade.However, the vast majority of trials have shown thesefirst generation compounds to have limited effects.What is now clearis that the biological activities of extracellular proteases,and their rolesin normal and diseased tissues, are much more complex than wasoriginally envisioned.The original notion of proteases solely as mediatorsof pathological tissue destruction is an oversimplification: in fact, someproteases have functions that inhibit tumour development andprogression, and moreover, their natural inhibitors (TIMPs, PAIs, etc)can in some instances enhance tumourigenesis. The identification ofprotease targets for the design of novel and specific interventions willoffer improvements for health care delivery and patient management.The knowledge obtained in this project can also be used to identifycancer susceptibility in otherwise healthy individuals.


CANCER

Overview of rat, mouse, and human degradomes.This figure represents the complete set of protease and protease homologue

genes from the indicated species.


Faculty of Chemistry, National and KapodistrianUniversity of Athens, Greece

Ecole Polytechnique Federale de Lausanne, Switzerland

Institut für Molekulare Medizin und Zellforschung,Freiburg, Germany

Dept of Genetic Toxicology, National Institute of Biology,Ljubljana, Slovenia

Mario Negri Institute for Pharmacological Research,Bergamo, Italy

Humboldt University, Berlin, Germany

Division of Cardiovascular and Medical Sciences,University of Glasgow, United Kingdom

Institut de Genetique et de Biologie Moleculaire etCellulaire, Illkirch, France

Institut fur Experimentelle Onkologie undTherapieforschung,Technical University of Munich,Germany

Proteros Biostructures GmbH, Martinsried, Germany

Division of Carcinogenesis and Differentiation, DeutschesKrebsforschungszentrum, Heidelberg, Germany

Dept of Molecular Biology, University of Aarhus,Denmark

Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, Naples, Italy

Istituto di Endocrinologia e Oncologia Sperimentale ‘G.Salvatore’, Naples, Italy

Institut de Biologia Molecular de Barcelona, Spain

University of Southampton Human Genetics Division,School of Medicine, United Kingdom

OncoMethylome Sciences SA, Liège, Belgium

Genoptics SA, Orsay, France

Laboratory for Radiopharmacy, University of Ghent,Belgium

KRKA, Department of Biochemical Research and DrugDesign, Lujbljana, Slovenia

Institute of Pathology, Cantonal Hospital, University ofBasel, Switzerland

Coordinator Prof. Edwards, Dylan

School of Biological Sciences

University of East Anglia

Norwich NR4 7TJ, United Kingsom

Phone:+ 44 1603 592184

Fax: + 44 1603 593222


Project web-site: http://www.cancerdegradome.org/

Key words: cancer, metalloproteinase, protease, metas-tasis, diagnostics, tumour imaging

PartnersThe Finsen Laboratory, Copenhagen University Hospital,Denmark

IFOM Institute of Molecular Oncology, Milan, Italy

CRCE Faculty of Medicine, University of Liège, Belgium

Dpto de Bioquimica y Biologia Molecular, Universidad deOviedo, Spain

Cambridge Institute of Medical Research, University ofCambridge, United Kingdom

Dept Medical Biochemistry and Biophysics, KarolinskaInstitute, Stockholm, Sweden

Departement d-Ingenierie et de’Etudes des Proteines,Gif-sur-Yvette, France

Unité d'Imagerie de l'Expression des Genes, Orsay,France

Laboratory for Experimental Oncology, Department ofMedical Oncology, University Hospital Gasthuisberg,Leuven, Belgium

Centre for Biotechnology,Turku, Finland

VTT Medical Biotechnology Group,Turku, Finland

Dept. of Vascular Biology & Thrombosis Research,University of Vienna, Austria

Max Planck Institute for Biochemistry, Planegg-Martinsried, Germany

Acronym: CANCERDEGRADOMEProject number: LSHC-CT-2003-503297EC contribution: €10 400 000 Instrument: Integrated ProjectDuration: 48 monthsStarting date: 01/01/2004

CANCER



SummaryTargeted delivery of therapeutic agents to the tumor microenvironment

is a novel avenue for cancer treatment toward the development of more

efficacious and better-tolerated anticancer drugs.

This project aims to identify new molecular targets which are selectively

expressed in tumor stroma and in the neo-vasculature of aggressive

tumors and to develop new therapeutic strategies based on high affinity

binding molecules capable of selective localization in tumor stroma

and/or vascular structures. Efforts to move the most promising

product(s) generated within this Integrated Project into Clinical Trials

is the ultimate scope of the project.

Potential application is the pharmacological treatment of solid

neoplasms, maintaining or improving present percentage of

respondents, survival, disease-free interval, with improved safety and a

better quality of life.

ProblemThe majority of pharmacological approaches for the treatment of solidtumors suffers from poor selectivity, thus limiting dose escalation (i.e.,the doses of drug which are required to kill tumor cells causeunacceptable toxicities to normal tissues).The situation is made moredramatic by the fact that the majority of anticancer drugs accumulatepreferentially in normal tissues rather than in neoplastic sites,due to theirregular vasculature and to the high interstitial pressure of solid tumors.

One avenue towards the development of more efficacious and bettertolerated anti-cancer drugs relies on the targeted delivery of therapeuticagents to the tumor environment, thus sparing normal tissues.

This experimental strategy requires a range of diverse experimentaltechniques, for the identification of targets, for the isolation of bindingmolecules, and for their conversion into imaging and therapeuticproducts. Our approach has the potential advantage that immuno-histochemistry, imaging and biodistribution data provide informationabout the selectivity of the anti-cancer drugs at several stages of thedrug development process,and allow a rational optimization of the mostpromising lead compounds.

AimIn the past,our Consortium has developed innovative anti-cancer imagingand therapeutic strategies, based on recombinant antibody fragments,which have moved from the bench to the clinic.With the STROMAProject, we plan to strengthen and extend a leading position of our

European Network in research and in the pharmaceutical developmentof ligand-based,targeted anti-cancer therapies,with a particular emphasison the targeting of tumor neo-vasculature and tumor stroma.

This project focuses on the:

- Identification and validation of molecular targets which areselectively expressed in the stroma and in neo-vascular sites ofaggressive solid tumors. Endothelial cells and stromal cells aregenetically more stable than tumor cells and can produce abundantmarkers, which are ideally suited for tumor targeting strategies.

- Isolation of high-affinity binding molecules [small organic compounds,antibodies], which are specific for markers of angiogenesis and/orthe tumor stroma, and are capable of selective localization in thetumor environment, after intravenous administration.

- Development of therapeutic strategies, based on specific bindingmolecules capable of selective localization around tumor vascularstructures and/or in the tumor stroma.

- Dissemination of the research activities of the Project.

Expected results

Potential applications We will consider the project as fully successful if at least one moleculeenters clinical development for pharmacological treatment of solidneoplasms, maintaning or improving present percentage of res-pondents, survival, disease-free interval, with improved safety andbetter quality of life.

Selective targeting of angiogenesis and of tumor stroma

CANCERSTROMA


Flow-chart, outlining the main expected results, leading from targetidentification to the development of novel anticancer therapeutics.


Coordinator Dr Giavazzi, Raffaella

Laboratory of the Biology and Treatment of Metastasis

Department of Oncology

Istituto di Ricerche Farmacologiche “Mario Negri”

Via Gavazzeni 11

24125 Bergamo, Italy

Phone: + 39 035 319888

Fax: + 39 035 319331


Project web-site:http://www.esh.org/DEFAULT/STROMA/sconsortium.htm

Key words: neoplasm, stroma, angiogenesis, selectivetargeting, combination therapy, antibody,small molecules, oncofetal antigens,tumour neo-vasculature

PartnersProf. Bikfalvi,Andreas Molecular Mechanisms of Angiogenesis LaboratoryINSERM E 0113Institut National de la Santé et de la Recherche MedicaleUniversité Bordeaux 1Talence, FranceDr Bicknell, Roy Molecular Angiogenesis LaboratoryCancer Research UK, Institute of Molecular Medicine University of Oxford John Radcliffe HospitalOxford, United KingdomProf. Neri, Dario Institute of Pharmaceutical SciencesSwiss Federal Institute of Technology ETH HönggerbergZurich, SwitzerlandProf. Begent, RichardRoyal Free CampusDepartment of OncologyUniversity College LondonLondon, United KingdomProf. Zardi, LucianoIstituto Giannina GasliniCentro di Biotecnologie Avanzate,Istituto Nazionale per la Ricerca sul CancroGenova, Italy

Prof. Castronovo,VincentFaculté de MédecineLaboratoire de Recherche sur les MetastasesUniversité de LiègeLiège, BelgiumProf. van Dongen, GuusLaboratory for Tumour BiologyDepartment of OtolaryngologyVU University Medical Center,Amsterdam,The NetherlandsDr Zanda, MatteoIstituto di Chimica del Riconoscimento Molecolare,Consiglio Nazionale delle RicercheMilan, ItalyDr Vajkoczy, PeterFaculty for Clinical Medicine MannheimDepartment of NeurosurgeryRuprecht-Karls-Universität HeidelbergMannheim, GermanyProf. Kosmehl, HartwigInstitute of PathologyHelios Klinikum Erfurt GmbHErfurt, GermanyDr Dinkelborg, LudgerRadiopharmaceuticals ResearchSchering AGBerlin, GermanyDr Viti, FrancescaPhilogen s.r.l.Siena, ItalyDr Umaña, PabloGlycart biotechnology AG,Wagistrasse 18Zurich, SwitzerlandDr Marsoni, SilviaSendo FoundationMilan, ItalyDr Jasmin, DidiEuropean School of HaematologyCentre Hayem, Hôpital Saint LouisParis, France

Acronym: STROMAProject number: LSHC-CT-2003-503233 EC contribution: €6 000 000Instrument: Integrated ProjectDuration: 48 monthsStarting date: 01/01/2004

CANCER



SummaryMutations in the p53 tumour suppressor gene are the most frequent

genetic alteration in human cancer, occurring in over 40% of all cases

of cancer. One well-studied outcome of these mutations is the loss of

the tumour suppressor activity of the wild type (wt) p53.However,there

is growing evidence that many of the mutations that occur in the p53

protein generate mutant p53 proteins (mutp53) have acquired new

biochemical and biological properties. Through this gain of function

(GOF),mutp53 is believed to contribute actively to the cancer process.

We propose to explore mutp53 as a target for novel anti-cancer

therapies. Such therapies should aim to either abrogate the GOF effects

of mutp53,or restore wt-like properties to mutp53, so that it can now

regain its tumour suppressor capabilities.A multi-disciplinary approach

will be undertaken to explore and exploit the contribution of mutp53

to cancer.

One component of this project will investigate in depth the molecular

properties of mutp53: structural studies will pinpoint the changes that

particular mutations inflict on the structure of p53, and allow the

classification of mutp53 into distinct subclasses. In parallel, biochemical

studies will explore the mode of action of mutp53 within cells, including

its impact on patterns of gene expression,identification of specific DNA

sequences targeted by mutp53, and discovery of mutp53-interacting

cellular proteins. Preclinical models for mutp53-driven cancer will also

be developed, as a critical instrument for pre-clinical studies.

The other component will aim at translating this wealth of information

into better cancer therapy.One avenue will address the clinical relevance

of particular p53 mutations in human cancer, particularly its impact on

the patient’s response to chemotherapy.This should lead to guidelines

for more effective use of conventional therapy.The other avenue will

explore novel therapies targeted at mutp53 and mutp53-expressing

tumour cells. A major effort will focus on the discovery of small

compounds that can restore wtp53-like activity to mutp53.An innovative

approach to immunotherapy directed against mutp53-overexpressing

cancer cells will also be explored.Owing to the extremely high frequency

of p53 mutations, the success of this project will impact on a very large

number of cancer patients in Europe and worldwide.

ProblemCancer is a major cause for human suffering in Europe as well aselsewhere in the world. It causes immense effects on the cancerpatients themselves, on their families, as well as on society at large.In additional to the severe human suffering and their immediatesocietal impact, cancer treatment and management is also a majoreconomic burden.The importance of this problem and the urgencyof the need for novel approaches to cancer management andtreatment have been recognised by the EC, as reflected by theestablishment of a specific call in the area of “Combating Cancer”.

Mutations in the p53 tumour suppressor gene are the most frequentgenetic alteration in human cancer, occurring in over 40% of all casesof cancer.We propose to explore mutp53 as a target for novel anti-cancer therapies. Such therapies should aim to either abrogate thegain of function (GOF) effects of mutp53,or restore wt-like propertiesto mutp53,so that it can now regain its tumour suppressor capabilities.A multi-disciplinary approach will be undertaken to explore andexploit the contribution of mutp53 to cancer.

The p53 tumor suppressor pathway. p53 is normally an unstableprotein but becomes stabilized in response to various forms of cel-

lular stress, e.g. DNA damage, oncogenic singalling and hypoxia.The accumulation of p53 protein triggers cell cycle arrest, apopto-

sis and/or senescence.

Mutant P53 as a target for improved cancer treatment

CANCERMutp53



AimIn our proposed project, we introduce a multidisciplinary approachto explore mutp53 as a new target for innovative treatment.

A primary objective of the “Combating Cancer” initiative is “to combatcancer by developing improved patient-oriented strategies… to bettertreatment with minimal side-effects” with a focus on “encouraging thedevelopment of evidence-based guidelines for good clinical practice”.

Our project meets these requirements in at least two distinct ways:

1.We aim to improve the use of contemporary chemotherapythrough providing better guidelines based on correlations betweenp53 genotype of the tumour and its response to particular typesof anti-cancer drugs.

It is important to keep in mind that, although novel therapeuticapproaches are very exciting and promising, millions of cancerpatients all over Europe are being treated every day with standardchemotherapy.Beyond its limited efficacy,this is also associated withsignificant toxicity and therefore often unjustified patient suffering.The ability to make better predictions as to which particularchemotherapeutic regimen is most likely to work for a particularpatient thus has far-reaching implications, both in ensuring betterand more effective treatment and,not less importantly, in preventingunnecessary suffering from severe side-effects in cases where it isclear that a particular treatment is not going to work.Providing newrecommendations to oncologists, allowing them to “individualise”the chemotherapy course chosen for a given patient,will thereforemeet the objective of better treatment with minimal side-effects,and will provide evidence-based guidelines for good clinical practice.

2.A major component of this project is aimed at developing noveltherapies, based on mutp53 knowledge to be gained by theconsortium.

The increased selectivity and specificity of such drugs is most likelyto reduce side-effects on normal patient tissue,because such tissuedoes not express any mutp53,unlike the targeted tumour cells.Thus,any successful drug that comes out of this project is highly likely tolead to improved clinical practice and to better treatment, withreduced side-effects as compared to the presently available options.Moreover, the fact that close to half of all human tumours possessmutp53 in abundant amounts makes any new drug emanating fromthis endeavour potentially valuable to a very large number of cancerpatients.Such drug, if successful,may thus have far-reaching impacts,not only on individual cancer patients,but also on European societyas a whole.

Expected resultsThe proposed project will address the following main objectives:

1. elucidate the biochemical basis for mutp53 GOF (GOF),with specialemphasis on genomics and proteomics approaches;

2. evaluate the contribution of mutp53 to the malignant propertiesof cancer cells;

3. explore in depth the structural properties of selected mutp53 proteins,in order to provide leads for structure-based rational drug design;

4. evaluate the impact of mutp53 status on the response of selectedtypes of human tumours to chemotherapy,and use this informationto formulate guidelines for more effective use of currently availableanti-cancer therapies;

5. search for molecules and compounds that can selectively interferewith mutp53 GOF or restore wtp53 activity to mutp53,and explorethem as potential anti-cancer drugs;.

6. initiate clinical trials (Phase I) with one mutp53-selective drug thathas already gone successfully through pre-clinical studies;

7. generate leads and new tools towards the development of mutp53-based immunotherapy.

p53 is a transcriptionfactor that binds spe-cific DNA motifs in

p53 target genes andactivates transcrip-tion.The consensusp53 binding motif isRRRCWWGYYY N0-13 RRRCWWGYYYwhere R is purine,W

is A or T, and Y ispyrimidine.

p53 missense muta-tions in human tumors

cluster in the DNA-binding core domain

(approximately residues100-300). So called hotspots mutations include

Arg248 and Arg273(DNA contact mutants)and Arg175, Gly245,Arg249, and Arg282(structural mutants).

Ma jor D i seases Research (2003-2005)188

CANCER


Potential applicationsCancer represents one of the most severe health problems in theEuropean community. Cases are growing with the age of thepopulation. The economic and emotional burden is enormous.Mutp53 protein is expressed in about 50% of all human tumours.In some categories with growing incidence, e.g. lung cancer, coloncarcinoma and skin tumours,more than 60-70% of the tumours areassociated with mutated p53.This may be due to the induction ofp53 mutations by dietary and environmental carcinogenic insults,which are encouraged by modern western society’s lifestyle (expo-sure to sun,very heavy smoking in most parts of Europe,high-fat diet).

In some types of cancer, expression of mutp53 appears to beparticularly highly correlated with the more aggressive tumourstages.Yet, in many cancers,mutation of p53 appears to occur duringthe very early steps of carcinogenesis.This is particularly true forcancers of the lung, head-and-neck, bladder, skin and oesophagus.In these pathologies, mutp53 is amongst the earliest tumourigenicchanges that can be detected in the patient, sometimes ahead ofthe clinical diagnosis of a cancer lesion.The expression of mutp53is relatively easy to diagnose, employing immunohistochemicalassays that are already available as commercial kits and are in usein many pathology laboratories throughout Europe.However, there

is still a lack of rapid, low-cost and sensitive assays for mutationdetection, and this is the key to the systematic implementation ofmutp53-based strategies for cancer diagnosis, prognosis, andtreatment.This is why one of the activities of our consortium willbe to support the validation and the transfer into production of anew type of micro-array developed by Asperbio, an SME partner ofour consortium. Improved detection of p53 mutations may enableearlier cancer diagnosis, increased curability and reduction in thesocietal impact of cancer morbidity and mortality.

An effective novel treatment of cancers expressing mutp53 couldhelp to prolong life expectancy and quality of life. Such a treatmentmay be applicable for eradicating small lesions in pathologies wheremutation is an early event, thus providing low-cost, low-stressapproaches for lesions that are currently managed through surgeryand/or chemotherapy. On the other hand, mutp53-based therapiescan be applied synergistically with conventional therapy regimensin patients with advanced cancers.The mutp53-based approach thusopens a whole range of possibilities that can be implemented incurrent medical practice without costly equipment, infrastructuresor extensive training programmes.

Development of effective anti-cancer therapy for mutp53-expressing tumours would lower direct and indirect costs byreduction of surgery and intensive care, reduction of duration ofmedical survey, reduction of emotional burden for patients and theirfamily and faster reintegration of patients as part of the workingeconomy. In addition, one should keep in mind that although novelanti-cancer therapies are a very exciting avenue, millions of cancerpatients in Europe are presently being treated with conventionalchemotherapy. Current chemotherapy has severe adverse effectson the quality of life of the treated patient.The combination of datafrom experimental model systems and the cancer patient mutp53database might potentially identify groups of patients who are notsuitable for particular types of contemporary chemotherapy.Bettertools to decide which patients should be treated and which to beleft untreated are extremely important in reducing the suffering ofthose patients who will not benefit from the currently availablecancer therapy modalities.

Mutant p53 gain-of-function.Wild type(wt) p53 binds spe-

cific DNA motifsand activates p53

target genes.Mutant p53 fails tobind specific DNAmotifs and activatep53 target genes.Putative gain-of-

function activity ofmutant p53 may

include protein-pro-tein interactions andillegitimate activa-tion of targets thatcontribute to tumor

progression.

Mutant p53 reac-tivation as a novelstrategy for cancer

therapy.Restoration of wildtype conformationand function to

abundant mutantp53 by a novel

drug triggers mas-sive apoptosis and

thus eliminatesthe tumor.


CANCER


Coordinator Prof.Wiman, Klas

Karolinska Institute

Department of Oncology-Pathology

Cancer Center Karolinska (CCK), R8:04

Karolinska Hospital

SE-171 76, Stockholm, Sweden

Phone: + 46 8 5177 9342

Fax: + 46 8 32 10 47


Project web-site: www.mutp53.com

Key words: p53 tumour suppressor, mutations, gain-of-function, p53 status, clinical outcome, mutantp53-reactivating drugs, novel cancer therapy

PartnersDivision of Tumor Biology,The Netherlands CancerInstitute,Amsterdam,The Netherlands

Department of Cell Cycle & Cancer, Institute of CancerBiology, Copenhagen, Denmark

Molecular Oncogenesis Laboratory, Regina Elena CancerCenter, Rome, Italy

Department of Genetics, Institute for Cancer Research,Oslo, Norway

Laboratorio Nazionale CIB,Trieste, Italy

Heinrich-Pette Institute, Hamburg, Germany

Department of Physics of Complex Systems,TheWeizmann Institute of Science, Rehovot, Israel

Department of Chemistry, University of Cambridge,United Kingdom

International Agency for Research on Cancer (WHO),Lyon, France

Department of Hematology & Oncology, Johannes-Gutenberg-University Medical School, Mainz, Germany

Department of Oncology-Pathology, Karolinska Hospital,Stockholm, Sweden

Department of Molecular Cell Biology,The WeizmannInstitute of Science, Rehovot, Israel

Institute of Biophysics,Academy of Sciences of the CzechRepublic, Brno, Czech Republic

Laboratorio Oncogenesi Molecolare, Istituto ReginaElena - CRS, Rome, Italy

Microbiology & Tumor Biology Center (MTC), KarolinskaInstitute, Stockholm, Sweden

Dept. of Structural Biology,The Weizmann Institute ofScience, Rehovot, Israel

Division of Molecular Biology H8,The NetherlandsCancer Institute,Amsterdam,The Netherlands

Johannes Gutenberg-University, Department ofHematology and Oncology, Mainz, Germany

Asper Biotech,Tartu, Estonia

GanyMed, Mainz, Germany

Aprea AB, Karolinska Institute, Stockholm, Sweden

Acronym: Mutp53Project number: LSHC-CT-2004-502983EC contribution: €8 000 000 Instrument: Integrated ProjectDuration: 60 monthsStarting date: 01/02/2004

CANCER



SummaryThe cellular immortality enzyme telomerase (one of the most

promising universal cancer markers) and associated telomere

maintenance mechanisms represent novel anti-cancer targets of

enormous therapeutic and diagnostic potential. In MOL CANCER

MED, a multinational EU translational cancer research consortium has

been established, in which expert cancer geneticists and molecular

biologists will interact with prominent pharmacologists,clinicians and

pathologists to develop these exciting new cellular targets into

measurable pre-clinical advances, within a four-year time-frame.

The project has been structured into three, highly interactive areas

of activity, involving the fundamental evaluation and pre-clinical

validation of: (i) telomerase as a target for cancer treatment and

diagnosis based on new molecular knowledge about its expression

and function, (ii) associated downstream telomere maintenance

mechanisms as additional targets for novel drug design, and (iii) new

anti-cancer drugs based on these targets.The consortium will bring

to bear diverse and complementary technological know-how of

considerable power to deliver the above primary objectives.Effective

management will maximise synergies across MOL CANCER MED in

order to produce genuine improvements in the design of new

treatments that promise to be active against a broad spectrum of

common human malignancies.

ProblemCancer is a leading cause of death in the western world, second onlyto cardiovascular disease, and is therefore a European public healthproblem of overwhelming human and economic significance. Theincidence of cancer is set to increase substantially with demographicand possibly environmental influences playing a part. However, thereis now an improved molecular understanding of the key genetic,biochemical and cellular changes leading to cancer, in significant partdue to the efforts of diverse groups of world-class EU-based scientists.With the completion of the human genome sequence imminent, it isnow timely to initiate a major European coordinated effort to translatefundamental scientific knowledge about cancer into safer, moreeffective, therapies and improved early diagnostic procedures.

MOL CANCER MED is focused on a single group of highlypromising anti-cancer targets associated with telomerase andtelomere maintenance. Repression of telomerase in the somatictissues of humans, and probably other long-lived mammals, appears

to have evolved as a powerful protective barrier against cancer.Immortalisation in vitro of normal human cells that lack telomeraseinvolves the reactivation of telomerase or, rarely, an alternative(ALT) mechanism for maintaining telomeres. It is clear thattelomerase is obligatory for continuous tumour cell proliferation,clonal evolution and malignant progression. Because telomerase isfound in around 90% of human cancers and is essential for thecontinued proliferation (and clonal evolution) of cancer cells, itrepresents one of the most exciting anti-cancer targets thus fardiscovered. Results with a variety of telomerase inhibitorystrategies in human cancer cells have confirmed that its functionalinactivation results in progressive telomere shortening, leading togrowth arrest and/or cell death through apoptosis. Promisingcandidate small molecule inhibitors are beginning to emerge thatwill form the basis for anti-telomerase drug development. MOLCANCER MED is based on successful Framework 5 researchconcerned with establishing the value of the cellular immortalityenzyme telomerase as an anti-cancer target (Project: QLG-1999-01341;TACIT) and represents an expansion and elaboration of this.TACIT yielded results that have triggered new translational researchwith clearly defined clinical applications.To this set of activities havebeen added carefully selected new EU research teams, notably inthe area of drug development.

AimThe principal aim of MOL CANCER MED is to fully exploit theresults of recent fundamental advances in understanding the roleof telomerase and telomere maintenance mechanisms in humancancer development, in order to achieve genuine clinical benefit (i.e.in developing both improved diagnostics and anti-cancer therapies).The principal measurable objectives of the project, over thecomplete 48 month period, are: (i) to validate further the potentialof telomerase and telomere maintenance systems in cancer therapyand diagnosis, (ii) to identify novel molecular targets based on

Developing molecular medicines for cancer in the post-genome era

CANCERMOL CANCER MED


(A) Normal human skin(B) organotypic culture of the immortal HaCat skin keratinocytesBoth are co-stained with an antibody against hTERT (red nuclear

staining) and an antibody decorating the basement membrane (greenstaining). All nuclei are counterstained with DAPI (in blue)


telomere structure, function & stability, that may be of value intreatment and diagnosis of the common human cancers, (iii) tocreate a programme of novel small molecule drug developmentbased initially on recently identified (but thus far poorly exploited)targets and, later (from month 12 onwards) exploiting completelynew targets identified during the project.

Expected results1. Novel anti-cancer drug targets and diagnostic methodologies

derived from advances in: (i) the understanding and definition ofbiochemical response pathways underpinning the telomerecheckpoint for somatic cell proliferation, (ii) the identification andmolecular/functional characterisation of natural mechanisms oftelomerase repression and cell self-renewal (including hTERTrepressor genes and chromatin remodelling factors) in normalhuman cells and their dysregulation in human cancers, and (iii)understanding the mechanisms of action and pharmacologicalactivity of existing small molecule telomerase inhibitors (egBIBR1532), and (iv) establishment of the precise roles of telomereaggregates and telomere-length-independent functions oftelomerase in human cancer.

2. An advanced molecular understanding of telomerase regulation atchromosome ends (eg involving the key telomere-binding proteinsPOT1 and hEST1A) and a comprehensive evaluation of suchproteins as anti-telomerase drug targets

3. New and effective molecular inhibitors (eg siRNAs, ribozymes &peptide nucleic acids) of telomerase and telomere maintenance(targeting hTERT transcription and telomere-related proteinsdiscovered within the MOL CANCER MED Consortium) for thepurpose of vasli.

4. Panels of new molecular markers of telomerase repression,telomere maintenance and associated signalling pathways, that canbe developed into precise, rapid assays for use in novel ‘kits’ forearly cancer diagnosis and prognostic evaluation.

5. An understanding of the differential effects of telomerase/telomeremaintenance inhibition on normal human tissues and in cancersusing organotypic in vitro human cell models.

6. Rational design of libraries of novel small molecule compounds forscreening against new targets, and selection of small molecule anti-telomerase/telomere maintenance drug leads active againstindividual new targets discovered during the course of MOLCANCER MED.

7. Identification of potential anti-cancer drugs from the above,following biochemical, pharmacological and functional (in vitro andin vivo) anti-tumour assays.

8. Preclinical exploitation of potential novel cancer drugs throughinterface with clinical oncology centres and SMEs.

Potential applicationsThe emphasis of the LIFESCIHEALTH Priority is very firmly placedupon multidisciplinary translational research, in which fundamentalscientific knowledge is harnessed for the specific purpose ofgenerating, within the timeframe of FP6, reagents, treatments anddiagnostics that are of clinical value. In MOL CANCER MED, a highlyfocused strategy will be adopted towards applying molecular geneticknowledge about the mechanisms underlying the cancer process tothe development of completely new approaches to cancer treatment,eg in bringing molecular biology, cell biology, genomics and targetevaluation together with small molecule drug discovery.

CANCER


Human Telomeres


Coordinator Prof. Newbold, Robert

Brunel University

Kingston Lane

Uxbridge UB8 3PH, United Kingdom

Phone: + 44 1895 203090


Project web-site:www.brunel.ac.uk/research/molcancermed/

Key words: cancer, therapy, genome, telomerase,diagnosis, drugs

PartnersProf. Neidle, Stephen

London School of Pharmacy


Dr Mergny, Jean-Louis

INSERM

Paris, France

Prof. Mann, John

Queens University Belfast

Belfast, United Kingdom

Dr D’Incalci, Maurizio

Istituto de Richerche “Mario Negri”

Milan, Italy

Dr Lingner, Joachim

ISREC

Epalinges, Switzerland

Dr Parkinson, Kenneth

University of Glasgow

Glasgow, United Kingdom

Dr Martens, Uwe

Medical University Center Freiburg

Freiburg, Germany

Prof. Boukamp, Petra

DKFZ

Heidelberg, Germany

Dr Blasco, Maria

CNIO

Madrid, Spain

Prof. Keith, Nicol

University of Glasgow

Glasgow, United Kingdom

Dr Zaffaroni, Nadia

National Cancer Institute

Milan, Italy

Dr Serakinci, Nedime

University of Aarhus

Aarhus, Denmark

Dr Roos, Goran

Umea University

Umea, Sweden

Acronym: MOL CANCER MEDProject number: LSHC-CT-2004-502943EC contribution: €4 000 000Instrument: Integrated ProjectDuration: 48 monthsStarting date: 01/10/04

CANCER



SummaryThe last decade's basic and clinical oncology research has revealed a

number of so far unrecognised regulating responses (e.g.HIF-1) in cells

exposed to hypoxia.

These processes have been proven to have a major impact on tumour

progression and resistance to radiotherapy and certain types of

chemotherapy.Because of their strong over-expression in solid cancer

tumours in comparison to adjacent normal tissue of these processes,

this new knowledge may open a therapeutic window for cancer

treatment by utilising hypoxia-responsive processes as drug targets.

Over the first two to three years we will dissect relevant steps in cancer

cell response to hypoxia, develop a technology platform for in vitro

control of oxygen tensions peri-cellularly, further identify and

characterise marker/target molecules, and do the initial in vitro drug

development.

Our mid-term evaluation will then select which hypoxic processes may

be suitable as targets for cancer-specific treatment.

Simultaneously, we will study diagnostic tagging and therapeutic

strategies leading up to a selection process of promising compounds

to be further developed after the end of the project period.

The new treatments will be developed along two lines:targeting known

cytostatics towards the newly discovered hypoxia-responsive molecules

and searching for so far unused compounds, preferably toxic to

pathways active during hypoxia.

The consortium’s final effort shall ensure industry use of our results.

Targeting newly discovered oxygen-sensing cascades for novel cancer treatments

Coordinator Ebbesen, Peter Laboratory of Stem Cell ResearchResearch ParkGustav Wiedsvej 108000 Aarhus C, DenmarkPhone: + 45 86 12 73 66 Fax: + 45 86 19 54 15E-mail: [email protected] Key words: Biology Equipment, Drug Candidates, Hypoxia,

HIF-1, CA IX, Preclinical, Drug Development.

PartnersAstraZeneca UK Limited, United KingdomAventis Pharma, FranceInstitute of Biotechnology - LithuaniaCharité - Universitätsmedizin Berlin, Campus VirchowKlinikum, GermanyUniversity of Zurich, SwitzerlandDeutsches Herzzentrum Münche, Klinik an der TU München,GermanyJobst Technologies GmbH, GermanyUniversiteit Maastricht / Research Institute GROW,Maastricht,The NetherlandsLEA Medizintechnik GmbH, GermanyLeo Pharma A/S, DenmarkImperial College of Science,Technolgy and Medicine, UnitedKingdomOxford BioMedica Plc, Oxford, United KingdomInstitute of Virology, Slovak Academy of Sciences, SlovakiaThe University of Oslo, NorwayKarolinska Institutet, SwedenThe Chancellor, Masters and Scholars of the University ofOxford, Oxford, United KingdomRiNA-Netzwerk RNA Technologien GmbH, GermanyUniversity of Florence, Department of Chemistry, Florence,ItalyThe Victoria University of Manchester, Manchester, UnitedKingdomAlbert Ludwigs University Freiburg, Freiburg, GermanyViVoX ApS, Denmark

CANCER EUROXY


Acronym: EUROXYProject number: LSHC-CT-2003-502932EC contribution: €8 000 000Instrument: Integrated ProjectDuration: 60 monthsStarting date: 01/02/2004


Summary

At the beginning of the third millennium one European citizen out of

three will have to deal with a cancer episode in the course of his/her

life.Worldwide the estimated number of new cancer cases each year

is expected to rise from 10 million in 2000 to 15 million by 2020.Cancer

is currently the cause of 12% of all deaths worldwide.

Within the European Union over 2 million new cancer cases are

diagnosed every year and over 1 million people die of cancer.The two

leading cause of cancers in Europe are breast and prostate.Therefore

combating cancer is a major societal and economic issue for Europe.

To face these new challenges strong mobilisation among the scientific

community and industrial manufacturers is needed.

Today’s approaches to treat cancer are the surgical removal of the

tumour tissue, radiotherapy, chemotherapy, and emerging immuno-

therapy.Among them radiotherapy remains a major technique to treat

cancer.More than a half of all cancer patients are treated by radiation

therapy thanks to the technical progress made with irradiation

equipment in the last years. For external radiation therapy (RT), high-

energy photon or electron beams are mainly produced by linear

accelerators, for internal radiation therapy or ‘brachytherapy’,

radioactive sources are put in the tumour with undeniable advantages

for the patient in given situations.

AimThe present project,MAESTRO,proposes innovative research to developand validate in clinical conditions the advanced methods and equipmentneeded in cancer treatment for new modalities in high conformalexternal radiotherapy employing electrons,photons and protons beams.

The project aims at improving the conformation of the dose deliveredto the target (tumoural tissues) whatever its shape in order to spare thesurrounding tissues.To do this new technologies in the field of patientpositionning and organ tracking,advanced software for treatment planningsystem,dose calculation and measurement,are to be developed,and linkedto the emerging IMRT (Intensity-Modulated Radiation Therapy) technique.

Programme of activities MAESTRO incorporates major research and technologicaldevelopment programmes involving clinics and manufacturers whichwill be linked throughout.The project includes four work packageson research and development activities and two work packages oftraining and management activities:

- adaptive radiation delivery, tracking and control for radiotherapy(WP1),

- radiotherapy software development (WP2),- sensors for dose evaluation in radiotherapy (WP3),- clinical requirements, protocols and validation (WP4),- organs at risk assessment studies (WP4),- clinical workshops for training and dissemination purposes (WP5),- management (WP6)

Expected results The project has the potential to accelerate development of advanceddevices, to ensure their dissemination, to increase the compromisebetween treatment efficiency and patient safety, to consolidatecollaboration between European teams and to spread new methodsand knowledge through workshops.

A major expected result of the project is to decrease the number ofdeaths due to primary tumours without metastases.

CANCERMAESTRO


Coordinator Jean-Philippe NicolaïCommissariat à l’Energie Atomique (CEA)31-33, rue de la Fédération75752 Paris FranceE-mail: [email protected] web-site: www.maestro-research.orgKey words: quality assurance, clinical validation, IMRT, proton-

therapy, multimodality image registration, virtualsimulation software, Monte Carlo dose calcula-tion TPS, in vivo dosimeters, risk assessment,accurate patient positioning

PartnersIon Beam Applications S.A, BelgiumTechnische Universiteit Delft,The NetherlandsIstituto Nazionale Di Fisica Nucleare, ItalyDosisoft S.A, FranceInstytut Fizyki Jadrowej Im. Henrika Niewodniczanskiego,Polska Akademia Nauk, PolandEldim S.A, FranceNuclear Research and Consultancy Group,The NetherlandsUniversita Degli Studi Di Firenze, ItalyREM Radioterapia SRL, ItalyIstituto Superiore Di Sanita, ItalyCoventry University, United-KingdomNPL Management Limited, United-KingdomInstitut Gustave Roussy, FranceCentre National de la Recharche Scientifique, FranceCentre National François Baclesse, FranceUniversitaet Duisburg-Essen, GermanyUniversity of East Anglia, United KingdomUniversidad de Castilla, La Mancha - SpainUniversity Hospitals Coventry and Warwickshire NHS Trust,United KingdomCentrum Onkologii Oddzial W Krakowie, PolandInstitut National de la Recherche en Informatique et enAutomatique, FranceUniversitat de Barcelona, SpainScanditronix Medical AB, Sweden

Acronym: MAESTRO Project number: LSHC-CT-2004-503564 EC contribution: €7 000 000Instrument: Integrated ProjectDuration: 60 monthsStarting date: 01/05/2004


SummaryCCPRB is a Network of Excellence project within the Sixth

Framework Programme of the European Union. It is aimed at

improved control of cancer by facilitating research linking biobanks

and cancer registries. The project involves a systematic quality

assurance of European biobanks, as well as improved integrity

protection in the handling of sensitive information in connection with

biobank-based research.The samples in the biobanks will be used in

large-scale cancer research searching for genetic and infectious causes

to cancer, in particular in the areas of breast and colorectal cancer

and childhood leukaemias.

BackgroundLongitudinal studies nested in biobanks enable more reliable andefficient study designs, both for design and evaluation of cancertreatment and cancer prevention as well as for exploring andevaluating etiologic hypotheses.However, several prerequisites apply:

There must exist very large-scale biobanks with several decades offollow-up.

It must be possible to link biobanks with quality-assured population-based cancer registries to enable population-representative studieswith minimal case ascertainment bias.

Important problems regarding overview, accessibility, quality control,phenotypic characterisation,efficiency and avoiding risks for violationof personal integrity must be addressed.

The participants The present network has linked large biobank projects with up to 30years of follow-up and >60 000 prospectively occurring cancer casesand cancer registries with >40 years of population-based registration.There are 19 partners in the project from nine European countries,including e.g.sevencancer registries,20 biobank projects and a numberof platforms for advanced technological analysis of biobank samples.

AimProvide the study base for uniquely large population-basedprospective studies on cancer.

Define and implement a European Quality Standard for biobanking.

Define and promote the implementation of integrity-proof methodsfor biobank-based research involving well defined and secure thirdparty code-keeping systems.

Enable large-scale, population-based research on:

a) evaluation of cancer treatment and role of molecular markers intreatment selection;

b) identification and evaluation of genetic markers associated withincreased cancer risk using over-generation linkages;

c) exploration and evaluation of intrauterine exposures associatedwith increased cancer risk using overgeneration linkages;

d) design of optimal strategies for cancer prevention and its evaluation.

Establish a Europe-wide network for spreading the awareness ofpossibilities and best practice quality standards for biobank-basedresearch.

Cancer control using population-based registries and biobanks


CANCER CCPRB

The samples inthe prospective

research biobanks arealiquoted into

color-coded tubes (buffy coat, EDTA-plasma, heparin-

plasma and so on).

The freezer facility of the

Medical Biobankin

Umeå



CANCER

Coordinator Prof. Dillner, JoakimLund UniversityDepartment of Medical MicrobiologyMalomo University HospitalEntrance 78,205 02 Malmo, SwedenPhone: + 46 40 338126 Fax: + 46 40 337312E-mail: [email protected]

PartnersProf. Hakulinen,Timo

Finnish Cancer Registry

Helsinki, Finland

Dr Thoresen, Steinar

Kreftregisteret/The Cancer Registry of Norway

Oslo, Norway

Prof. de Villiers, Ethel-Michele

Deutsches Krebsforschungszentrum AngewandteTumorvirologie/Tumorvirus-Charakterisierung

Heidelberg, Germany

Prof. Lenner, Per

Umeå Universitet Institutionen för StrålningsvetenskaperOnkologi, Umeå, Sweden

Prof. Jellum, Egil

The Norwegian Cancer Society Institute of ClinicalBiochemistry

Oslo, Norway

Prof. Hemminki, Kari

Karolinska Institutet Department of BioSciences

Huddinge, Sweden

Prof. Ögmundsdóttir, Helga M.

Icelandic Cancer Society Molecular and Cell BiologyResearch Laboratory

Reykjavik, Iceland

Dr. Koskela, Pentti

National Public Health Institute

Department of Microbiology

Laboratory of Prenatal Serology

(Finnish Maternity Cohort serum bank)

Oulu, Finland

Prof. Bartram, Claus R

University Hospital Heidelberg Institute of Human Genetics Heidelberg, Germany

Acronym: CCPRBProject number: LSHC-CT-2004-503465EC contribution: €6 050 000Instrument: Network of ExcellenceDuration: 60 monthsStarting date: 01/06/2004

Prof. Garnett, Geoffrey Imperial College of Science,Technology and Medicine Dept. Infectious Disease EpidemiologyFaculty of Medicine St Mary’s HospitalLondon, United Kingdom Dr Lehtinen, Matti University of Tampere Public Health School and MedicalSchool Tampere, Finland Prof. De Paoli, Paolo Centro di Riferimento Oncologico Department of Laboratory MedicineLaboratory of Microbiology Aviano, Italy Dr Houlston, Richard Section of Cancer Genetics Institute of Cancer Research Sutton, Surrey, United Kingdom Dr. Grzybowska, EwaCentre of Oncology M. Sklodowska-Curie Memorial InstituteBranch GliwiceDepartment of Tumour BiologyCancer Genetics LaboratoryGliwice, PolandDr Marc Arbyn Scientific Institute of Public Health Unit of Epidemiology – I.P.H.Brussels, Belgium Prof. Buntinx, Frank Limburgse Kankerstichting Limburg Cancer Registry(LIKAR),Hasselt, Belgium Prof. Löve,ArthurLandspitali University Hospital Department of MedicalVirologyLandspitali University Hospital Reykjavik, Iceland Hansson, Mats G.Uppsala University Dept. of Public Health and Caring SciencesUppsala, Sweden


SummaryThe lifespan of the European population is increasing and,

accordingly, diseases that become prevalent in old age,

such as brain tumours, will afflict a larger percentage of

this population. In addition, brain tumours are now one

of the leading causes of death from cancer: the first in

children under the age of 15 and the second from age

15 to 34.Brain tumours do not have a lifestyle-associated

etiology,and so prevention is not yet possible.Diagnosis

and treatment of brain tumours is based on clinical

symptoms, radiological appearance and often a

histopathological diagnosis of a biopsy.

The current gold standard classification of a brain tumour

by histopathological analysis of biopsy is an invasive

surgical procedure and incurs a risk of 1-2% morbidity, in

addition to healthcare costs and stress to the patients.

For tumours that evolve slowly in malignancy (e.g.pilocytic

astrocytoma in children) repeated biopsy may not be

advisable at all. On the other hand, diagnosis using

Magnetic Resonance Imaging (MRI) is non-invasive, but

only achieves 60-90% accuracy depending on tumour type

and grade.Likewise,treatment response of histological or

radiologically similar tumours can vary widely,particularly

for childhood tumours. Therefore, there is a need to

improve brain tumour classification, and to provide non-

invasive methods for brain tumour diagnosis and

prognosis, to aid the patient management and to have a

personalised treatment. Two molecular techniques are

available to address these needs. Magnetic Resonance

Spectroscopy (MRS) which can provide metabolic

information on tissue either in vivo (non-invasive) or ex

vivo (biopsy) and more recent DNA microarray analysis can determine

tumour phenotype from gene expression profiles and genotype.The aim

of eTUMOUR project is to coordinate European health care

professionals with a validated Decision Support System (DSS) for non-

invasive diagnosis of brain tumours, and the monitoring of tumour

progression, and response, for future new therapies.This DSS product

is based in an improved classification of brain tumours using molecular

technologies such as Genomic and Metabolomic whose contributions

will provide new knowledge of brain cancer biochemistry which could

be used for developing new bio-markers for a more precise diagnosis

and for developing more selective and appropriated treatments. A

particular and important feature of eTUMOUR is the quality control and

validation system enclosed in the project that ensures the quality and

efficacy of the final products.This European consortium is unique and

we are not aware of any similar system being developed anywhere else

worldwide.

Web-accessible MR decision support system for braintumour diagnosis and prognosis, incorporating in vivoand ex vivo genomic and metabolomic data

CANCER eTUMOUR



Coordinator Prof. Celda, Bernardo

University of Valencia

Spain


Project web-site: http://www.uv.es/etumour,http://www.etumour.net

Key words: DNA, micro-arrays, HR-MAS of biopsies,DSS, GUI, Molecular Imaging

PartnersUniversitat Autònoma de Barcelona, Spain

St George’s Hospital Medical School, London, UnitedKingdom

University Medical Centre Nijmegen,The Netherlands

Stichting Katholieke Universiteit,The Netherlands

INSERM U594, France

INSERM U318, France

MICROART, S.L., Spain

Hospital San Joan de Deu, Spain.

Pharma Quality Europe, s.r.l. Italy

Hyperphar Group SpA. Italy

Katholieke Universiteit Leuven, Research &Development, Belgium

Siemens AG, Medical Solutions, Germany

SCITO S.A., France

Universidad Politécnica de Valencia, Spain

Deutsche Krebsforschungszentrum Heidelberg, Germany

BRUKER BIOSPIN SA, France

Institute of Child Health, University of Birmingham,United Kingdom

FLENI,Argentina

Medical University Lodz, Poland

Acronym: eTUMOUR Project number: LSHC-CT-2004-503094EC contribution: €7 499 982Instrument: Integrated ProjectDuration: 60 monthsStarting date: 01/02/04

CANCER



SummaryThe key to individualising treatment for cancer lies in finding a way to

quickly ‘translate’ the discoveries about human genetics made by

laboratory scientists in recent years into tools that physicians can use

to help make decisions about the way they treat patients.This area of

medicine that links basic laboratory study to the treatment of patients

is called translational research. TRANSBIG has been created as a

multidisciplinary network of excellence devoted specifically to this type

of research in breast cancer.

TRANSBIG is a research network of 39 world-class institutions in 21

countries. Each participating organisation brings with it expertise that

ranges from being specialised in cutting-edge biomedical technologies

and cancer treatment programmes to lobbying governments on behalf

of patient groups and supporting cancer societies. As a network,

TRANSBIG will be dedicated to high-level collaboration that will

contribute dramatically to advancing individualised treatment for breast

cancer patients.Among its many strengths is the fact that it is linked to

an already existing network of groups around the world that conduct

clinical breast cancer research together – the Breast International

Group (BIG).BIG’s 33 member organisations are active in 36 countries.

The central secretariat is located in Brussels, and will coordinate the

activities of both TRANSBIG and BIG.By linking the two networks and

by benefiting from a central coordinating body, the fragmentation

currently existing in the field will be reduced,and translational research

in Europe will be strengthened and accelerated.

New technologies will only gain acceptance by physicians and patients

after first being validated in large, independent clinical trials. Microarray

technology has enabled scientists to determine the signature of individual

tumours,but it must be proven that this information is more reliable than

existing methods for determining how to best treat individual patients.

Aim• to develop ways of individualising breast cancer treatment, so that

treatment is tailored to the person receiving it.

• to integrate, strengthen and facilitate translational clinical breastcancer research in Europe and internationally by linking it to anexisting network for clinical breast cancer trials (BIG).

• to develop and run a major clinical trial aimed at validating thehypothesis that understanding the genetic make-up (signature) of atumour can lead to better targeted treatment.

ProblemBreast cancer is the most common cancer among women indeveloped countries,with one out of eight to ten women developingthe disease in her lifetime.While incidence has steadily increased overthe past decades, only recently has a slight decrease in deaths frombreast cancer been noted, and that only in a few countries.

Breast cancer is curable in about 70% of cases if diagnosed and treatedearly enough. But because of uncertainty over the best treatment inindividual cases, many women receive chemotherapy or hormonaltreatment after surgery based on the assumption that the risk is highthat their breast cancer will recur. However, some women benefitsignificantly from such treatment and others only very little or not atall.The reason for this is because breast cancer is a disease that developsvery differently in each woman. If individual tumours were betterunderstood, physicians would be better able to make decisions aboutwhich treatments are best for individual patients and which patientsneed no further treatment after surgery at all. Presently it is estimatedthat about 12% to 20% of patients are over-treated,resulting in avoidablecosts both to health services (financial) and patients (side-effects).

Technical approachAlthough TRANSBIG will ultimately develop many projects, it will startwith a clinical trial called MINDACT (Microarray for Node NegativeDisease may Avoid Chemotherapy). This trial will compare twodifferent ways of assessing the probability or risk that a woman’s breastcancer will come back. The traditional method is based oninternational guidelines and looks at specific characteristics such asthe size of a patient’s tumour and whether the disease has spread tothe lymph glands (nodes).The new method uses microarrays as a wayof analysing the genetic components of a tumour. Specifically,traditional methods of assessing risk will be compared to a 70 genetumour ‘signature’ identified by a group of scientists at the NetherlandsCancer Institute that appears to predict very accurately whether aparticular woman’s breast cancer will come back. MINDACT willinvolve 5000 women over a three-year period.

Other cutting-edge techniques and technologies will be used in theproject over time,and tumour and blood samples donated by patientswill create an invaluable resource for further research that will helpus to better understand and treat breast cancer.

Translating molecular knowledge into early breast cancer management: building on the BreastInternational Group (BIG) network for improved treatment tailoring


CANCER TRANSBIG


Expected resultsImpact of MINDACT

The TRANSBIG partners believe that the results of MINDACT will showthat using the new technology to assess risk will result in fewer womenbeing treated unnecessarily.This, in turn, will mean that fewer womenwill suffer from the unpleasant side-effects of chemotherapy. Not onlywill the overall quality of life of breast cancer patients be improved,butthe health care costs associated with such cancer treatment will bereduced as well, thus providing a significant benefit to society.

As the first project in TRANSBIG, MINDACT will also establishvaluable resources for future research and establish links betweenresearch and biotechnology enterprises in order to develop furtherdiagnostic tools that can be widely disseminated and easily used byscientists and physicians alike.

Impact of TRANSBIG

The long-term aim is to develop TRANSBIG into a permanentnetwork for translational research that is complementary to theclinical work done by BIG.This guarantees a connection between whatscientists learn in the laboratory and what physicians and patientsdecide together about treatments in the clinic.

But TRANSBIG’s reach will be wider than simply research. It will alsobe concerned with education through the provision of traineeshipsfor young scientists and physicians and public education on the issuesinvolved with genomics by working closely together with cancersocieties and patient advocacy groups.

By bringing together scientists, clinicians, and representatives frompatient groups, cancer societies and industry,TRANSBIG will bring acoherence and synergy to breast cancer research that has previouslynot existed in Europe.


CANCER

The European Organization for the Research andTreatment of Cancer, Brussels, BelgiumUniversity of Glasgow, Glasgow, United KingdomUniversitaet Wien,Vienna, Austria Grupo Oncologico Cooperativo Chileno de Investigacion,Santiago, Chile Bank of Cyprus Oncology Centre, Nicosia, CyprusUniverzita Karlova v Praze, Prague, Czech RepublicFinsen Centre - Rigshopitalet, Copenhagen, DenmarkInstitut Gustave Roussy,Villejuif, FranceWest German Study Group, UniversitaetsklinikumDusseldorf, Dusseldorf, Germany Klinikum der Johann Wolfgang von Goethe Universitaet,Frankfurt, GermanyTechnische Universitaet Muenchen, Munich, GermanyUniversitaetsklinikum Eppendorf, Hamburg, Germany National and Kapodistrian University of Athens, Athens,Greece St Vincent’s University Hospital, Dublin, IrelandGruppo Oncologico Italiano di Ricerca Clinica, Parma, ItalyCentre Hospitalier de Luxembourg, Luxembourg Universiteit Maastricht, Maastricht,The Netherlands Medical University of Gdansk, Gdansk, Poland Portuguese Institute of Oncology Francisco Gentil, Porto,Portugal N. N. Blokhin Cancer Research Centre, Moscow, RussiaInstitute of Oncology, Ljubljana, SloveniaInstitute of Oncology of Southern Switzerland Mendrisio,Switzerland Marmara University Medical School Hospital, Istanbul,TurkeyFederation of European Cancer Societies, Brussels, Belgium Europa Donna – The European Breast Cancer Coalition,Milan, Italy Instituto de Patologia e Imunologia Molecular daUniversidade do Porto, Porto, PortugalGSF – Forschungszentrum fuer Umwelt und Gesundheit,Munich, GermanyAgendia,Amsterdam,The Netherlands International Institute for Drug Development, Brussels,Belgium Fundacion Institut per la Recerca Vall d’Hebron, Barcelona,Spain Grupo Español de Estudio,Tratamiento y otras EstrategiasExpirementales en Tumores Sólidos, Madrid, Spain Swiss Institute of Bioinformatics, Lausanne, Switzerland University of Oxford, Oxford, United Kingdom

Coordinator Piccart, MartineJules Bordet Institute1, rue Héger-Bordet1000 Brussels, BelgiumPhone: + 32 2 541 3526 Fax: + 32 2 541 3199E-mail: [email protected] words: Breast cancer

PartnersBreast International Group (BIG-aisbl), Brussels, Belgium Institut Jules Bordet / Jules Bordet Instituut, Brussels,BelgiumThe Netherlands Cancer Institute, Amsterdam,The Netherlands Istituto Europeo di Oncologia - European Institute of Oncology, ItalyKarolinska Institutet, Stockholm, SwedenUniversity of Wales, Swansea, United Kingdom

Acronym: TRANSBIGProject number: LSHC-CT-2004-503426EC contribution: €7 000 000 Instrument: Network of ExcellenceDuration: 60 monthsStarting date: 01/03/2004


SummaryLeukaemias are a challenge to society and a cost factor because of their

frequency in all age groups.They also serve as a model for a variety of

diseases and possess exemplary relevance for basic research and patient

care.Leukaemia research and therapy have achieved high standards and

even a leading position in several European countries with regard to

clinical trials,standardisation of diagnostics and molecular studies of signal

transduction and gene expression. A true European world leadership,

however, has not been accomplished yet due to national fragmentation

of leukaemia trial groups,diagnostic approaches and treatment research

activities and a need for central information and communication

structures.

AimMultiple drug resistant bacteria are a major threat to human healthand a significant burden on already stretched medical budgets.Thisthreat is predicted to increase in severity, and remedial actions ofreducing antibiotic use in animal husbandry and limiting currentprescribing activities for non-lethal human disease are both unlikelyto reduce the danger in the short-term. Of major concern areantibiotic-resistant nosocomial infections.The economic and societalcosts of these hospital-acquired infections are enormous: the UKNational Health Service has estimated an annual cost of €1.5 billionfor extra patient care and that 5000 deaths result each year. Inaddition, the incidence of infection by multiple drug resistant strainsof Mycobacterium tuberculosis, the causative agent of the tuberculosis,is rapidly increasing,particularly among the disadvantaged in society.Investment in R&D into antibiotic discovery by the majorpharmaceutical companies has declined dramatically in the last 15years as a perception has taken hold that easily obtained naturalproducts may have been fully exploited. Hence conventionalscreening of natural products for new drugs is no longer consideredeconomically worthwhile. Unfortunately, the downturn in drugdiscovery has coincided with a dramatic worldwide increase in theincidence of resistance to all the antibiotics currently used inmedicine.

The objective is to integrate the 78 leading leukaemia trial groups(chronic myeloid leukaemia (CML), acute myeloid leukaemia (AML),acute lymphoblastic leukaemia (ALL), chronic lymphoid leukaemia(CLL), myelodysplastic syndromes (MDS), chronicmyeloproliferative disorders (CMPD)), their 83 interdisciplinarypartner groups (diagnostics, treatment research, registry,

guidelines), industry and SMEs across Europe to form a cooperativenetwork for advancements in leukaemia-related research and healthcare. Integration will be supported by central information,communication,education and management structures.Other goalsare to intensify target and drug discovery, to shorten the timeperiod to clinical translation, to apply advanced genomics, telematicsand biotechnology to therapeutic progress and to promoteresearch relevant also for solid cancers by large clinical trials.Furthermore, meta-analyses of specific subaspects, elaboration ofprognostic scores, recognition of gender-specific differences,creation of uniform data sets for trials and registration, introductionof standards for diagnostics and treatment and development ofevidence-based guidelines will be promoted throughout Europe.Theproposed network will have the expertise and critical mass forEuropean added value and world leadership. It will structureEuropean research durably, spread European scientific excellencein the field of leukaemias and can start immediately.

The 78 leukaemia trial groups and their 83 interdisciplinary partnergroups representing several thousand participating centres and tenthousands of study patients treated within the trial groups formthe backbone of the network. The network consists of 18 workpackages. Of these, six deal with the various diseases (AML, ALL,CLL,CML,MDS,CMPD) and represent sub-networks on their own.Nine work packages represent interdisciplinary platforms whichprovide the support and research expertise required for high qualitynetworking and excellence. Three core work packages providecentral communication and management services for the wholenetwork.

The integration and interdisciplinary cooperation brings together 116participants and approximately 900 researchers from 22 countries.The network will overcome national fragmentation and provide thecritical mass to achieve research and treatment goals that cannot beachieved by single European countries.

Expected results1. Establishment of central information and communication structures tocreate networks and platforms for all leukaemias and their interdisciplinarypartners.

Integration is mediated by exchange of current trial protocols andprocedures, information on participating centres and recruitedpatients and employment of uniform common data sets forcomparable study outcomes and evaluations provided by thebiometrical center (WP 17).This objective will be achieved throughcentral services: Network Management Center (NMC, WP 1),European Leukaemia Information Center (ELIC,WP 2) and Central

Strengthen and develop scientific and technological excellence in research and therapy of leukaemia (CML,AML,ALL, CLL, MDS,CMPD) by integration of the leading national leukaemia networksand their interdisciplinary partner groups in Europe

CANCER European LeukaemiaNet



Information and Communication Services (CICS,WP 3).The centralservice groups benefit from a three years' experience in similartasks for the German Competence Network for Acute and ChronicLeukaemias funded by the German Ministry for Education andResearch (BMBF) and provide the basis for a head start of thenetwork. These groups will also provide training programmes,workshops, symposia, exchange of researchers and informationprogrammes, thereby spreading excellence to health carepersonnel, researchers and to other countries not yet participatingin the network.With the support of NMC (WP 1) the network willbe managed in a two-layer networking organisation. Clinical trialgroups for each leukaemia and their interdisciplinary partner willform their own European subnet organizations with coordinators,steering groups and management structures. These subnets andplatforms will then be integrated in the European LeukaemiaNetwork which will conduct the integrated research programmedetailed below. The network will be managed by the NetworkCoordinator (NC), the Scientific Network Manager (SNM) and theSteering Committee (SC) consisting of the coordinators (=Leadparticipants) of the work packages (WP). The University ofHeidelberg will provide the expertise for financial, legal andcontractual management.

2.Set-up of European networks for each leukaemia and related syndrome.

These networks will comprise the national trial groups for eachleukaemia and represent the first stage of networking and Europeanintegration.

3. Set-up of European platforms for each interdisciplinary specialty.

These platforms are sub-networks of excellenceof diagnostic, therapeutic and biometric researchgroups on their own and constitute inter-disciplinary partners enabling the clinical trialgroups to achieve the high quality patient care andresearch required for European leadership.

4. Performance of clinical trials (all leukaemias).

Employing uniform common data sets the trialgroups will continue their current trials funded byalternative sources and will start new trials usingdiagnostic standards established by the diagnosticplatforms (WPs 10-13) and employing new drugsprovided by pharmaceutical companies and/or thesub-network on treatment research/new targets/new drugs (WP 16). Criteria for accreditation oftrials will be set up.

Lung infection and inflammation is a growingproblem within all states of the EU, and theinfections are routinely treated with antibiotics.The pharmaceutical industry is interested in thedevelopment of protein therapeutics, which canbe used as alternatives to antibiotics.There is arelatively fragile protective barrier, the alveolarlining layer, which controls the interactionbetween the atmosphere and the lung.The film,known as lung surfactant, plays two important

roles, prevention of lung collapse during respiration and provisionof a first line of defence against the extremely varied range ofparticles, allergens and microbes that are present in theenvironment. The lung surfactant is a surface-active mixture ofphospholipids and four main surfactant proteins – SP-A, SP-B, SP-Cand SP-D.The SP-B and SP-C proteins are small, highly hydrophobic,polypeptides, which are strongly associated with the phospholipidportion of the surfactant, whereas SP-A and SP-D are large(approximately 600kDa) and complex, disulphide-bonded, proteinsof a more hydrophilic nature.They can bind, via their lectin domains,to arrays of carbohydrate structures on the surfaces of pathogenicmicrobes and to glycosylated allergens, thus initiating defence againsta range of viral, fungal and bacterial lung infections and modulatingallergic reactions.There is evidence of lowered levels of SP-A, andSP-D, in the lung surfactant of a growing number of types of infection-or allergy-mediated lung inflammation, which strengthens the casefor testing the use of recombinant forms of these proteins astherapeutic alternatives to antibiotics.

5. European Registry (all leukaemias).

A European registry will allow to determine incidence and diseasepatterns across Europe including gender, age and ethnic differences,investigate familiar aggregations, overlap syndromes or precursorconditions, explore risk factors associations and differences in geneenvironment interaction, using data from cytogenetic analyses (WP11) and genomic profiling (WP 13),perform quality of life assessments,recognize sub-entities on the basis of cytogenetic or gene profilinginformation, follow-up patients for the development of prognostic

Geographic distribution of lead participants and participants representing national studygroups comprising more than 1,000 centers in 22 countries

CANCER



scores for old and new therapies and determine proportions ofpatients in individual countries treated on specific protocols or withspecific therapies e.g. SCT (WP 14).The registry will be run by theexpert group Biometry for Registry, Epidemiology, Metaanalyses andPrognosis (WP 17). This group has gained a long-standing broadexperience in collecting data, performing meta-analyses andestablishing prognostic scores. The database established by thenetwork will have far-reaching implications for research and publichealth planning far beyond the period of EC funding.

6. Standardisation

Standardised and quality controlled diagnosticprocedures and therapies constitute the basis forimprovements of clinical outcomes. Thisconcerns all diagnostic approaches such asmorphological diagnosis of blood and marrowcells (WP 10), cytogenetics (WP 11), detectionof minimal residual disease (WP 12) and geneexpression profiling (WP 13) as well as therapiessuch as transplantation,anti-infection prophylaxisand treatment and the testing of new drugs inphase I/II trials (WP 14-16).The establishmentof standards for a wide spectrum of diagnosticand therapeutic applications will raise the qualityof research and patient care beyond the periodof EC funding and will predictively have aprofound impact on outcome as measured byprolongation of life and cure rates across Europe.

7. Metaanalyses and guidelines

Whenever randomised trials are available for analysis (mostly CMLand AML), meta-analyses will be performed and published (WP 17).On the basis of meta-analyses,evidence-based guidelines (WP 18) willbe worked out and used for the improvement of patient managementand for educational purposes (training programmes, workshops inassociated countries, exchange of researchers and physicians fortraining purposes).Meta-analyses will be also performed on combineddata sets with rare subtypes of leukaemias (WP6).

Network Structure: The different platforms are grouped into workpackages(WP). Central services:WP 1: Network Management Center (NMC),WP2:

Leukemia Information Center (ELIC),WP3: Central Information andCommunication Services (CICS). Clinical trial platforms:WP4: CML,WP5:AML,WP6: ALL,WP7: CLL,WP8: MDS;WP9: CMPD. Diagnosis/Follow-up:WP10: Diagnostics;WP11: Cytogenetics;WP12: MRD;WP13: Gene Profiling.

Treatment Research:WP14: Stemcell Transplantation;WP15: Supportive Care,Anti-infection Prophylaxis and Treatment;WP16:Treatment Research / Drug

Development. Registry/Education:WP 17: Biometry of Registry, Epidemiology,Metaanalyses and Prognosis;WP18: Guidelines.


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CANCER

Coordinator Prof. Hehlmann, Rüdiger

III. Medizinische Universitätsklinik

Ruprecht-Karls-Universität Heidelberg

Wiesbadener Str. 7-11

68305 Mannheim, Germany

Phone: + 49 621 383 4115

Fax: + 49 621 383 4201


Project web-site: http://www.leukaemia-net.org

Key words: leukaemia, CML,AML,ALL, CLL, MDS,CMPD

PartnersUniversitätsklinikum Frankfurt, Germany

Ludwig-Maximilians-Universität München, Germany

Uppsala Universitet, Sweden

Universita di Bologna - Unita Complessa di Istituti diCardiologia ed Ematologia, Italy

Université de Poitiers, France

Ruprecht-Karls-Universität Heidelberg, Germany

Universitätsklinikum Münster, Germany

University of Wales, College of Medicine, UnitedKingdom

Fundacion Hospital Universitario “La Fe”, Spain

Les Hospices - CHUV - Switzerland

Dipartimento di Biotecnologie Cellulari ed Ematologia,Universita degli Studi di Roma “La Sapienza”, Italy

Leiden University Medical Center,The Netherlands

Institut Pasteur, France

Universität Ulm, Germany

Universität Köln, Germany

Stichting Katholieke Universiteit, Univ. Medical CenterNijmegen,The Netherlands

Azienda Ospedaliera - Ospedali Riuniti di Bergamo, Italy

IRCCS Policlinico S. Matteo, Italy

Université Henri Poincaré Nancy 1, France

St. Marien-Krankenhaus Siegen gem. GmbH, Germany

Medizinische Unversität Wien,Austria

Philipps-Universität Marburg, Germany

King's College London, United Kingdom

Imperial College London, United Kingdom

University of Basel, University Hospitals - Switzerland

Universität Leipzig , Germany

Karolinska Institutet, Sweden

Eberhard-Karls Universität Tübingen, Germany

Uniersity of Newcastle upon Tyne, United Kingdom

Association pour la Recherche sur les TransplantationsMedullaires, France

Acronym: European LeukaemiaNetProject number: LSHC-CT-2004 503216EC contribution: €6 000 000 Instrument: Network of ExcellenceDuration: 60 monthsStarting date: 01/01/2004


SummaryA key clinical question in the management of

primary breast cancer concerns the

assessment of information provided by risk

factors measured in blood and tissue that

support the choice of an optimal adjuvant

treatment regimen for the individual patient.

The basic understanding of breast cancer

initiation and progression is still far from being

understood.Apart from that, we will need to

develop highly reliable methods to classify

breast cancer patients in different risk groups,

based on their detailed tumour characteristics.

Cancer is a genetic as well an epigenetic

disease. A prominent epigenetic alteration is

DNA-methylation in the promoter region of

the gene that prevents the gene to be

expressed.Our translational project uses newly

developed state-of-the-art DNA methylation

approaches that recently have become available

through partners of this consortium.The aim

of the project is to develop prognostic and

predictive DNA methylation profiles for breast

cancer patients.

ProblemBreast cancer is the leading malignancy in women and a leading causeof death.The mortality rate has slightly decreased over the past fewyears, but statistic tends indicate that the incidence is rising furtherdue the aging of the population.The high importance of the necessityof improved breast cancer diagnosis and therapy is without any doubt.Markers that allow better targeting of available therapies to particularpatients will most likely improve outcome in cancer in the future.Indeed, the dilemma of optimal treatment of primary breast canceris complex for both patients with primary breast cancer and forpatients with recurrent disease (metastases). To enable and allowtailored therapy concepts that take the individual tumour biology intoaccount, new and specific tumour-associated factors are needed thatguide the physician in the prediction of the patient's prognosis and oftherapy response. Even though enormous efforts have been put intothe identification of prognostic and predictive factors over the yearsthe successful identification of strong markers has been limited.This

is due to imperfect technologies, limited size and heterogeneity ofpatient cohorts studied and lack of reproducibility and uniform assaymethodologies as well as quality assurance programs.

Background on DNA methylation in cancer DNA methylation occurs only on cytosines, and methyl-cytosine isconsidered the fifth base (Figure 1). In cancer,DNA methylation shiftstowards the regulatory regions of genes resulting in silencing oftumour suppressor genes. Promoter DNA methylation is a boomingfield in cancer biology since it has become apparent that thisepigenetic type of gene regulation contributes to many aspects ofcancer biology, such as tumour initiation, tumour aggressiveness,tumour metastasis, and tumour behaviour during systemic therapy.

The fifth base in the genome:Methylation of the carbon 5 position is the epigenetic modification in the mammalian

genome that contributes to cancer © Epigenomics AG, Berlin.

Epigenetic profiling of breast cancer: prognostic and therapeutic applications


CANCER DNA METHYLATION


DNA methylationas diagnostics Several properties makeepigenetic changes at the level ofthe DNA attractive as diagnostictargets. DNA methylation is verystable and localised; it can beturned into genetic informationand subsequently amplified byclassic PCR. Finally, methylationdetection is feasible in fixed,paraffin-embedded material.Thesefeatures allow for sensitive andquantitative detection and rapidtransfer of a diagnostic test toclinical routine. Furthermore,since DNA methylation regulatesgene expression and results froma simple change, a methylation ona cytosine residue or not, it can beconsidered as a binary genotypicchange that is responsible for theobserved phenotypic difference (Figure 2). Although DNA-methylation markers have not found their way to the clinic yet,they could be important and powerful diagnostic or predictivemarkers not far ahead.

AimThe key activity of this project is to identify and validate DNAmethylation markers with clinical value. The project addresses theclinical need to come to tailored treatment of breast cancer patients,of whom a large proportion is over-treated, or would benefit from

other types of systemic therapy.To identify the markers genome-widehigh-throughput DNA methylation screening will be performed onwell-defined breast tumour tissue banks (>20,000 tumour tissuesamples) with complete computerized follow-up information onpatient's course of the disease and treatment response.We intend toidentify DNA methylation markers that predict prognosis and therapysuccess. The 9 participating centres contribute complementaryproprietary technical expertise, large and well-documented tissueresources, and extensive clinical knowledge.To maximize the chancesto successfully identify specific risk-associated targets for tumouraggressiveness and effectiveness of systemic endocrine andchemotherapy,DNA is prepared from carefully selected tumours from


CANCER

DNA methylation as molecular switch:Methylation of cytosine in the regulatory region of a gene turns it ON or OFF.This way it con-

tributes to the cancer phenotype with respect to aggressiveness and therapy responsiveness.Theproject aims to identify the key molecular switches. Since the simple nature of the change, methy-

lation or not, it can be treated as binary information © Epigenomics AG, Berlin.

Binary epigenetic predictor:Predictive DNA methylation patterns identified during this project and indicated by the bar-code here can guide the clinician todecide whether to treat or not thetreat and to determine the besttype of treatment for the individualpatient © Epigenomics AG, Berlin.


the large tissue collectives that are available through members of thisconsortium.After the identification of potential target genes for someof the major clinical questions regarding breast cancer prognosis andtherapy prediction, validation steps are carried out. The latter alsoinvolves biochemical validation of mRNA and protein expression ofthe differentially methylated genes,and clinical validation of the newlydiscovered targets in large numbers of tumours.

The ultimate goal of the project is to improve breast cancer prognosisand treatment in the European Community and beyond and give theEuropean Union the lead in this important field of cancer diagnostics.

Expected results and potential applications The prime spin-off of our current project is to provide a majorrefinement of breast cancer classification allowing accurateprediction of patient prognosis and response to therapy based onnewly identified DNA methylation markers as exemplified in Figure3. The intellectual property generated during this project will bepatented. We expect the diagnostic tests to be used for clinicaldecisions about the choices of treatment.

Prof. Dr. Nils Brünner

Royal Danish Veterinary and Agriculture University

Institute of Pharmacology and Pathobiology

Frederiksberg C, Denmark

Dr. Fred CGJ Sweep

Department of Chemical Endocrinology

University Medical Center Nijmegen

Nijmegen,The Netherlands

Dr. Sabine Maier

Epigenomics AG

Berlin, Germany

Dr. Frédérique Spyratos

Centre René Huguenin

Laboratoire d'Oncobiologie

St-Cloud, France

Dr.Tanja Cufer

Department of Medical Oncology

Institute of Oncology

Ljubljana, Slovenia

Dr. Joe Duffy

National University of Ireland

Nuclear Medicine Department

St.Vincent's University Hospital

Dublin, Ireland

Dr. Serenella Eppenberger-Castori

Prof. Dr. Urs Eppenberger

Stiftung Tumourbank Basel

Riehen, Switzerland

CoordinatorDr. John A. Foekens

Department of Medical Oncology

Erasmus MC Rotterdam

Josephine Nefkens Institute, Rm BE426

Dr. Molewaterplein 50

3015 GE Rotterdam,The Netherlands

Phone: +31 10 4088369

Fax: +31 10 4088365


Project web-site:http://www.erasmusmc.nl/interne_oncologie/FP6/

Key words: breast cancer, DNA methylation, diagnosticmarkers, prognosis, chemotherapy, endocrine therapy.

PartnersProf. Dr. Manfred Schmitt

Dr. Nadia Harbeck

Department of Obstetrics and Gynecology

Technische Universität München

Klinikum rechts der Isar

Munich, Germany

Acronym: DNA METHYLATIONProject number: LSHC-CT-2003-504586EC contribution: €2 533 758Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/01/2004

CANCER



SummaryMantle cell lymphoma (MCL) is a subtype of malignant lymphoma with

an especially poor prognosis. Recently, a European MCL Network of

clinicians, basic scientists and pathologists has been established to

investigate the clinical as well as molecular aspects of MCL. In previous

clinical trials,the superiority of innovative treatment options (high dose

therapy,combined immuno-chemotherapy) has been confirmed,and cell

proliferation has been identified as the most important prognostic

factor. Based on these extensive prerequisites, we have initiated a

translational approach to evaluate innovative treatment options (like

immuno-chemotherapy, radioimmunotherapy, high dose consolidation

and molecularly targeted approaches) and molecular prognostic

markers in prospective randomised studies.All study cases are subjects

of innovative molecular analyses and continuous detection of minimal

residual disease.This translational approach will not only lead to more

effective therapeutic strategies based on the molecular profiling but also

pave the way to molecular targeted treatments.

ProblemMantle cell lymphoma (MCL) is a distinct, clinically very aggressivesubentity of malignant lymphoma with a median survival of three years.However, a small subset of patients represents long-term survivors.So far, the discriminative power of different prognostic parametershas been limited and did not allow the reliable identification of theindividual patient's risk profile. Thus, a better understanding of theunderlying molecular mechanisms is eagerly warranted.

Aim Based on the previously established European MCL Network ofclinicians,basic scientists and pathologists and the recent developmentof innovative molecular techniques (matrix CGH,RNA array chips,RQ-PCR, proteomics), we are performing a global approach to investigateinnovative treatment options of MCL and evaluate new predictive(pharmacogenomics, minimal residual disease) and prognosticmolecular markers (genomic alterations, RNA/proteome profiles) incontrolled prospective studies. This translational approach of theEuropean MCL Network will not only lead to more individualisedtherapeutic strategies based on the molecular risk profile but will alsofinally elucidate the way to future molecular targeted treatment optionsin a subtype of malignant lymphoma with an otherwise dismal clinicaloutcome.

Expected results1. Prospective evaluation of combined immunochemotherapy and

myeloablative consolidation in patients <65 years: R-CHOPfollowed by myeloablative consolidation vs. R-CHOP/R-DHAPfollowed by high dose Ara-C therapy

2. Prospective evaluation of combined immunochemotherapy anddifferent maintenance strategies in patients >65 years:R-CHOP vs.R-FC followed by IFN vs. Rituximab maintenance;

3. Regular histomorphological panel review of study cases (subtypingaccording to cytological criteria);

4. Prospective evaluation of a panel of proliferation-associated andnew oncogenic markers (immuno-histochemistry);

5. Prospective evaluation of MRD detection (PCR,FACS, FISH) in thepatient cohort of the European MCL Network;

6. Prospective evaluation of the proliferation-associated genesignature in the patient cohort of the European MCL Network(RNA array).

European Mantle Cell Lymphoma Network:Translation evalua-tion of molecular prognostic factors and pharmacogenomics inEuropean interdisciplinary collaboration

CANCEREuropean MCL Network



Potential applicationsMalignant lymphoma is currently the fourth most frequent malignantdisease and displays the highest increase in annual incidence of allhematological neoplasias. In this regard, the exploration of innovativetreatment strategies and evaluation of prognostic markers in therather rare disease of mantle cell lymphoma is also a model diseasefor much more frequent diseases which have a profound impact onthe public health system as well as the general society.The prospectivestudies of the European MCL Network studies will enable us to gaina deeper understanding of the pathophysiological network of cellprogramme regulation in malignant lymphoma. In addition, applyingthis multivariate procedure, the critical biological players of malignanttransformation will be identified which may represent the suitabletarget genes of future treatment strategies in a disease with otherwisedismal prognosis. Moreover, this collaboration of outstanding clinicalas well as molecular scientists will be a paradigm for other fields ofbiological research interlinking clinical and basic science as well asscientific excellence from all over Europe.


CANCER

Coordinator Dr Dreyling, Martin

Wolfgang Hiddemann University Hospital Großhadern

Ludwig-Maximilian-University Munich

Dept. of Medicine III

Marchioninistr. 15

81377 München, Germany

Phone: + 49 89 7095 2202

Fax: +49 89 7095 2201


Project web-site: www.lymphome.de

Key words: mantle cell lymphoma, therapy, molecularrisk factors, minimal residual disease (MRD),pharmacogenomics, RNA array profiling,proteomics

PartnersDr Smedegaard, Niels

Andersen Rigshospitalet

University Hospital Copenhagen

Dept. of Hematology

Copenhagen, Denmark

Prof. Campo, Elias

Hospital Clinic

University of Barcelona

Hematopathology Section

Laboratory of Pathology

Barcelona, Spain

Prof. van Dongen, J J M

Erasmus University Medical Center Rotterdam

Department of Immunology


Prof. Kluin, Philip M

Academic Hospital Groningen

Dept. of Pathology and Laboratory Medicine

Groningen,The Netherlands


Prof. van Krieken, Johannes H J M

Stichting Katholieke Universiteit

University Medical Centre Nijmegen

Department of Pathology

Nijmegen,The Netherlands

Prof. Macintyre, Elizabeth

Assistance Publique-Hopitaux de Paris

Hopital Necker-Enfants Malades

Hematology Laboratory

Paris, France

Dr Martinez-Climent, Jose Angel

Fundacion Para la Investigacion Medica Aplicada (FIMA)

Centro para la Investigacion Medica Aplicada (CIMA)

Laboratorio de Oncologia Molecular 108

Universidad de Navarra

Pamplona, Spain

Prof. Meitinger,Thomas

GSF National Research Institute for Environment andHealth

Institut für Humangenetik Ingolstädter

Neuherberg, Germany

Dr Ott, German / Dr Rosenwald,Andreas

Bayerische Julius-Maximilian-Universität Würzburg

Pathologisches Institut

Würzburg, Germany

Prof. Parwaresch, Reza / Dr Klapper,Wolfram

Universitätsklinik Kiel Institut für Hämatopathologie

Würzburg, Germany

Dr Pott, Christiane

University Hospital Schleswig-Holstein

Campus Kiel

II. Med. Klinik und Poliklinik

Kiel, Germany

Dr Ribrag,Vincent

Institut Gustave Roussy, Sce d'Hematologie

Villejuif, France

Prof. Salles, Gilles

Universite Claude Bernard Lyon-1

Centre Hospitalier Lyon-Sud

Service d´Hematologie

Pierre-Benite, France

Prof. Schlegelberger, Brigitte

Medizinische Hochschule Hannover

Inst. für Zell- und Molekularpathologie

Hanover, Germany

Dr Siebert, Reiner

University Hospital Schleswig-Holstein

Campus Kiel

Institute of Human Genetics

Kiel, Germany

Dr Stilgenbauer, Stephan

Universitätsklinikum Ulm Innere Medizin III

Ulm, Germany

Dr Thieblemont, Catherine / Dr Callet-Bauchu,Evelyne

Universite Claude Bernard Lyon-1

Equipe Associee Pathologie des Cellules Lymphoides

Pierre-Benite, France

Dr Trnény, Marek

Univerzita Karlova v Praze (Charles University of Prague)

1st Dept. of Medicine

1st Faculty of Medicine

Praha, Czech Republic

Dr Walewski, Jan

Maria Sklodowska-Curie Memorial Cancer Center

Institute of Oncology

Warszawa, Poland


CANCER

Acronym: European MCL Network Project number: LSHC-CT-2004-503351 EC contribution: €2 493 900 Instrument: Scientific Targeted Research Project Duration: 36 monthsStarting date: 01/07/2004


SummaryThe objectives of this project are to identify genes, proteins and

molecular pathways involved in regulating the metastasis of breast cancer

to specific organs.To achieve these objectives we will use a combination

of gene expression profiling, bioinformatic analysis, histology of human

female breast cancer samples, genetic manipulation of transplantable

tumor cells and transgenic mouse technology. In addition to finding new

genes,we aim to analyse to what extent genes already known to play a

role in breast cancer metastasis specify which organs breast tumors

metastasise to.We will also establish how the currently known genes

that are associated with breast cancer dissemination and the new ones

we identify fit together into pathways that regulate organ-specific

metastasis.These findings will be coupled with the analysis of clinical trials

in which participants in this consortium are involved.Further deliverables

include the development of improved animal models for the study of

breast cancer metastasis, and the development of diagnostic methods

for determining whether primary tumours already have metastatic

potential. Together, the work packages in this project will establish a

pipeline of activities that unite basic research into the organ-specific

metastasis of breast cancer with target validation and clinical application.

ProblemBreast cancer is a major health issue and is highly gender relevant. It isthe most often diagnosed female cancer, and the majority of cases arealready invasive at diagnosis.More than 17% of cancer deaths result frombreast tumours, making breast cancer a major societal problem.Treatment involves radical and disfiguring surgery,often with long-termside effects such as the development of lymphedema of the arm, andradiotherapy and chemotherapy,again associated with severe side effects.The effects of metastatic spread of the tumour cells and the formationof secondary deposits in a wide variety of organs are the cause of deathdue to breast cancer. Metastases to organs such as bone and brain aremajor causes of suffering in terminally ill patients.

The incidence of breast cancer increases sharply between the agesof 30 and 50 meaning that many women in the prime of life are affectedby this disease. Not only does this mean that many families aretraumatised,but it also has severe economic consequences,removingeconomically active women from society. Further economicconsequences arise as a result of the high health care costs associatedwith treating breast cancer patients.

Clearly improvements in the treatment and management of breastcancer would have impact on both health and the economy.By analysingmolecular mechanisms that regulate organ-specific metastasis in breastcancer, the BRECOSM project will identify tools that will contribute to

improved clinical decision-making, prognostic evaluation and therapy inbreast cancer.

Aims• to identify genes that are specifically up- or down-regulated in breast

cancer metastases in specific organs;

• to identify gene expression signatures in primary breast tumoursthat predict metastasis to specific organs or predict the prognosisof ductal carcinoma in situ (DCIS);

• to determine whether genes already associated with breast cancerinvasiveness and metastasis are expressed in metastases in all or onlya subset of organs;

• to demonstrate whether genes found to be specifically expressedin breast cancer metastases to given organs play a functional role inorgan-specific metastasis;

• to elucidate molecular pathways that regulate breast cancermetastasis to specific organs;

• to develop improved animal models for studying organ-specificmetastasis of breast cancer;

• to produce a prototype microarray chip for diagnostic/prognosticevaluation;

• to apply the findings on organ-specific metastasis in the clinicalsetting.

Expected results• The results of this project will begin to explain the molecular basis

for organ-specific metastasis in breast cancer.

• This project will identify regulatory pathways and cellular events thatcoordinate organ-specific metastasis of breast cancers.Novel targetsfor therapy will thereby be identified.

• This project will identify gene expression signatures in tumoursassociated with metastasis to particular organs. This will be animportant advance in understanding the underlying genetic changesthat regulate organ-specific metastasis in breast cancer.

• This project will bring together European experts working ondifferent aspects of the molecular basis of tumour metastasis.As a

Mammary tumorshowing the lymphaticvessels that impingeupon the tumor (bluestaining). Increased

lymphatic vessel densi-ty promotes metastasis

to regional lymphnodes

Identification of molecular pathways that regulate the organ-specific metastasis of breast cancer


CANCER BRECOSM


result of coordinated efforts, pathways that regulate metastasis tospecific organs will be determined, and genes that play a functionalrole in organ-specific metastasis will be identified.

• This project will generate improved animal models for the furtherstudy of breast cancer metastasis to specific organs.

• This project will identify gene expression signatures in primarybreast tumours that predict patterns of metastasis.The applicationof these findings will assist clinical decision making and prognosticevaluation.

Potential applicationsThe gene expression signatures in primary tumours identified in thisproject that predict organ-specific metastasis and the prognosis of DCISwill have obvious potential for clinical application in diagnosis andprognostic assessment.Gene expression signatures in primary tumoursassociated with either organ-specific metastasis or progression of DCISwill be extensively validated retrospectively and as a prelude tointroducing these gene expression signatures into clinical diagnosis andprognostic evaluation, we will perform prospective studies todemonstrate the efficacy of examining gene expression signatures inprimary breast cancers for predicting the likelihood and location ofmetastases and the probability that DCIS will progress and metastasiseafter partial mastectomy. The prototype microarray chips we createbased on gene expression profiles produced as part of this project willbe applied in the clinical setting to investigate their diagnostic andprognostic value for breast cancer in a prospective study. This willconstitute a major step towards exploitation of the results.It is also highlylikely that genes are identified in this project will be candidate targetsfor the development of novel cancer therapies.The development of suchtherapies lies outside the time-frame and scope of the proposal.

Wholemount staining of the epithelial ductal structure in a mousemammary gland.The lymph nodes are also visible as densely-stained

spheroidal structures.


CANCER

Coordinator Sleeman, Jonathan Forschungszentrum Karlsruhe

Institut für Toxikologie und Genetik

Postfach 3640

76021 Karlsruhe, Germany

Phone: + 49 7247 826089


Project web-site:http://itgmv1.fzk.de/itg/brecosm/brecosm.htm

Key words: cancer, breast, metastasis, gene expression profiling

PartnersVan Roy, Frans Department for Molecular Biomedical Research (DMBR)

VIB - Ghent University,

Ghent, Belgium

Christofori, GerhardInstitute of Biochemistry and Genetics, Department of Clinical-Biological Sciences, University of Basel

Basel, Switzerland

Lukanidin, Eugene Danish Cancer Society, Institute of Cancer Biology

Copenhagen, Denmark

Thiery, Jean Paul CNRS UMR 144,

Institut Curie, Cell Biology Department

Paris, France

Georg-Speyer-HausFrankfurt am Main, Germany

Noël,Agnès Laboratoire de Biologie des Tumeurs et du Développement

Liège, Belgium

Collard, JohnThe Netherlands Cancer Institute, Division of Cell Biology


ten Dijke, Peter The Netherlands Cancer Institute

Division of Cellular Biochemistry


Stauber, Roland Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus,Paul-Frankfurt am Main, Germany

Zollo, Massimo TIGEM-Telethon

Naples, Italy

Acronym: BRECOSMProject number: LSHC-CT-2004-503224EC contribution: €3 430 273 Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/05/2004


SummaryMetaBre is a EU-funded research project that aims to

identify the underlying mechanisms that cause metastasis

in breast cancer.There has been considerable success in

the treatment of breast cancer in recent years,if detected

in its early stages.However,breast cancers are very prone

to metastasise, and cause secondary tumours in bone,

liver, lungs, brain and lymph nodes.Once solid metastatic

tumours are established, the likelihood of complete

remission falls, and patients can suffer symptoms

generated by metastases that affect quality of life.

• More than 200,000 women are diagnosed in Europe

every year.

• Lifetime risk of developing breast cancer is 1 in 10.

• It is the leading cause of death in women between ages

35 to 55.

Metastasis in breast cancer is a complex multistep process.

Genetic changes in tumour cells give rise to aggressive

metastatic cells, and these home in on specific organs

because of a complex web of molecular and matrix interactions with

the organ microenvironment. Understanding the key molecular

mechanisms of these metastatic processes can lead to improvements in

the prognosis and treatment of breast cancer patients.

Aims MetaBre will aim to discover new gene and protein markers that canbe used for diagnosis as a signature of metastasis to specific organs,and also can be targets for therapy.

To achieve this, the partners will analyse samples of breast tumoursand metastases, with due care of the ethical aspects, as well asestablished breast cancer cell lines.

MetaBre will also study genes and molecules that are alreadysuspected of involvement in metastasis.This builds on previous workof the partners and will enhance understanding of the role of thesemolecules in metastasis, as well as identifying new therapies anddiagnostic methods against these targets.

Expected resultsMetaBre has research activities aimed at:

• gene profiling and proteomic analysis to identify new moleculartargets

• functional analysis of new targets in in vitro and in vivo models

• mechanisms of angiogenesis and invasion

• organ-cancer cell interactions

• development of new pharmacological therapies and diagnostictechniques

preliminary clinical trials.

MetaBre will use state-of-the-art Affymetrix™ chips for geneprofiling and will develop novel in vitro and in vivo models forvalidation of molecular targets and screening of therapeuticmolecules.

Metastases will be detected in vivo with optical imaging of luciferase-expressing cancer cells and magnetic resonance techniques.


CANCER MetaBre

Main group, L to R: Roberto Buccione, Olivier de Wever, Pavel Gromov,Anna Teti, DavidWaltregny, Keltouma Driouch, Michael Baldwin,Akeila Bellahcene, Gabri van der Pluijm,

Nadia Rucci, Philippe Clement-Lacroix, Sue Eccles, Marc Bracke, Rosette Lidereau,VincentCastronovo,Angels Sierra, Ben-Tsion Williger, Rachel Klein, Rita Paro.

Insets L to R: Lenaic Paon,Verena Collazo, Nick Henriquez Philippe Clezardin., RichardBachelier, Philippe Pujuguet, Marcela Chavez, Maciej Ugorski,Anna Laskowska

not pictured:,Thomas Landemaine

Molecular Mechanisms involved in organ-specificMetastatic growth process in Breast Cancer


Progress The MetaBre kick-off meeting (below) was successfully organisedin February 2004 and received regional and national media coveragein Italy. As well as the MetaBre partners, the meeting was alsoattended by Dr Pavel Gromov of the Danish Cancer Society whowill advise on the proteomics research.

The research activities in the project include identification of newgenes and proteins involved in molecular mechanisms of metastasisin breast cancer, as well as work on targets already identified.Toassist the collaboration, inventories of cell lines and in vivo modelsavailable among the partners have been compiled.

There was a strong emphasis in the first year of MetaBre on organisingcollection of tissue samples that will be used in gene profiling andproteomics work. Partner CRH is leader of this work package andthey have supplied a number of tissue samples of liver and lungmetastases, and primary breast tumours from their own collection.Several other partners have access to tissue banks and clinics and havealso collected tissue samples.A meeting of the partners involved ingene profiling was arranged in Paris in April 2005, and a commonspecification sheet has been prepared.CRH collated the data on tissuesamples into a confidential database.

The gene profiling has mainly used the Affymetrix™ platformprovided by partner PSK, but the partners will also use othermicroarray systems in order to maximise the opportunities for geneprofiling in the project.The first gene profiling with Affymetrix™has been completed on a breast cancer cell line sub-clone “B02”developed by partner INSERM that strongly metastasises to bone.

This has generated interesting results that are being analysed by allpartners. Currently samples of clinical bone metastases are beingcollected in order to validate these data. Also analysis wassuccessfully performed on liver and lung metastases and primarybreast tumours, though good quality RNA was not extracted fromall samples. Further analysis and comparison of gene profiles shouldidentify genes of interest. Functional analysis will follow.

Partner IRO has worked on identification of protein markers of organ-specifity,particularly in lung and brain metastases.A number of proteinshave been identified from analysis of organ-specific breast cancer celllines, and these are being characterised and verified. For proteomicanalysis,advanced methods are being implemented to obtain accurateresults from smaller quantities of material.

Partner WAU is investigating the role of carbohydrate antigens inbreast cancer metastasis.So far no suitable cells lines have been foundas models of the Sialyl LewisX antigen known to be found in 30-40%of breast cancers, so WAU aim to develop a modified cell line for thispurpose. In comparison,TF-antigen is expressed in most cell lines andexperiments are progressing with gene silencing using siRNAs. ULgis also using siRNAs to silence histone deacetylases, which aresuspected to have a role in angiogenesis in breast cancer, for studywith in vitro and in vivo models.

LUMC are working on some innovative tools for studying of geneexpression in in vitro and in vivo models.They are also working towardsa 3D model of epithelial-mesenchymal transition in breast cancer.

Partner CMNS is studying the basic cell biology of MMP trafficking,and has also started work with UNIVAQ on the characterisationof the podosomes features of osteoclasts that are involved in thedevelopment of bone metastases through degradation of bonematrix. These may be similar or even identical to invadopodia ofcells involved in degradation of extra-cellular matrix.

ICR are working to understand molecular mechanisms of metastasisto lymph nodes and have been testing cell lines for expression offactors that are suspected of involvement.Work has started witha 3D epithelial cell culture and ICR will use microarrays to identifygenes upregulated when cancer cells interact with the lymphaticendothelium.

A number of new therapeutic approaches are being tested already inthe project, against known molecular targets. UNIVAQ has built onprevious work on the role of c-Src in the development of bonemetastases. New results from in vivo experiments show that c-Src


CANCER

Image of a bone metastasis obtained by 3 dimensional computerised micro-tomo-densitometry


inhibitors have a significant effect on the incidence and growth of bonemetastases. Also INSERM has found new evidence of interactionsbetween breast cancer cells and blood platelets that stimulate boneresorption in osteolytic bone lesions.

Image of a bone metastasis obtained by three-dimensionalcomputerised micro-tomo-densitometry INSERM is testingendogenous anti-angiogenic agents such as thrombospondin.Thesehave been transfected into the B02 cell line to assess their effecton the growth of bone metastases in-vivo. Also PSK are testing newcompounds that inhibit an adhesion molecule, known to beimportant for the vicious circle between breast cancer cells andosteoclasts. In vivo bioluminescent imaging has been used to detectbone metastases at an early stage, thus permitting short-durationin vivo experiments.

Many of the molecular targets of MetaBre will be suitable asprognostic markers.The University of Ghent has already identifiedthe soluble extra-cellular fragment of N-cadherin as a marker ofinvasive breast cancer and is developing an ELISA assay for accurateand rapid detection. This has involved development of suitablemonoclonal antibodies and recombinant sN-cadherin for calibrationof the ELISA. Tests with serum samples from patients havecommenced. The sN-cadherin marker is useful not only forfollowing progress of breast cancer treatment but also for otherdiseases.

IRO has also commenced work on magnetic resonance imaging andmagnetic resonance spectroscopy for detection of brain metastases.This is useful for non-invasive measurement of experimentalmetastases in vivo and also may ultimately have a clinical application.

The project has received good publicity through two pressconferences in Italy and Belgium, and being profiled in Questmagazine in December 2004.A website has been developed as wellas a project flyer. Some of the project partners attended theMetastasis Research Society meeting in September 2004 and a high-profile presentation is planned for a major European breast cancerconference in 2006.

Coordinator Prof.Teti,Anna

Department of Experimental Medicine

University of L’Aquila

Via Vetoio – Coppito 2

67100 L’Aquila, Italy

Phone: + 39 0862 433511

Fax: +39 0862 433523


Project web-site: www.metabre.org

Key words: Breast cancer, metastasis, gene profiling,organ-specific

PartnersDr. Buccione, Roberto,

Consorzio Mario Negri Sud (CMNS), Italy

Dr. Lidereau, Rosette

Centre Réné Huguenin (CRH), France

Dr. Clezardin, Philippe

INSERM U664, France

Dr. Clement-Lacroix, Philippe,

ProSkelia SaS (PSK), France

Dr. van der Pluijm, Gabri,

Leiden University Medical Centre (LUMC),

The Netherlands

Dr.Williger, Ben-Tsion

CancerTek Pharmaceuticals Ltd (CTP), Israel

Prof. Ugorski, Maciej,Wroclaw

Agricultural University (WAU), Poland

Dr. Eccles, Suzanne,

Institute of Cancer Research (ICR), United Kingdom

Dr. Sierra,Angels,

Institut de Recerca Oncologica (IRO), Spain

Prof. Bracke, Marc,

Ghent University (UGent), Belgium

Prof. Castronovo, Vincent,

University of Liège (ULg), Belgium

Acronym: MetaBreProject number: LSHC-CT-2004-506049 EC contribution: €4 005 294Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/01/2004

CANCER


In MetaBre, metastases will bedetected in-vivo with optical imagingof luciferase-expressing cancer cellsand magnetic resonance techniques


SummaryProspective clinical material will be collected during the life of the

programme and new and existing tumour tissue, PBMC and serum

banks will be available for use in the study.This common resource of

material will be distributed to partners for the immunological,genomic,

biochemical and proteomic analysis of tumour and host response(s) to

immunotherapy.The results will be subjected to bioinformatic analysis

in the context of clinical outcome of vaccine-based immunotherapy

trials from five European clinical centres.Analysis of the results in the

context of gender will allow prominent inter- and intra-tumour / host

biomarkers to be identified for translation back into clinical practice.

ProblemCancer remains a major health problem, with untold physical,psychological and economic costs to society. Elimination of cancerwould reduce health care costs and enhance quality of life. Alongwith cardiovascular disease and ageing, it is currently the mostintractable source of suffering and health care cost. Recent resultsfrom immunotherapy trials would suggest that inducing tumour-specific T-cell responses to tumour antigens can, in some patients,cause the regression of tumours or the stabilisation of the disease.However the mechanisms underlying the failure of immunotherapyto control and destroy residual cancer remains to be fullyestablished. Experimentally, it can be shown that tumour rejectionis mediated by CD8+CTLs aided by CD4+T-helper cell activity.However animals that fail to respond may fail to demonstrate apronounced (if any) CTL response. In addition data from manylaboratories have shown that tumour escape from CTLs can occuras a result of downregulation of MHC class I antigens, and in someinstances cancer cells that show successive mutations maydemonstrate progressive and complete loss of MHC expression.Thecurrent status of our understanding of adoptive cancer immunityalso suggests that immune tolerance can equate with lack ofresponse, with possible regulation by CD4+CD25+T-lymphocytesas well as other regulatory cells. Breaking tolerance throughimmunotherapy therefore represents one possible approach topromote T-cell responses and tumour regression.

AimENACT aims to identify markers of response and tumour antigensthat associate with ovarian, breast and prostate cancer andmelanoma progression and resistance to immunotherapy. Thepresent application will address these issues in a number of waysand directly analyse the important biomarkers that are expressedby cancer and may therefore be considered as novel targets byestablishing a European network for collaboration.The cancer typesto be included will address the issue of sex-related biomarkersassociating with resistance to therapy.Cell biological, immunological,biochemical and molecular biology-based technologies will be usedand knowledge generated in this project will not only result in adesired and highly competitive technological base for vaccinedevelopment (not necessarily restricted to cancer vaccines),but alsowill provide a better understanding of basic biological mechanismsunderlying antigen presentation and recognition of tumours byCD8+ and CD4+ T lymphocytes and NK cells.

Expected results1. to establish a database for the analysis of clinical and experimental

results in order to identify markers related to the outcome ofimmunotherapy

2. to provide clinical material and cancer cell lines for scientificinvestigation conducted within the programme

3. to assess the cellular and humoral immune response in patientsundergoing immunotherapy

4. to identify biomarkers using proteomics and computer basedalgorithms

5. assessment of the importance of immunological, genetic andproteomic biomarkers as indicators of therapeutic response relatedto gender

6. dissemination of the information to the scientific community andthe community at large.

CANCERENACT


European Network for the identification and validationof antigens and biomarkers in cancer and their application in clinical cancer immunotherapy


Potential applicationsThe use of therapeutic cancer vaccines still has to be firmly establishedand previous clinical trials strongly indicate that not all patients benefitfrom receiving such treatment. The present study will allow us toestablish whether the results of ENACT can be used in a clinicalsetting. The identification of indicators of patient response toimmunotherapy would allow clinicians to target vaccination to thosepatients who are most likely to respond.The findings of the presentstudy could result in assays that could be used to predict treatmentoutcome and / or monitor patients during the course of treatment.This would benefit the health care industry and patient care and thefindings may be applicable to cancers other than those included in theresearch programme. The approach will allow us to gain furtherscientific understanding of the immune response to tumour antigens,which may influence the development of future generations of cancervaccine.This research represents a valuable contribution to the welfareof patients who would be considered to be suitable candidates forvaccine-based therapy.

Coordinator Prof. Rees, Robert

Interdisciplinary Biomedical Research Centre

Nottingham Trent University

Faculty of Science and Land Based Studies

School of Science

Clifton Lane

Nottingham, NG11 8NS, United Kingdom


Project web-site: https://www.enactcancerresearch.org

Key words: Tumour progression, biomarkers, tumourescape, melanoma, prostate cancer, ovarian cancer

PartnersLaboratory of Clinical Immunology, University Hospital,Sofia, Bulgaria

Abt.Innere Medizin II Zentrum fur MedizinischeForschung, ZMF, Universitatsklinikum Tuebingen, Germany

Department of Oncology-Pathology, Karolinska Institute,Stockholm, Sweden

INSERM U463, Institue de Biologie, Nantes, France

Institute of Medical Biochemistry, Jagiellonian UniversityMedical College, Krakow, Poland

Biomedical Research Study Centre, University of Latvia,Riga, Latvia

Departamento de Analisis Clinicos, HospitalUniversitario, Granada, Spain

Skin Cancer Unit (DO70), University Hospital Mannheim,Germany

Department of Immunology, Institute for CancerResearch, Section for Immunotherapy,The NorwegianRadium Hospital, Oslo, Norway

The Anthony Nolan Research Institute,The Royal FreeHospital, London, United Kingdom

Loreus Ltd, Nottingham, United Kingdom

Dept. of Immunology, Hellenic Anticancer Institute,Athens, Greece

Onyvax Ltd, St George’s Hospital Medical School,London, United Kingdom

CANCER


Acronym: ENACTProject number: LSHC-CT-2004-503306EC contribution: €4 166 513Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/01/2005


SummaryThe project through collaborative studies will define prognostic

markers and new therapeutic targets in the Ewing’s sarcoma family

of tumours (ESFT) to provide rigorous scientific justifications for the

development of clinical trials for this rare disease, which is mainly

manifested in children.The main objective of this project is to evaluate

the prognostic relevance of selected markers (EWS/FLI-1, secondary

genetic alterations, CD99, IGF-IR, NOVH, erbB-2 and TTF1) and the

effectiveness of therapeutic approaches targeting some of these

molecules.Another major goal of the project is the construction of

ESFT c-DNA microarrays and tissue arrays, which will be used for

the analysis of different histological subtypes of ESFT, primary and

metastatic tumours and poor and good responders to chemotherapy.

This will lead to: 1) the definition of forthcoming risk-adapted

strategies and targeted molecular treatments to be advantageously

combined with established therapies; 2) improved quality of life and

survival for ESFT patients; 3) prevention on risk in groups at risk.

ProblemThe Ewing’s sarcoma family of tumours (ESFT) includes: Ewing’ssarcoma; primitive neuroectodermal tumour; Askin’s tumour;paravertrebral small-cell tumour; atypical Ewing’s sarcoma. ESFTrepresents a peculiar entity in oncology. In spite of its absolute rarity(about 300-400 cases per year in Europe), ESFT is one of the mostfrequent solid neoplasm in paediatric age groups. Due to this fact, itsimpact on the health system is particularly important.The adoptionof multimodal treatments with very aggressive chemotherapeuticregimens have significantly improved the chance of survival of ESFTnon-metastatic patients, shifting the five-year survival rates to around60%.Despite these important clinical results,which are usually difficultto obtain in rare diseases, several problems related to histogenesis,prognosis and treatment response are still open. In particular:

a.The histogenesis of ESFT is still uncertain and the normalcounterpart of ESFT cells is still unknown.

b.The lack of prognostic factors obliges the use of non-differentiatedtreatments for all patients, leading to over-treatment of thosepatients who could benefit from less toxic therapies.The reductionof delayed side-effects is particularly important in this diseaseconsidering the young age of the patient and their long lifeexpectancy.

c. In the current state of ESFT treatment there is a survival ‘plateau’(around 60% for patients with localised disease and 25% for high-risk groups) due to the lack of new drugs and toxicity that impedesmore intense use of existing drugs. The identification of newtargets for innovative therapeutic strategies is, therefore, stronglyneeded for this tumour.

Progress is generally hampered by the rarity of the disease (in Europeabout 400 cases/year) implying a limited number of cases for effectiveresearch. Moreover, because ESFT is an orphan disease, no privatecompany will develop new therapeutic tools and take on the coststo conduct pre-clinical investigation.

AimThe project will define prognostic markers and new therapeutictargets in the Ewing’s sarcoma family of tumours (ESFT) throughcollaborative studies to provide rigorous scientific justification forthe development of new therapeutic strategies for this rare disease,which is manifested for the most part in children. Goals expectedto be achieved:

1.With respect to the problem of toxicity, the project,by identifyingthe clinical relevance of a number of markers, may allow thedifferentiation of patients in terms of risk to recur.This will enablemore aggressive treatments where these are justified, and avoidtoxicity in cases where such treatments may be known to beunnecessary, with particularly significant consequences for thequality of life of the patients.

2. Successful treatment of therapy-resistant patients requires newstrategies. Indeed, there is a desperate need for new therapeuticapproaches in ESFT. A thorough study of the pre-clinicaleffectiveness of new targeted therapeutic strategies will beperformed with the aim of the identification of the Achilles’ heelin this disease and the consequent development of a tailoredbiological therapy to be used in association with conventionalchemotherapy.

3. By providing an organisational framework for collaboration theproject will also allow multi-centre collection and analysis of casesas well as suitable collaborative research to allow genetic studiesfor the screening of high-risk patients and patients respondingdifferently to chemotherapy.

Histological features of Ewing’s sarcoma

Ewing’s sarcoma: stain for CD99

Prognosis and therapeutic targets in the Ewing family of tumours

CANCERPROTHETS



Expected results1.The identification of prognostic factors in ESFT as a basis for the

definition of individual therapeutic regimens,which would limit theincidence of acute side-effects and long-term morbidity as well asthe economic and social consequences of intensive chemotherapy.

2.The definition of patient selection criteria to be used as a basis forbeginning a pivotal clinical trial.

3.The creation of new therapeutic bullets against ESFT.They will beavailable at the end of the project as new drugs for ESFT treatment,together with the required toxicological and pharmaco-kineticsstudies.This is an important point because ESFT is an orphan diseaseand no private company will develop new therapeutic tools and takeon the costs of conducting pre-clinical investigation.

4. New therapeutic strategies for oncologists to increase the survivalrate of ESFT patients through the pre-clinical evaluation of newdrugs and strategies based on an immunological approach.

5.New clues in the diagnosis and the screening of high-risk groupsthrough the creation of an extensive tissue bank and the genetic profileanalysis (cDNA microarray and tissue array analyses) of these samples.

Potential applicationsTherefore the project,aiming to ameliorate treatment of ESFT,will havean impact on child health.In particular,the main objective of this projectis to develop patient-oriented strategies for Ewing’s sarcoma patientsby: a) integrating different disciplines and advanced technologies todevelop effective approaches or new tools for diagnosis,prognosis andtreatment. b) elucidating the contribution of specific molecular andgenetic factors to the histogenesis of the disease.

This work will unlock the potential of the individual studies carried outby each of the consortium partners, and it will define targetedtherapeutic strategies of practical value in clinical settings and the clinicalrelevance of a number of markers that will allow the differentiation ofpatients in terms of risk of recurrence. It will also unlock the biologicaland clinical information potential behind multi-centre data collectionand genetic analysis of patients, bringing basic knowledge to theapplication stage. Progress is generally hampered by the rarity of thedisease, implying a limited number of cases for effective research.Thecreation of a multi-centre tissue bank and data collection will help toovercome a big obstacle.The application of new technology will be usedto identify ESFT-related molecular mechanisms.The gene expressionprofile of ESFT will be analysed and new markers to be used fordiagnostic, prognostic and therapeutic purposes will be identified.

The project made efforts in the integration of multi-disciplinary researchcapacities across Europe. The consortium includes pathologists,oncologists, immunologists, and molecular and cellular biologists.Moreover, PROTHETS lays emphasis on collaboration with small andmedium-sized enterprises (SMEs),devoted to the development of specifictools for prognostic and therapeutic applications.

Finally, the development of evidence-based guidelines will ensure thatthe knowledge held and developed by and within the project will bedistributed as widely as possible to have the highest possible impact

on the biomedical world. Specified actions of the project are devotedto dissemination activities to ameliorate harmonious relationsbetween cancer researchers and society, with particular regard topatient associations.

Coordinator Dr Picci, Piero

Department of Musculoskeletal Oncology “I. F. Goidanich”

Istituti Ortopedici Rizzoli

Via di Barbiano 1/10

40136 Bologna, Italy

Phone: + 39 051 6366759

Fax: + 39 051 582244


Project web-site: under construction(www.prothets.org).There will be a link in: http://www.ior.it.

Key words: Ewing’s sarcoma, EWS/FLI1, CD99, insulin-like growth factor, microarrays

PartnersLaboratory of Oncologic Research, Istituti OrtopediciRizzoli, Bologna, Italy

Institut National de la Santé et de la Recherche Médicale,Nice, France

Laboratory for Experimental Orthopaedic Research,University Hospital of Münster, Germany

Haartman Institute, Department of Medical Genetics,University of Helsinki, Finland

Department of Pathology, Medical School, HospitalClinico Universitario,Valencia, Spain

Laboratory for Molecular Biology, Children´s CancerResearch Institute, St.Anna Children´s Hospital,Vienna,Austria

Université Paris 7 Denis-Diderot, Paris, France

Centre National de la Recherche Scientifique, UMR8121CNRS Institute Gustave Roussy PR2,VilleJuif, France

Belozersky Institute of Physico-Chemical Biology,Moscow State University, Russia

GenX Laboratories srl,Vignate, Italy

Mabgène S.A.,Ales, France

CANCER


Acronym: PROTHETSProject number: LSHC-CT-2004-503036EC contribution: €2 530 500 Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/01/2005


SummaryThe current diagnostic markers for prostate cancer have a low

specificity and lead to over-diagnosis and over-treatment due to the

detection of small non-aggressive or non life-threatening cancers. In

addition, there are currently no efficient serum or urine markers

available for the prognosis of this malignancy.The P-Mark project will

address the growing need for improved diagnostic and prognostic

markers for prostate cancer.

ProblemIn Europe, prostate cancer (Pca) is the second most frequent lethalmalignancy in men. Yearly about 40 000 men die of Pca in the EUcountries.There is a slow increase of mortality and in addition, due toan ageing population, a 50% increase in incidence is expected by 2020.So far,the only chance for cure is early detection and treatment by eithersurgery or radiotherapy.Diagnosis of Pca is made by ultrasound guidedtransrectal biopsy of the prostate for histology.An increased level ofthe serum marker prostate specific antigen (PSA) predominantlyindicates such a biopsy.A major disadvantage of this diagnostic markeris its low specificity, resulting in a significant amount of false biopsyindications.PSA is a normal excretion product of the prostate cells andis therefore not only found in the circulation of men with prostatecancer but also of men with a normal prostate and men with benignprostatic hyperplasia, a phenomenon that is associated with ageing.Nevertheless,PSA is the standard marker for Pca diagnosis and has beendemonstrated to be effective in advancing the diagnosis by detectingPca at earlier stages.A growing number of men choose to be screenedfor Pca by PSA analysis,even up to 60-70% of men in the USA.However,the value of screening for Pca has not been established yet and iscurrently the subject of investigation in the European Randomised Studyof Screening for Prostate Cancer (ERSPC). A major drawback of thestandard diagnostic tools for Pca is the detection of small non-aggressiveor non life-threatening cancers, leading to over-diagnosis and over-treatment, as well as the detection of tumours that are too advancedto cure. Currently, there are no serum or urine markers available forthe prognosis of Pca at early disease stages apart from PSA.It is apparentthat improved diagnostic and prognostic serum or urine markers arerequired that can discriminate men with clinically irrelevant Pca,curablePca, or life-threatening Pca.

AimFor three years, P-Mark will search for improved diagnostic andprognostic Pca markers by the identification and evaluation of novelmarkers as well as the evaluation and validation of recently developed

promising markers.Novel serum and urine markers will be identified inclinically well-defined biomaterials using innovative mass spectrometrytools, and antibody-based immunoassays will be developed for thesemarkers.The novel markers will be evaluated for their clinical importanceusing these assays. Recently developed promising markers that provetheir clinical value during the evaluation will be validated on a sampleset derived from two European screening studies (the ERSPC study andthe ProtecT study).Eventually, the markers arising from this project willbe offered to SMEs for commercialisation and to ongoing large Europeanclinical studies for clinical implementation.

Expected results 1. the establishment of a serum biorepository and a urine

biorepository for the discovery, evaluation and validation ofdiagnostic and prognostic Pca markers

2. the discovery of novel Pca markers in human body fluids byinnovative mass spectrometry tools

3. the establishment of the clinical utility of recently developedpromising Pca markers, including PCA3DD3, bone morphogeneticprotein-6 (BMP-6), osteoprotegerin (OPG), nicked PSA, humankallikrein 2 (hK2) and cytochrome P450 3A5*3 polymorphism(CYP3A5*3)

4. the validation of Pca markers and identification of risk groups inthe general population in Europe

5. the development of guidelines for cost-efficient strategies for Pcadetection and therapy.

Validation of recently developed diagnostic and prognostic markers and identification of novel markersfor prostate cancer using European databases

CANCERP-MARK



Potential applications P-Mark will evaluate the clinical value of recently developed promisingPca markers and of novel Pca markers. If a marker meets the definedP-Mark marker criteria (improved sensitivity and specificity overcurrent markers for diagnosis or prognosis; indicative for earlydetection,over-treatment, risk for progression or therapy resistance;clinically relevant target in relation to tumour biology; reliable andcost-efficiently determinable in non-invasively obtained specimens;stable component in specimen), it will be developed further for thevalidation in a mono-centre or multi-centre setting. In addition, themarker will be offered to commercial enterprises forcommercialisation.Validation will lead to guidelines for cost-efficientstrategies for detection and treatment as well as recommendationsfor marker application, that have to be discussed in the public domainof related European professional societies.Validated markers will beoffered to the principal investigators of ongoing screening studies inEurope for implementation in the study.Taken the duration of P-Markinto consideration (three years), clinical marker implementation willcontinue beyond this project.

Coordinator Prof. Bangma, Chris H

Department of Urology

Erasmus MC, room H1074

Dr. Molewaterplein 40, 3015

PO Box 2040,

3000 CA Rotterdam,The Netherlands

Phone: + 31 10 463 3607

Fax: + 31 10 463 5838


Project web-site: http://www.p-mark.org

Key words: prostate cancer, markers, diagnosis, progno-sis, serum, urine, proteomics, mass spec-trometry

PartnersDepartment of Laboratory Medicine, Division of ClinicalChemistry,Wallenberg Laboratory, University HospitalMalmö, Sweden

Department of Urology, University Hospital Malmö,Sweden

Department of Experimental Urology, University ofNijmegen,The Netherlands

Department of Urology, University of Sheffield, UnitedKingdom

Department of Clinical Chemistry, Helsinki University,Central Hospital, Finland

Department of Biotechnology, University of Turku,Finland

Centre for Pharmacy,Analysis of Biomacromolecules,University of Groningen,The Netherlands

Innotrac Diagnostics OY,Turku, Finland

CanAg Diagnostics AB, Göteborg, Sweden

Acronym: P-MarkProject number: LSHC-CT-2004-503011EC contribution: €3 480 764 Instrument: Specific Targeted Research ProjectDuration: 36 monthsStarting date: 01/11/2004

CANCER



Summary

The overall objective is to create a permanent European overview

process for the award, audit and recording of all research on breast

cancer: This will be the creation of the funding bodies themselves

which, for each project, will retain the absolute power of award.

The project aims to create:

1.A European overview process for project proposals received by all

funding bodies.This will

i) prevent research from being funded for similar work in multiple

projects

ii) result in a few large, rather than multiple small series, which are

much more likely to yield definite results.

2.A body of the leading researchers in breast cancer which agree the

areas most likely to give results of clinical relevance and agree

certain issues that must be included in all proposals (such as

validation of the results).

3.An audit process of research work.This addresses the problem that

many projects do not address their aims.The audit outcomes will

be accessible to research funders, so that institutes most likely to

complete valuable projects are identified (and the converse!).This

project will be divided into 3 parts; i) a workshop of leading

European research workers in breast cancer to define the most

important areas for research and to make suggestions on an

overview process ii) a workshop of the funding organisations &

other interested parties to discuss and agree a strategy for

harmonising research in the identified areas and iii) validation of

projects funded to date against criteria established within the

project.

ProblemThe present methods of awarding research grants in cancer sufferfrom many defects and appear to result in repetitive research, oftenwith no clear result and no clinical relevance.There is no agreementas to which areas are the most important, there is no attempt toensure claims are validated,there is no audit process for success/failureand no ranking of ability of individual units to complete projects andtheir value.This means that monies for research are often spent poorly.

Aim1. LONG TERM AIMS

• To harmonise breast cancer research through individual fundingorganisations operating within Europe

• To encourage research to be focused on that which will have ultimateclinical application

• To ensure that validation is a part of the design of all applications

• To establish an audit system backed by a database that allowsassessment of the success rate of individual research groups.

2. PROJECT SPECIFIC AIMS

• To bring together all organisations involved in developing,supportingand undertaking breast cancer research in Europe to design astrategy for the pan-European harmonisation of breast cancerresearch.

• To develop a process of audit of completed research whereby researchprojects will also be judged as to whether they have advanced thescience and to what degree they are relevant to clinical practice.

• To maintain a database of projects and of the audit of completedprojects

• Audit of past projects and production of a policy paper forimplementation

• To influence journal editors, to ensure higher standards are set foracceptances for publication of results; validation and clinicalrelevance will be the most important issues.

A European strategy for the integration of research on breast cancer

CANCEREUSTIR



Expected results• A European overview process for project proposals received by all

funding bodies.This willi) prevent research from being funded for similar work in multiple

projects

ii) result in a few large, rather than multiple small data sets, whichare much more likely to yield definitive results

2.Agreement and ranking of the areas most likely to give results ofclinical relevance.

3.Agreement on certain issues that must be included in all proposals(such as validation of the results)

4.An audit process of the results of funded research.This will initiallyshow if the contentions expressed above with regard to fundedresearch, are in fact correct.The audit outcomes will be accessibleto research funders, in that institutes most likely to completevaluable projects will be identified (and the converse!).

Potential applicationsAside from the obvious and intended application in breast cancerfunding across Europe,the model created by the project can be appliedto many funding areas where multiple sources of funding create thesame problems as seen in breast cancer.

Coordinator Prof. Roger Blamey

Breast Institute

Nottingham City Hospital NHS Trust

Hucknall Road

Nottingham NG5 1PB, United Kingdom

Tel: +44 115 962 5707

Fax: +44 115 962 7765


Key words: breast cancer, funding, harmonisation

Acronym: EUSTIRProject number: LSSC-CT-2005-517659EC contribution: €198 640 Instrument: Specific Support ActionDuration: 24 monthsStarting date: 01/01/2006

CANCER



SummaryA key issue remains how effective coordination of Cancer Research in

Europe can see the European Union (EU) benefit from the advantage

of scale, which its population provides. Cancer research in EU is

fragmented and frequently duplicative. Resources are wasted and

implementation of closer cooperation to develop a strategy for Cancer

Research by the Member States would clearly be cost-efficient and

hasten the development of major advances and their delivery to the

population. Barriers to collaboration in cancer research need to be

identified and ways sought to encourage the development of

collaborations in the Member States.

ProblemCancer remains a major Public Health problem worldwide withEurope hit hard and the situation set to worsen in absolute terms asthe population ages.Around one half of cancer patients still die fromtheir disease. On the other hand, there are currently greatexpectations that we are on the brink of making huge progress againstthe disease. Elucidation of the human genome and rapid advances inunderstanding details of its function allied to rapid progress intechnology,gives great hope of rapid advances taking place.The currentera offers more real hope than any previous.

Cancer remains the subject of significant research effort at both theEuropean level and in the Member States.Between 2002 and 2006, theEuropean Union will be devoting more than €435 Million to this fieldof research.This is in addition to national funding in Member States.

An important aim for the Commission is to achieve a betterframework for collaboration in cancer research in Europe, and thereis a recognition that coordination of national cancer research effortsat the European level is far from being achieved. Among the keyelements proposed to explain this situation are the barriers betweendisciplines and fields of research; the fragmentation of researchactivities dedicated to the different types of cancer and the resultantsub-optimal critical mass; the weakness of the links between basic,applied and clinical research, leading to a rather limited integration ofbasic and clinical research;and the implementation of all these activitiesmainly in a national framework and a national context. As aconsequence, Europe is unable to fully benefit from the advantage ofscale afforded by its 500 million population.

Europe is at present, and has been for many years, unable to retainmany of its most talented scientists and is unable to provide a scientificenvironment capable of attracting top young scientists from outwiththe continent. In addition, there is no national incentive to promotemobility within the Member States. Consequently, the developmentof transnational research activities is impeded by the obstacles to themobility of researchers.

A further obstacle is the lack of common core elements in thecurriculum of professionals.Common quality standards in training areneeded to facilitate the collaboration at European level as well as themutual recognition of the qualifications between European countriesand therefore the mobility of researchers and physicians.The situationis particularly exemplified by the absence of recognition of Oncologyas a Medical discipline by many European countries and its variablestatus in most Member States.

Consequently, although a large amount of financial resources isinvolved,and a substantial portfolio of initiatives is carried out,cancerresearch efforts are not currently benefiting from the advantages thata coherent and more co-ordinated framework would bring about.

AimOn the basis of an overview as complete as possible of Cancerresearch in Europe, objectives of the project are to:

1. Identify the fields, topics and research subjects where the lack ofco-ordination of national activities is particularly detrimental forthe progress of knowledge and the quality of care;

2. Identify those specific fields,topics and research subjects where theawareness of the need, as well as the willingness and readiness toachieve a better co-ordination, are established enough as to makesuch an achievement likely;

3. Explore the suitability, for this purpose, of the various supportschemes available in the 6th Framework Programme (Co-ordinationactions; ERA-NET schemes;“Article 169”);

4. Explore, in particular,the interest and feasibility of an initiative basedon “article 169” (participation of the EU into national researchprogrammes jointly implemented);

5. Help determine the means by which further exploring thepossibilities and ways to progress in the direction of a better co-ordination (study, workshop, conference, survey);

6. Give orientation on all the issues above raised and practicalrecommendations on the last points.

Expected resultsThe project shall provide key answers to the following questions throughthe exploration of barriers to Research Collaboration in the EU inspecific fields as well as by dealing with some of the key issues includingmobility of cancer research workers throughout the European Union:

Irrespective of the prospects generated by considerations of alternativelegal, governance and financial matters, including article 169, what canbe done to facilitate Cancer Research in the European Research Area?

What could be done to enhance Cancer Research in the EuropeanResearch Area by new application(s) of available legal,governance andfinancial considerations, including Article 169?

Feasibility Study for Coordination of National Cancer Research Activities

CANCEREUROCAN +PLUS



Potential applicationsThe project is certainly going to have a major impact on the structurationof Cancer Research,basic and clinical,throughout the EU.Furthermore,the EU will dispose of concrete and practical recommendations for thedefinition of priorities in research programmes.

Coordinator Dr Peter Boyle

International Agency for Research on Cancer

150 cours Albert Thomas

69008 LYON

Tel.: +33 4 72 73 85 77

Fax: +33 4 72 73 85 64


PartnersProf. Harry Bartelink

The Netherlands Cancer Institute

Department of Radiotherapy

The Netherlands Cancer Institute/

Antoni van Leeuwenhoek ziekenhuis


Dr Filippo Belardelli

Department of Cell Biology and Neurosciences

Istituto Superiore di Sanita'

Rome, Italy

Prof. Julio Celis

Institute of Cancer Biology

Danish Cancer Society

Copenhagen, Denmark

Dr Diana Dunstan

MRC Research Management

UK Medical Research Council


Prof.Alexander M.M. Eggermont, MD, PhD

Surgical Oncologist

Erasmus University Medical Center

Department of Surgical Oncology

Erasmusc MC - Daniel Den Hoed Cancer Center


Prof. John M Fitzpatrick

Surgical Unit- Mater Misericordiae Hospital

CANCER


Acronym: EUROCAN+PLUSProject number: LSSC-CT-2005-015197EC contribution: €3 000 000 Instrument: Specific Support ActionDuration: 24 monthsStarting date: 2005

University College Dublin

Dublin, Ireland

Dr Jan-Willem Hartgerink

International Affairs Department

Ministerie van Volksgezondheild,Welzijn en Sport

The Hague,The Netherlands

Prof. David Kerr

Department of Clinical Pharmacology

The Chancellor, Masters and Scholars of the Universityof Oxford

Radcliffe Infirmary

Oxford, United Kingdom

Dr Peter Lange

Unterabteilung 61: Gesundheit, Biowissenschaften

Bundesministerium für Bildung und Forschung

Berlin, Germany

Prof Jose Martin Martin-Moreno

Professor of Medicine and Public Health

Medical School, University of Valencia

Valencia, Spain

Prof Herbert Michael Pinedo

VUmc Cancer Center Amsterdam


Ulrik Ringborg, MD, Ph.D.

Radiumhemmet-Dept. of Oncology

Karolinska University Hospital Solna

Stockholm, Sweden

Prof. Dimitrios Trichopoulos

Department of Hygiene and Epidemiology

School of Medicine

National and Kapodistrian University of Athens

Athens, Greece

Prof Thomas Tursz

Direction Générale

Institut Gustave Roussy

Villejuif, France


• Acronym 228

• Contract number 230

• Coordinator 232

Indexes


ActinoGEN 70

Active p53 170

AGEACTION 156

AMIS 77

ANABONOS 152

Angiotargeting 166

APOPIS 93

AUTISM MOLGEN 106

AUTOROME 62

BIOCARE 164

Bloodomics 18

BrainNetEurope II 102

BRECOSM 212

CANCERDEGRADOME 182

CCPRB 196

Cells into Organs 148

COBRA 82

Diabesity 32

DNA METHYLATION 206

ECRIN-RKP 14

Eicosanox 12

EMBIC1 46

EMIL1 73

ENACT 217

ESNI course 2003 135

eTUMOUR 198

EUGENE 236

EUGINDAT 58

Eumitocombat 44

EURAPS 60

EUR-INTAFAR 68

EUROCAN + PLUS 225

EuroClot 26

Euroglycanet 47

EUROHEAD 111

EUROMEMO 132

European LeukaemiaNet 202

European MCL Network 209

EUROSCA 97

EuroWilson 52

EUROXY 194

EUSTIR 223

EVGN 20

EXGENESIS 34

FENS Forum 2004 137

FIRST 179

GEHA 144

GENADDICT 95

GENESKIN 49

GRIPANNT 124


Index by acronym


IMMIDIAB 141

INTACT 162

INTERDEVO 129

LINK-AGE 150

MAESTRO 195

MetaBre 214

micro-MATRIX 85

MIMAGE 142

MOL CANCER MED 191

MOLSTROKE 24

Mutp53 187

Myocardial Repair 28

NCL-MODELS 116

NeuroDisseminator 131

NEUROKCNQPATHIES 118

NeuroNE 100

NEWMOOD 90

Orphanplatform 64

OSTEOGENE 154

PainGenes 122

P-MARK 221

PNEUMOPEP 75

PREVIS 79

PRIMA 168

PROMEMORIA 88

PROTHETS 219

PWS 56

RABRE 139

SPASTICMODELS 113

STRESSPROTECT 126

STROMA 185

SYNSCAFF 108

TONECA 39

TRANSBIG 200

TRANSFOG 176

VIRGIL 73

X-ALD 120



LSHC-CT-2003-502932 194

LSHC-CT-2003-503233 185

LSHC-CT-2003-503297 182

LSHC-CT-2003-504586 206

LSHC-CT-2003-506803 162

LSHC-CT-2004-502943 191

LSHC-CT-2004-502983 187

LSHC-CT-2004-503011 221

LSHC-CT-2004-503036 219

LSHC-CT-2004-503094 198

LSHC-CT-2004-503216 202

LSHC-CT-2004-503224 212

LSHC-CT-2004-503306 217

LSHC-CT-2004-503351 209

LSHC-CT-2004-503426 200

LSHC-CT-2004-503436 179

LSHC-CT-2004-503438 176

LSHC-CT-2004-503465 196

LSHC-CT-2004-503564 195

LSHC-CT-2004-503569 173

LSHC-CT-2004-503576 170

LSHC-CT-2004-504587 168

LSHC-CT-2004-504743 166

LSHC-CT-2004-505785 164

LSHC-CT-2004-506049 214

LSHM-CT-2003-502852 58

LSHM-CT-2003-502941 154

LSHM-CT-2003-503020 152

LSHM-CT-2003-503041 32

LSHM-CT-2003-503051 116

LSHM-CT-2003-503254 20

LSHM-CT-2003-503304 97

LSHM-CT-2003-503330 93

LSHM-CT-2003-503335 82

LSHM-CT-2003-503382 113

LSHM-CT-2003-503413 79

LSHM-CT-2003-504468 148

LSHM-CT-2004-005033 12

LSHM-CT-2004-005139 129

LSHM-CT-2004-005166 95

LSHM-CT-2004-005206 24

LSHM-CT-2004-005224 70

LSHM-CT-2004-005264 62

LSHM-CT-2004-005268 26

LSHM-CT-2004-005272 34

LSHM-CT-2004-005310 126

LSHM-CT-2004-502800 122

LSHM-CT-2004-502987 120

LSHM-CT-2004-503038 118

LSHM-CT-2004-503039 102


Index by contract number


LSHM-CT-2004-503116 44

LSHM-CT-2004-503245 39

LSHM-CT-2004-503270 144

LSHM-CT-2004-503359 73

LSHM-CT-2004-503430 52

LSHM-CT-2004-503474 90

LSHM-CT-2004-503485 18

LSHM-CT-2004-504837 111

LSHM-CT-2004-504839 41

LSHM-CT-2004-511963 14

LSHM-CT-2004-511995 108

LSHM-CT-2004-512013 36

LSHM-CT-2004-512020 142

LSHM-CT-2004-512039 100

LSHM-CT-2004-512040 146

LSHM-CT-2004-512093 77

LSHM-CT-2004-512138 68

LSHM-CT-2004-512158 106

LSHM-CT-2005-005223 60

LSHM-CT-2005-005320 124

LSHM-CT-2005-512012 88

LSHM-CT-2005-512053 156

LSHM-CT-2005-512099 75

LSHM-CT-2005-512117 49

LSHM-CT-2005-512131 47

LSHM-CT-2005-512136 56

LSHM-CT-2005-513866 150

LSSC-CT-2005-015197 225

LSSC-CT-2005-517659 223

LSSM-CT-2003-502801 85

LSSM-CT-2003-502993 135

LSSM-CT-2003-503373 132

LSSM-CT-2003-504752 131

LSSM-CT-2004-005100 137

LSSM-CT-2004-503246 64

LSSM-CT-2004-511992 28

LSSM-CT-2005-013043 139



Adlkofer, Franz 93

Andrew, Peter W. 75

Aymé, Ségolène 64

Bailey,Anthony James 106

Bangma, Chris H. 221

Berger, Johannes 120

Bjerkvig, Rolf 166

Blamey, Roger 223

Blandino, Giovanni 170

Bock, Elisabeth 88

Boyle, Peter 225

Brahme,Anders 164

Brambilla, Riccardo 132

Casari, Georgio 113

Castro-Lopes, José 137

Celda, Bernardo 198

Chaouat, Gérard 146

Claussen, Bjørgulf 41

Coppes, Rob 179

De Libero, Gennaro 24

Deakin, Bill 90

Demotes-Mainard, Jacques 14

Devor, Marshall 122

Di Luca, Monica 108

Dickson, Suzanne L. 32

Dillner, Joakim 196

Dreyling, Martin 209

Durston,Anthony J. 148

Dyson, Paul 70

Ebbesen, Peter 194

Edwards, Dylan 182

Fawcett, James 100

Ferrari, Michel 111

Foekens, John A. 206

Franceschi, Claudio 144

Frère, Jean-Marie 68

Gautvik, Kaare M. 154

Giavazzi, Raffaella 185

Gilhus, Nils Erik 135

Gutmann, Laurent 82

Haeggström, Jesper Z. 12

Hardie, D. Grahame 34

Hehlmann, Rüdiger 202

Helin, Kristian 162

Henriques Normark, Birgitta 79

Herdegen,Thomas 126

Holland,Tony 56

Jalanko,Anu 116

Kämpe, Olle 60

Kirkwood,Thomas B.L. 156


Index by project coordinator


Kitchen, Ian 95

Kretzschmar, Hans 102

Lenzen, Sigurd 39

Marín, Oscar 129

Matthijs, Gert 47

Newbold, Robert 191

Nicolaï, Jean-Philippe 195

Olesen, Jes 139

Osiewacz, Heinz D. 142

Ouwehand,Willem H. 18

Palacín, Manuel 58

Petter Ottersen, Ole 124

Piccart, Martine 200

Picci, Piero 219

Rees, Robert 217

Resink,Thérèse 24

Rieß, Olaf 97

Roland, Per 131

Schalken, J.A. 168

Siminiak,Tomasz 28

Sleeman, Jonathan 212

Smeitink, Jan 44

Smith, Ulf 36

Spector,Tim 26

Storme, Guy 176

Stuart, H. Ralston 152

Tanner, Stuart 52

Tavitian, Bertrand 173

Tedgui,Alain 20

Teti,Anna 214

Thiesen, Hans-Jürgen 62

Toussaint, Olivier 150

van Strijp, Jos 77

Vicente, Miguel 85

Villarroel,Alvaro 118

Wiman, Klas 187

Zambruno, Giovanna 49

Zoulim, Fabien 73



European Commission

Major Diseases Research - Catalogue of Research Projects (2003-2005) in the Sixth Framework Programme

Luxembourg: Office for Official Publications of the European Communities

2005 – 233 pp. – 21.0 x 29.7 cm

ISBN 92-894-8153-6

Interested in European research?

RTD info is our quarterly magazine keeping you in touch with main developments (results, programmes, events, etc.).It is available in English, French and German. A free sample copy or free subscription can be obtained from:

European Commission

Directorate-General for Research

Information and Communication Unit

ß-1049 Brussels

Fax (32-2) 29-58220


Internet: http://europa.eu.int/comm/research/rtdinfo/index_en.html

EUROPEAN COMMISSION

Directorate-General for ResearchDirectorate F – HealthUnit F.2 – Major Diseases

Contact: Alain Vanvossel

European CommissionOffice CDMA 2/22B-1049 Brussels

Tel. (32-2) 29 62 578Fax (32-2) 29 55 365



KI-61-04-880-E

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9 789289 481 5 33

ISBN 92-894-8153-6

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Major Catalogue Complet