BioengineeringBioengineering is a multidisciplinary field that combines traditional engineering disciplines with that of biology and medicine. It contributes to a better understanding of life sciences using mathematical models and quantitative approaches. It also develops new processes, materials and devices for use in the biomedical sciences.

Key ObjectivesBioengineering uses physics, chemical and engineering principles to solve problems in biology and medicine. Our aim is for the prevention, diagnosis and treatment of diseases, patient rehabilitation and improving health.

Bioengineering ResearchThe Division of Bioengineering at NUS has set up cuttingedge laboratories to facilitate research and provide a good research environment to facilitate exchange of new ideas. We have chosen to focus on four areas in which our Bioengineering Faculty excels in:

Bioimaging A new research thrust in the Bioengineering Programme is Bioimaging. A research group is set up to develop novel instruments and techniques in optical imaging for biomedical applications, including multiphoton microscopy, optical coherence tomography (OCT), Raman spectroscopy and imaging, endoscopy and diffusive optical imaging. Biomaterials The biomaterials group looks into the development of biomimetic composite materials for dental and orthopaedic applications. The tissue repair group designs and fabricates textile and nanofiber based novel scaffolds for tissue engineering applications. The chemotherapeutic engineering group aims to develop advanced engineering devices such as nanoparticles of biodegradable polymers/bioadhesive materials and lipid bilayers vesicles (liposomes) that possess the best efficacy and least side effects for the clinical and oral administration of anti-cancer drugs. Tissue Modulation The Tissue Modulation Lab aims to discover the secrets to preventing scar formation, with a view to improving the healing process that takes place after an injury or surgical operation. The team is working on the three most common kinds of scars: keloids (skin scarring), pterygium (scarring of the cornea) and pannus (caused by arthritis). Its work includes testing and evaluating currently available enzyme inhibitors to stop the scarring process. The prevention or control of the production of collagen around the wound is expected to limit the formation of scars.

Biomaterials/Tissue Engineering & Repair Biosignal Processing/Bioimaging Nanobioengineering Biomechanics/Computational Bioengineering

The research in these areas has applications in biopharmaceutical engineering, medical devices, biosensors & bioinstrumentation, regenerative medicine, cancer therapy, etc.

Research HighlightsBiosignal Processing This laboratory undertakes activities related to the measurement, processing and analysis of biomedical signals. These can be physiological signals (EEG, ECG), human images (CT, MRI, ultrasound) or microscopic images (cells and spores). Applications can include 3D image visualisation in orthodontics, image data fusion for image-guided spinal surgery and automated classification of airborne spore images.

BioengineeringBiomechanics The biomechanics group investigates the complete characterisation of the viscoelastic and mechanical responses of bone tissues in healthy subjects as well as in those who are affected by degenerative diseases such as cancer. Numerical analyses and experimental tests are also employed to find the optimal solution of using various anti-cancer and bisphosphonate drugs.PCL Nanofiber

Collagen immonilized

PCL nanofiber

Nanobioengineering Both basic and applied research are performed in this interdisciplinary area to develop functional nanostructured materials or devices for ultrasensitive biodetection/imaging, disease diagnostics and treatment. There is a strong emphasis on developing functional nanomaterials, multicolor nanoprobes and advanced biochips for multiplexing and high-throughput analysis of genes, proteins and cells. Our aims are to apply nanotechnologies to develop and promote biotechnologies/bioengineering for genomics, proteomics and molecular diagnostics.

Selected Recent Publications 1 A Corrias, ML Buist. Quantitative cellular description of gastric slow wave activity. Am J Physiol Gastrointest Liver Physiol, 294(4), G989G995. (2008) B Legrand, CS Chang, SH Ong, SY Neo, N Palanisamy. Automated identification of chromosome segments involved in translocations by combining spectral karyotyping and banding analysis. IEEE Trans. SMC-A, 38(6), 1374-1384. (2008) Z Huang, SK Teh, W Zheng, J Mo, K Lin, X Shao, KY Ho, M Teh, KG Yeoh. Integrated Raman spectroscopy and trimodal wide-field imaging techniques for real-time in vivo tissue Raman measurements at endoscopy. Optics Letters, 34(6), 758-760. (2009) N Chen, CH Wong, CJR Sheppard. Focal Modulation Microscopy. Optics Express, 16(24), 18764-18769. (2008) EKF Yim, MV Sefton. Amidine surface modification of poly(acrylonitrile-co-vinyl chloride) reduces platelet adhesion. Journal of Biomedical Materials Research Part A. 89(3), 780-90. (2009) SJ Tan, L Yobas, GYH Lee, CN Ong, CT Lim. Microdevice for the isolation and enumeration of cancer cells from blood. Biomedical Microdevices. (2009) DP Nickerson, A Corrias, ML Buist. Reference descriptions of cellular electrophysiology models. Bioinformatics. 24(8), 11121114. (2008) DK Chatteriee, AJ Rufalhah, Y Zhang. Upconversion fluorescence imaging of cells and small animals using lanthanide doped nanocrystals. Biomaterials 29, 7, 937-943. (2008) HB Fan, HF Liu, SL Toh, JCH Goh. Enhanced differentiation of mesenchymal stem cells co-cultured with ligament fibroblasts on gelatin/silk fibroin hybrid scaffold. Biomaterials 29, 8, 1017-1027. (2008)

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Mechanical stretching of a (a) normal, (b) mid-stage and (b) late stage malaria infected red blood cell using laser tweezers. The cell becomes progressively stiffer as the parasite matures within the cell.

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Nanobiomechanics It is known that diseases can cause or be caused by physical changes in individual cells biomolecules. Our nanobiomechanics research involves the study of how mechanical properties of cells and biomolecules can be altered by or contribute towards human diseases, in particular in cancer and malaria. Using state-of-the-art nanotechnological tools, we seek to probe the structure-property-function relationship changes at the cellular and molecular levels arising from these diseases. It is hoped that from this research, we can assist in developing new and improved diagnostic devices and techniques in the detection and diagnosis of human diseases as the change in the cellular mechanical properties can quantitatively reflect their diseased states. Computational Physiology Current applications in computational electrophysiology range from cellular models, where processes such as electrical activation and mechanical contraction are integrated, through to whole organ models, for which high performance computers are needed to obtain solutions. This study now focuses on detecting disease conditions, such as diabetic gastroparesis, where degradation of the cells generates electrical activity.

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10 Feng SS. Snapshot: Nanoparticles of Biodegradable Polymers for Cancer Diagnosis and Treatment. Biomaterials. 29(30), 4146-4147. (2008)

Contact Details Professor Colin Sheppard Division of Bioengineering Faculty of Engineering National University of Singapore 7 Engineering Drive 1, Singapore 117576 Block E3A #04-15 Tel : (65) 6516 1610 Fax : (65) 6872 3069 Email : biesec@nus.edu.sg Website : http://www.bioeng.nus.edu.sg

Bioinformatics and Computational BiologyBioinformatics has attracted considerable attention in the life sciences. This arises from the accumulation of biomedical data and the imminent need to turn such data into useful knowledge. Bioinformatics plays a central role in this process. It guides experiments in wet laboratories and increases effectiveness while saving time and cost. For example, accurate prediction on functional sites of genes allows scientists to home in and identify previously unknown genes for further study. Similarly, comparative analysis of the expression profiles of genes from microarray measurements of diseased and normal samples has enabled scientists to pinpoint genes relevant to the control of the disease in question. Patterns discovered from large databases of clinical records capturing genetic, environmental and drug response information also help in identifying the significant factors for disease diagnostic and treatment.

Key ObjectivesTo become a globally admired centre for research in bioinformatics technologies and their applications to the improvement of human life.

Research AreasOur research leads to fundamental advances in the following areas: Knowledge discovery technologies Database technologies Combinatorics and Algorithms

We translate these advances into improvements to human life by applying them on

Analysis of clinical data Analysis of sequence data Specialty databases Molecular evolution Analysis of protein structure & networksResearch Areas

Bioinformatics and Computational BiologyResearch Highlights Protein complexes are important for understanding principles of cellular organization and function. However, protein interaction data produced by highthroughput experiments are often associated with high false-positive and false-negative rates, which makes it difficult to predict complexes accurately. We used an iterative scoring method to assign weight to protein pairs, and the weight of a protein pair indicates the reliability of the interaction between the two proteins. We developed an algorithm called CMC (Clustering based on Maximal Cliques) to effectively discover complexes from the weighted PPI network. Among different epigenetic modifications, the differential histone modification sites (DHMSs) are of great interest to study the dynamic nature of epigenetic and gene expression regulations among various cell types, stages or environmental responses. We proposed an approach called ChIPDiff for the genome-wide comparison of histone modification sites identified by ChIP-seq. We demonstrated that the H3K27me3 DHMSs identified by our approach are of high sensitivity, specificity and technical reproducibility. ChIPDiff was further applied to uncover the differential H3K4me3 and H3K36me3 sites between different cell states.

Proportion of interacting proteins with common cellular functional roles increases at significantly at higher NeMoFinder thresholds compared to other protein interaction reliability measures.

Selected Recent PublicationsJournal papers 1 Z Aung, SH Tan, SK Ng, et al. PPiClust: Efficient Clustering of 3-D Protein-Protein Interaction Interfaces. J Bioinformatics and Comput Biol 6:415-433 (2008) 2 HN Chua, K Ning, WK Sung, et al. Using Indirect Protein-Protein Interactions for Protein Complex Prediction. J Bioinformatics and Comput Biol 6:435-466 (2008) 3 HN Chua, L Wong. Increasing the Reliability of Protein Interactomes. Drug Discovery Today 13:652-658 (2008) 4 HH Do, KP Choi, FP Preparata, et al. Spectrum-based de novo repeat detection in genomic sequences. J Comput Biol 15:469-487 (2008) 5 TW Lam, WK Sung, SL Tam, et al. Compressed indexing and local alignment of DNA. Bioinformatics 24:791-797 (2008) 6 WH Lee, WK Sung. RB-Finder: An Improved Distance-Based Sliding Window Method to Detect Recombination Breakpoints. J Comput Biol 15:881-898 (2008) 7 K Ning, N Ye, HW Leong. On preprocessing and anti-symmetry in de novo peptide sequencing: Improving efficiency and accuracy. J Bioinformatics and Comput Biol 6:467-492 (2008) 8 E Wijaya, SM Yiu, NT Son, et al. MotifVoter: A novel ensemble method for fine-grained integration of generic motif finders. Bioinformatics 24:2288-2295 (2008) 9 H Xu, CL Wei, F Lin, et al. An HMM approach to genome-wide identification of differential histone modification sites from ChIP-seq data. Bioinformatics 24:2344-2349 (2008) 10 JL Yang, LX Zhang. Run Probabilities of Seed-Like Patterns and Identifying Good Transition Seeds. J Comput Biol 15:1295-1313 (2008)

Recent Awards Spore Youth Award Medal of Commendation 2006

(Professor Wong Limsoon) Spore National Science Award 2006 (Dr Wing-Kin Sung) Best-performer, PPI Subnetwork Problem, DREAM Challenge 2007 (Professor Wong Limsoon & team) Prediction

Best-performer, BCL6 Target Gene Finding Problem, DREAM Challenge 2007 (Dr Wing-Kin Sung & team)

Contact Details Professor Wong Limsoon Department of Computer Science School of Computing National University of Singapore Com1, #03-08 Singapore 117417 Tel : (65) 6516 2726 Fax : (65) 6779 4580 Email : dcswls@nus.edu.sg Website : http://www.comp.nus.edu.sg/~wongls/bp/

Precision versus Recall curves for Neighbour Counting (NC), x2, PRODISTIN and FS Neighted Averaging in predicting the MIPS Functional Categories for proteins from the GRID interaction dataset.

Biophysical SciencesThe availability of completed and annotated genome sequences of human and several representative organisms provides key information for biology and biomedicine. Embedded within these sequences are the genetic instructions required to unravel the complexities of biological systems. Elucidating the content, structure and regulation of genomes, especially identifying the functions of the myriad encoded elements, will allow connection to be made between genomics and biology. This will also accelerate the exploration of all realms of the biological sciences. As the Programme comprehensively identifies the structural and functional components encoded in the genome, elucidates the organisation of genetic networks and protein pathways, establishes how they contribute to cellular and organismal phenotypes and understands evolutionary variation across species and the mechanisms underlying it, new conceptual and technological approaches are being developed.

Key Objectives To make NUS/Singapore a world class centre for research in structural biology and proteomics To build up state-of-the-art core facilities in structural biology and proteomics in NUS To initiate and formulate major inter-disciplinary flagship programmes in structural biology and proteomics To make important contributions in the development of biomedical and bio-pharma industries in Singapore To provide expertise/consultation to researchers in NUS and Singapore To provide excellent training programs undergraduates and postgraduates for

Research HighlightsThe Biophysical Sciences Research Group presently has a large number of experts with excellent track records in all the following focus areas of structural biology and proteomics. These team members hail from the Faculty of Science and School of Medicine in NUS, and national research institutes including the Genome Institute of Singapore (GIS) and Institute of Material Research Engineering (IMRE). This Research Group also includes nine investigators funded by the Biomedical Research Council and the Life Sciences Institute. Researchers of this research group are conducting cutting edge basic research with immense biomedical relevance, which led to over 180 publications in peer-reviewed journals and 17 patents. The group also attracted over S$47 million in thirdparty research funds.

To serve as the focal point for regional and international collaborations

Biophysical SciencesResearch focus Structure, Function and Biotechnological Applications of Bioactive Macromolecules Toxins, Factor C and Anti-bacterial Peptides Structural Elucidation of Proteins andSelected Recent Publications 1 Ding JL, Li P & Ho B. The sushi peptides: structural characterization and mode of action against Gram negative bacteria. Cell Mol Life Sci 65, 1202-1219. (2008) Fan ZH, Wang X, Lu JH, Ho B & Ding JL. Elucidating the function of an ancient NF-kB p100 homologue, CrRelish, in antibacterial defense. Infect & Imm 76(2), 664-670. (2008) He W, Ladinsky MS, Huey-Tubman KE, Jensen GJ, McIntosh JR & Bjorkman PJ. FcRn- Mediated antibody transport across epithslial cells revealed by electron tomography Nature 455(7212), 542-546. (2008) Hou X, Hu WW, Shen L, Lee LYC, Tao Z, Han JH & Yu H. Global identification of flower development. Plant Physio 147, 1126-1142. (2008) Shi J, Lua S, Du N, Liu XY & Song J. Identification, recombinant production and structural characterization of flour silk proteins from the Asiatic Honeybee Apis cerana. Biomaterials 29, 2820-2828. (2008) Liu J & Song J. NMR evidence for forming highly populated helical conformations in the partially folded hNck2 SH3 domain. Biophys J 95, 4803-4812. (2008) Long D, Liu M & Yang D. Accurately probing slow motions on millisecond timescales with a robust NMR relaxation experiment. J Amer Chem Soc 130(8), 2432-2433. (2008) Lu Z, Liu W, Huang H, He Y, Han Y, Rui Y, Wang Y, Li Q, Ruan K, Ye Z, Low BC, Meng A & Lin SC. Protein encoded by the Axin(Fu) allele effectively down-regulates Wnt signaling but exerts a dominant negative effect on c-Jun N-terminal kinase signaling. J Biol Chem 283(19), 13132-13139. (2008) Ng C, Jackson RA, Buschdorf JP, Sun Q, Guy GR & Sivaraman J. Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl- TKB domain substrates. EMBO J 27(5), 804-816. (2008) Wang F, Bi X, Chen LM & Hew CL. ORF018R, a highly abundant virion protein from Singapore grouper iridorvirus, is involved in serine/threonine phosphorylation and virion assembly. J Gen Virol 89(Pt 5), 1169-1178. (2008)

Macromolecular Assemblies related to Human Diseases Cancer, Hepatitis and Neurological Disorders Structure and Assembly of Virus and

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Virus Proteins De Novo Protein and Drug Design Proteomic Analysis of Cancer Biomarkers and Virulent Factors of Bacterial and Viral Pathogens Platform Technologies Development NMR methodology, Protein Chips, Quantum Dots and Single Molecule Spectroscophy CryoEM Diseases through the mechanisms of cell and tissue mechanics

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Graduate ProgrammeThe Biophysical Sciences Research Group is actively seeking outstanding students in life sciences, chemistry, physics and mathematics for our joint graduate programme. Various graduate modules have been mounted or revamped, each receiving very good response from students across various disciplines and from other research institutes. Together with our regular weekly seminar series and the Visiting Scientists programme, the Group hopes to propel NUS and Singapore as one of the best training centres for young protein scientists.

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Contact Details Professor Paul Matsudaira Department of Biological Sciences Faculty of Science National University of Singapore 14 Science Drive 4, Singapore 117543 Tel : (65) 6516 2962 Fax : (65) 6779 2486 Email : dbshead@nus.edu.sg Website : http://www.dbs.nus.edu.sg/research/focus/structural/ index.html

Docking of small molecule inhibitor on the anti-apoptotic BclXL protein.

ImmunologyThe Immunology Programme at NUS brings together 30 immunologists at NUS and NUH. Its goal is to nucleate the immunology community and cement ties with local research institutions and hospitals for a seamless translation of basic science to clinical medicine.

Key Objectives To develop a world class centre for immunology research To work with the hospitals to translate immunology research into clinical practice To attract Singapore academic immunology talents to

Research AreasResearch in the Programme focuses on three fundamental aspects of the immune system: antigen processing and presentation, regulatory T cell networks, and inflammatory and infectious disease. The expertise will be focused on four main areas: infectious disease, tumour immunology, vaccine development and clinical immunology.

To provide a cohesive platform for clinical and basic immunologists in Singapore to interact and exchange views

Comprising 19 full members, the team is a multiskilled and multidisciplinary team of scientists with differing but complementary expertise. 10 of our principal investigators (PI) labs are now located under one roof at the Centre for Life Sciences, operating on an open laboratory concept, facilitating inter-lab communication and encouraging collaboration. Our new core facilities, which will aid development of key technologies, include the following: Immunohistochemistry Scintillation Centre Dark Rooms Transgenic and gene knockout mice Flow Cytometry and Cell Sorting Fluorescent and Confocal Microscopy Biochemistry and molecular biology Bacterial and viral containment

Research HighlightsTogether with Professor Chan Soh Ha, Dr Paul MacAry has raised a monoclonal antibody that recognizes EBV infected cells that will help early diagnosis of nasopharyngeal carcinoma that is particularly common among those of southern Chinese descent. In addition, with colleagues at Cambridge, he reported in Science that the chemokine receptor, CCR5, recognizes heat shock protein HSP 70. This has implications for both the pathophysiology of tuberculosis and tumourdirected immunotherapy. Professor Mike Kemeny was funded by the BMRC to lead a multi-disciplinary team that includes Professor Chua Kaw Yan and Associate Professor Fred Wong to develop asthma mouse, whose T cells constitutively recognise Asian environmental allergens. Associate Professor Lu Jinhua reported in Blood that betaig h3, which is selectively up-regulated in immature dendritic cells, regulates endoctytic antigen uptake. Immunology faculty continues to grow. We have recruited additional world class faculty: Dr Veronique Angeli from Mt Sinai Hospital, New York; and Dr Justin Wong from Scripps Institute.

We are part of the Singapore Immunology Network, with strong links to researchers at Biopolis. Internationally we have strong research links with Cambridge, Karolinska Institute, University of Glasgow, WEHI and Kings University College, London.

ImmunologySelected Recent Publications 1 Huang D, Cai DT, Chua RY, Kemeny DM, Wong SH. Nitric-oxide synthase 2 interacts with CD74 and inhibits its cleavage by caspase during dendritic cell development. J Biol Chem 283: 171322. (2008) Lo SY, Taylor JR, Wilkie S, Farzaneh F, Kemeny DM, Sadelain M, Dibb NJ, Maher J. Harnessing the tumour-derived cytokine, CSF-1, to co-stimulate T-cell growth and activation. Molecular Immunology 45: 1276-87. (2008) Naik MT, Chang CF, Kuo IC, Kung CC, Yi FC, Chua KY, Huang TH. Roles of structure and structural dynamics in the antibody recognition of the allergen proteins: an NMR study on Blomia tropicalis major allergen. Structure 16: 125-36. (2008) Sethu S, Mendez-Corao G, Melendez AJ. Phospholipase D1 plays a key role in TNF-alpha signaling. J Immunol 180: 6027-34. (2008) Lai WQ, Goh HH, Bao Z, Wong WSF, Melendez AJ, Leung BP. The role of sphingosine kinase in a murine model of allergic asthma. J Immunol 180: 4323-9. (2008) Quemeneur L, Angeli V, Chopin M, Jessberger R. SWAP-70 eficiency causes high-affinity plasma cell generation despite impaired germinal center formation. Blood 111: 2714-24. (2008) Wong SB, Bos R, Sherman LA. Tumor-Specific CD4+ T Cells Render the Tumor Environment Permissive for Infiltration by Low-Avidity CD8+ T Cells. J Immunol 180: 3122-31. (2008) Ho SY, Chua SQ, Foo DG, Locht C, Chow VT, Poh CL, Alonso S. Highly attenuated Bordetella pertussis strain BPZE1 as a potential live vehicle for delivery of heterologous vaccine candidates. Infect Immun 76: 111-9. (2008) Ho YH, Cai DT, Wang CC, Huang D, Wong SH. Vesicle-associated membrane protein-8/endobrevin negatively regulates phagocytosis of bacteria in dendritic cells. J Immunol 180: 314857. (2008)Talin/HLA-DR LFA-1/HLA-DR

19 Reddy ST, van der Vlies AJ, Simeoni E, Angeli V, Randolph GJ, ONeil CP, Lee LK, Swartz MA, Hubbell JA .Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nat Biotechnol 25: 1159-64. (2007) 20 Ye Z, Gan YH. Flagellin contamination of recombinant heat shock protein 70 is responsible for its activity on T cells. J Biol Chem 16; 282: 4479-84. (2007) 21 Bao Z, Lim S, Liao W, Lin Y, Thiemermann C, Leung BP, Wong WSF. Glycogen synthase kinase-3beta inhibition attenuates asthma in mice. Am J Respir Crit Care Med 176: 431-8. (2007) 22 Drenkard D, Becke FM, Langstein J, Spruss T, Kunz-Schughart LA, Tan TE, Lim YC, Schwarz H. CD137 is expressed on blood vessel walls at sites of inflammation and enhances monocyte migratory activity. FASEB J 21: 456-63. (2007) 23 Gasser S. DNA damage response and development of targeted cancer treatments. Ann Med 39: 457-64. (2007) 24 Alonso S, Pethe K, Russell DG, Purdy GE. Lysosomal killing of Mycobacterium by ubiquitin-derived peptides is enhanced by autophagy. Proc Natl Acad Sci 104: 6031-6. (2007)

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10 Ye Z, Lee CM, Sun GW, Gan YH. Burkholderia pseudomallei infection of T cells leads to T-cell costimulation partially provided by flagellin. Infect Immun 76: 2541-50. (2008) 11 Lippert U, Zachmann K, Ferrari DM, Schwarz H, Brunner E, Latif AH, Neumann C, Soruri A. CD137 ligand reverse signaling has multiple functions in human dendritic cells during an adaptive immune response. Eur J Immunol 38: 1024-32. (2008) 12 Mustafa FB, Ng FS, Nguyen TH, Lim LH. Honeybee venom secretory phospholipase A2 induces leukotriene production but not histamine release from human basophils. Clin Exp Immunol 151: 94-100. (2008)

13 Lo SY, Gorak-Stolinska P, Bachy V, Ibrahim MAA, Kemeny DM, Maher J. M-CSF-mediated inhibition of dendritic cell differentiation role of phosphatidylinositol 3-kinase and delayed caspase activation. J Leukocyte Biol 82: 1446-54. (2007) 14 Salagianni M, Wong KL, Thomas MJ, Noble A, Kemeny DM. An Essential Role for IL-18 in CD8 T Cell-Mediated Suppression of IgE Responses. J Immunol 178: 4771-4778. (2007) 15 Wells JW, Cowled CJ, Giorgini A, Kemeny DM#, Noble A#. Regulation of allergic airway inflammation by class I-restricted allergen presentation and CD8 T-cell infiltration. J Allergy Clinical Immunol 119: 226-34. (2007) 16 Javid B, MacAry PA, Lehner PJ. Structure and function: heat shock proteins and adaptive immunity. J Immunol 179: 2035-40. (2007) 17 Melendez AJ, Harnett MM, Pushparaj PN, Wong WSF, Tay HK, McSharry CP, Harnett W. Inhibition of Fc epsilon RI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes. Nat Med Nov 13: 1375-81. (2007) 18 Chen Y, Yuen WH, Fu J, Huang G, Melendez AJ, Ibrahim FB, Lu H, Cao X. The mitochondrial respiratory chain controls intracellular calcium signaling and NFAT activity essential for heart formation in Xenopus laevis. Mol Cell Biol 27: 6420-32. (2007)

Adoptive transfer of activatedCD8+ T cells

Adoptive transfer of activatedCD8+ and CD4+ T cells

Contact Details Professor David Michael Kemeny Department of Microbiology Yong Loo Lin School of Medicine National University of Singapore Immunology Programme Centre for Life Sciences 28 Medical Drive, #03-05, Singapore 117456Tel: (65) 6516 5518

Fax : (65) 6778 2684 Email : mickdm@nus.edu.sg Website : http://immunology.nus.edu.sg

Infectious DiseasesResearch on infectious diseases is a critical element in our defence against newly emerging and re-emerging microbial threats, a point brought home most devastatingly by the avian influenza and SARS epidemics. Flaviviruses, in particular dengue and West Nile viruses, are of significant medical importance given the increasing prevalence of mosquito-borne diseases with global warming. In addition, malaria kills some two to three million people every year. There is a strong causative link between peptic ulcers, gastritis and gastric cancers with Helicobacter pylori infections. Antibiotic resistance represents a serious international problem and is an area of intense public health interest. These strategic research areas were selected based on their importance in Singapore, the region or globally. Understanding their host-pathogen interactions will provide insights into potential target sites that can facilitate the design of feasible antimicrobial strategies against these important pathogens.

Key Objectives To conduct research in the key areas of influenza, dengue, bacterial virulence/ resistance and malaria To adopt platform technologies including Vaccinology (e.g. epitope mapping), Proteomics & Genomics, Nanobiomechanics and Structural Biology To focus on themes, including vaccines, animal models, host-pathogen interactions, antiinfectives, surveillance and epidemiology

Research Areas Influenza research on animal models of pneumonitis, genomics and proteomics of viral pathogenesis, expression of H5N1 antigens in bacterial hosts, human influenza monitoring and surveillance, molecular epidemiology and evolution.

Assembly process of functional infectious dengue and West Nile virus particles, including the involvement of host proteins. Bacterial pathogenesis and novel virulence factors of Helicobacter pylori. Epidemiology and mechanisms of antibiotic resistance, including the control and pathogenesis of methicillin-resistant Staphylococcus aureus. Host-pathogen interactions in malaria, including biomechanics of malaria-infected blood cells, bioimaging, cell death and microarray analysis of malaria. Golgi trafficking in protozoa.

Infectious DiseasesResearch Highlights Mechanistic studies on virus-host interactions that contribute to apoptosis, and that mediate virus attachment/recognition of target host cells. Identification and application of Factor C from the horseshoe crab for the detection of bacterial contaminants. Analysis of specific proteins transported from the surface of the malaria parasite that contribute to changes in mechanical properties and stickiness of infected cells. Role of centrins in Golgi duplication and cell division in protozoa.6 Selected Recent Publications 1 Yeo WM, Isegawa Y, Chow VT. The U95 protein of human herpesvirus 6B interacts with human GRIM19: silencing of U95 expression reduces viral load and abrogates loss of mitochondrial membrane potential. J Virol 82: 1011-20. (2008) 2 Chu JH, Chiang CC, Ng ML. Immunization of flavivirus West Nile recombinant envelope domain III protein induced specific immune response and protection against West Nile virus infection. J Immunol 178: 2699-705. (2007) Jiang N, Tan NS, Ho B, Ding JL. Respiratory protein-generated reactive oxygen species as an antimicrobial strategy. Nat Immunol 8: 1114-22. (2007) Hsu LY, Tan TY, Jureen R, Koh TH, Krishnan P, Tzer-Pin Lin R, Wen-Sin Tee N, Tambyah PA. Antimicrobial drug resistance in Singapore hospitals. Emerg Infect Dis 13: 1944-7. (2007) Mills JP, Diez-Silva M, Quinn DJ, Dao M, Lang MJ, Tan KS, Lim CT, Milon G, David PH, Mercereau-Puijalon O, Bonnefoy S, Suresh S. Effect of plasmodial RESA protein on deformability of human red blood cells harboring Plasmodium falciparum. Proc Natl Acad Sci USA 104: 9213-7. (2007) He CY. Golgi biogenesis in simple eukaryotes. Cell Microbiol 9: 56672. (2007)

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Contact Details Associate Professor Vincent TK Chow Department of Microbiology Yong Loo Lin School of Medicine National University of Singapore Block MD4, 5 Science Drive 2 Singapore 117597 Tel : (65) 6516 3691 Fax : (65) 6776 6872 Email : micctk@nus.edu.sg Website : http://medicine.nus.edu.sg/mbio/staff.html

Experimental Therapeutics Medicinal ChemistryThe Experimental Therapeutics Platform is designed to assist both basic and clinical researchers at NUS in the development of potential therapeutic compounds. The aim is to provide support from small molecule development (Medicinal Chemistry) through the modeling of human diseases in animals, pre-clinical safety assessment (Toxicology) all the way to drug evaluation in human subjects and a more personalised approach to drug treatment.

Key Objectives To establish NUS as a centre of excellence for medicinal chemistry research To initiate and establish major inter-disciplinary flagship programmes in medicinal chemistry To develop a strong graduate programme in Medicinal Chemistry and produce competent PhD/ MSc level graduates to meet the manpower needs of industry Setting up the high throughput- & high contents screening facility: The high throughput screening facility was fully set up equipped with 1536-well plate readers in 2008. In addition, facilities that will enable high content screening as a means of extracting more information from early stages of screening is also built by custom optimization of the existing machines. All the equipments are centralized in MCP core facility room. Using this high throughput screening set up, our program is testing chemical library in NCI-60 cancer cell lines for selective anticancer drug discovery. TB drug candidate discovery (collaboration with NITD: Novartis Institute for Tropical Disease) Drug resistant Tuberculosis is an emerging threat to human being, and this is one of the major targets of NITD. The discovery of new lead is highly challenging, and NITD requested collaboration with Med Chem Program. Upon agreeing on the collaboration, NITD screened Med Chem Library for TB, and already identified 12 promising hit compounds. We will further develop these compounds in collaborative work.

Research AreasMedicinal chemistry is an integral part of the drug discovery process. It provides the vital link between biological target identification and the final development of a therapeutic agent. The primary tasks of medicinal chemistry are duly addressed by the core areas of the Programme, which are (i) chemical synthesis for lead selection, (ii) rational design and optimisation, (iii) biological evaluation and (iv) molecular imaging for diagnosis.

Research Highlights Chemical Synthesis for Lead Selection The emphasis is on the development of novel synthetic methodologies with broad applications to medicinal chemistry. This is explored through target-oriented (natural products as leads) and diversity-oriented (building combinatorial libraries) synthesis. Rational Design and Lead Optimisation Structure-based and pharmacophore-based design approaches are employed for lead optimisation. Structurebased approaches require physical (Xray, NMR) and in silico (molecular modelling) determinations. The more widely employed pharmacophore-based approach utilises conventional structural modifications for optimisation. These approaches are employed in tandem. Biological Evaluation Proteomic approaches capable of high throughput identification and characterisation of enzymes are investigated with the aim of developing expression displays that combine DNA micro-array with protein display techniques.

Selected Recent Publications 1 Jiang Z, Pan Y, Zhao Y, Ma T, Lee R, Yang Y, Huang KW, Wong MW and Tan CH, Synthesis of Chiral Quaternary C-F Bond through Highly Enantioselective and Diastereoselective GuanidineCatalyzed Addition of Fluorocarbon Nucleophiles, Angewandte Chemie International Edition English, 48, 3627 3631. (2009) Lu CHS, Sun H, Bakar FBA, Uttamchandani M, Zhou W, Liou YC, Yao SQ* Rapid Affinity-Based Fingerprinting of 14-3-3 Isoforms Using A Combinatorial Peptide Microarray, Angew Chem Int Ed, 47, 7438-7441. (2008) Wagner BK, Carrinski HA, Ahn YH, Kim YK, Gilbert TJ, Fomina DA, Schreiber SL, Chang YT, Clemons PA. Small-molecule fluorophores to detect cell-state switching in the context of high-throughput screening. J Am Chem Soc 130, 4208-4209. (2008)

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Recent Developments Building Med Chem Program Chemical Library: It was aimed to construct a centralized high quality chemical library based on compounds presently synthesized by core members. Currently, 8281 compounds are collected from MCP core members lab, which are proprietary set of compounds. In addition, MCP initiated compound sharing program with more advanced chemical banks in other institutes. As the first example, MCP received 2,900 compounds from Korean Chemical Bank for collaboration. Program wide new diversityoriented library synthesis was initiated during FY 2007 to establish the high throughput synthesis platform. This chemical library is being used for internal Med Chem projects, and also distributed for collaborative project in different RICs at NUS, other RIs in Biopolis and also for international institutes.

Contact Details Associate Professor Chang Young-Tae Medicinal Chemistry Department of Chemistry Faculty of Science National University of Singapore 3 Science Drive 3, Singapore 117543Tel: (65) 6516 6774

Fax : (65) 6779 1691 Email : chmcyt@nus.edu.sg Website : http://medchem.science.nus.edu.sg/

Experimental Therapeutics - ToxicologyAssessment of toxic substances or potential drugs involves a complex array of invitro and in-vivo investigations aimed at identifying dose response relationship and possible target organs of action or toxicity. These studies are also necessary to reveal the possible mutagenic, carcinogenic and other toxic potential of candidate drugs. In addition, unraveling the underlying molecular mechanisms of drugs is pivotal. Not only do they help develop less toxic derivatives, they also facilitate identification of susceptible and high-risk populations.

Key Objectives To unravel the molecular mechanisms and pathways underlying toxicity. To analyze the role of differential expression of metabolising enzymes and their relationship to toxicity. To utilize proteomics, toxicogenomics, and metabonomics techniques to identify and evaluate Biomarkers, and to elucidate the molecular targets.Selected Recent Publications 1 Zhang SY, Lin Y, Kim YS, Liu ZG, Ong CN, Shen HM. c-Jun Nterminal Kinase Mediates Hydrogen Peroxide-Induced Cell Death via Sustained Poly(ADP-ribose) Activation. Cell Death and Differentiation 14: 1001-1010. (2007) 2 Shen, HM, Liu, ZG JNK Signaling Pathway is a Key Modulator in Cell Death Mediated by Reactive Oxygen and Nitrogen Species. Free Radic. Biol Med 40: 928-939. (2006) 3 Huang Q, Shen HM, Shui G, Wenk MR, Ong CN. Emodin inhibits tumor cell adhesion through disruption of the membrane lipid Raftassociated integrin signaling pathway. Cancer Res 66: 5807-15. (2006) 4 Yuan JM, Gao YT, Ong CN, Ross RK, Yu MC. Prediagnostic level of serum retinol in relation to reduced risk of hepatocellular carcinoma. J Natl Cancer Inst 98: 482-90. (2006) 5 Lam SH, Gong Z. Modeling liver cancer using zebrafish: a comparative oncogenomics approach. Cell Cycle 5: 573-7. (2006) Lam SH, Wu YL, Vega VB, Miller LD, Spitsbergen J, Tong Y, Zhan H, Govindarajan KR, Lee S, Mathavan S, Murthy KR, Buhler DR, Liu ET, Gong Z. Conservation of gene expression signatures between zebrafish and human liver tumors and tumor progression. Nat Biotechnol 24: 73-5. (2006) Bi X, Lin Q, Foo TW, Joshi S, You T, Shen HM, Ong CN, Cheah PY, Eu KW, Hew CL. Proteomic analysis of colorectal cancer reveals alterations in metabolic pathways: mechanism of tumorigenesis. Mol Cell Proteomics 5: 1119-30. (2006) Zhang H, Lin Q, Ponnusamy S, Kothandaraman N, Lim TK, Zhao C, Kit HS, Arijit B, Rauff M, Hew CL, Chung MC, Joshi SB, Choolani M. Differential recovery of membrane proteins after extraction by aqueous methanol and trifluoroethanol. Proteomics 7: 1654-63. (2007)

Research Areas Involvement of reactive oxygen species and oxidative stress in metabolism and bioactivity of xenoboiotics. Roles of detoxification enzymes in cancer chemoprevention. Mechanistic studies of natural compounds in cancer metastasis. Discovery of cancer biomarkers using proteomics, transcriptomics and metabolomics approaches. Roles of antioxidants in disease prevention. Potential environmental and human health hazard of engineered nano-materials.

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Research Highlights Use of zebrafish as a bio-model for water quality monitoring. This approach is useful for both translational research and for drug development. Mechanistics studies of cancer metastasis and their prevention. Various techniques for tumor metastasis have been recently developed by the group and used for drug discovery investigations.

Contact Details Professor Ong Choon Nam Department of Community, Occupational and Family Medicine Yong Loo Lin School of Medicine National University of Singapore MD3, 16 Medical Drive, Singapore 117597Tel: (65) 6516 4982 Fax: (65) 6779 1489

Email : choon_nam_ong@nuhs.edu.sg or cofongcn@nus.edu.sg Website : http://www.med.nus.edu.sg/cof/staff_ocn.html

Molecular EpidemiologyThe NUS-GIS Centre for Molecular Epidemiology (CME) is a joint development involving the NUS Department of Community, Occupational & Family Medicine (COFM) and the Genome Institute of Singapore (GIS). The Centre aims to discover gene-environment interactions for the promotion of public health.

Key Objectives To develop high quality research programmes in molecular epidemiology To develop leaders in molecular epidemiology by providing postgraduate training To enable and develop institutional and national infrastructure epidemiology for research in molecular

Research HighlightsSingapore Consortium of Cohort Studies (SCCS) This is a national effort to pool selected cohort studies and build on these to develop a large multi-ethnic population-based cohort study to facilitate research into the complex gene-environment interactions in diseases such as diabetes, cardiovascular diseases and cancers. Singapore Genome Variation Project (SGVP) This is an infrastructural project to characterize the extent of common genetic polymorphisms and the haplotypes in the human genome of the main ethnic groups in Singapore Chinese, Malay and Indian. This project is also the first to map the extent of copy number variations (CNVs) in these ethnic groups. SGVP will provide a comprehensive database of SNPs, haplotypes and CNVs in the Singapore population.

Research AreasThe Centre works on cohort studies focusing on gene environment interactions in cancer, infrastructural projects for population registers, record linkages.

NUS-KI Joint PhD Programme in Genetic and Molecular Epidemiology (GAME)

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This 4-year course aims to create a critical mass of young scholars with understanding of genomics and proteomics, along with the analytical skills of population science. At steady state, the Programme is expected to draw an international intake of 15-20 students bi-annually.

Drawing blood sample from SCCS participantSCGS nurse explaining urine sampling procedure

Molecular EpidemiologyRecent DevelopmentsSingapore Consortium of Cohort Studies (SCCS) This project kicked off in January 2006 and to date has accrued more than 9,000 biospecimens from healthy participants and more than 8,000 biospecimens from diabetic patients. The data and samples are available for research collaboration. CME is embarking on a genome-wide association study (GWAS) on diabetes. The project will compare prevalent diabetics with non-diabetics from the cohort studies. The center received S$1m from the National Medical Research Council (NMRC) to conduct this GWAS. Singapore Genome Variation Project (SGVP) The 100 DNA samples from each of the 3 ethnic groups have been genotyped on the Affymetrix 6.0 and Illumina 1M. Figure 1 shows how our samples compare with the International HapMap. The findings from this project will be used to guide and optimize the design of large-scale genetic association studies, as well as for investigating gene-environment interactions. Knowledge of the degree of genetic commonality across ethnic groups will also provide preliminary indication of whether genes involved in drug and enzyme metabolism are common across the ethnic groups. The SGVP data is available to researchers to tap on as a reference map for candidate-gene studies. NUS-KI Joint PhD programme in Genetic and Molecular Epidemiology This 4-year postgraduate research degree programme is developed jointly by NUS and Karolinska Institute (KI) in Sweden. The prgramme consists of 2 components: coursework and research. Coursework is conducted in 3 blocks (2 in NUS and 1 in KI). Research is conducted at the home university with 6 months in the partner university. The programme is into its 8th year and the fourth intake will be launched August 2009. It had its first graduate in February 2007.Selected Recent Publications 1 Sabanayagam C, Shankar A, Koh D, Chia KS, Saw SM, Lim SC, Tai ES, Wong TY. Retinal microvascular caliber and chronic kidney disease in an Asian population. American Journal of Epidemiology 169(5): 625-32. (2009) 2 Teo YY, Inouye M, Small KS, Fry AE, Potter SC, Dunstan SJ, Seielstad M, Barroso I, Wareham NJ, Rockett KA, Kwiatkowski DP, Deloukas P. Whole genome-amplified DNA: Insights and imputation [2]. Nature Methods 5(4): 279-80. (2008) 3 Maule M, Scelo G, Pastore G, Brennan P, et al. Risk of second: Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, Cooper GM, Roos C, Voight BF, Havulinna AS, Wahlstrand B, Hedner T, Corella D, Tai ES, Ordovas JM, Berglund G, Vartiainen E, Jousilahti P, Hedblad B, Taskinen MR, Newton-Cheh C, Salomaa V, Peltonen L, Groop L, Altshuler DM, Orho-Melander M. Six new loci associated with blood low-density lipoprotein cholesterol, highdensity lipoprotein cholesterol or triglycerides in humans. Nature Genetics 40(2):189-97. (2008) 4 Chuang SC, Hashibe M, Scelo G, Brewster DH, Pukkala E, Friis S, Tracey E, Weiderpass E, Hemminki K, Tamaro S, Chia KS, PompeKirn V, Kliewer EV, Tonita JM, Martos C, Jonasson JG, Dresler CM, Boffetta P, Brennan P. Risk of second primary cancer among esophageal cancer patients: a pooled analysis of 13 cancer registries. Cancer Epidemiology 17(6):1543-9. (2008) 5 Biomarkers and Prevention

Tan JT, Dorajoo R, Seielstad M, Sim X, Rick OT, Seng CK, Yin WT, Saw SM, Kai CS, Aung T, Tai ES. FTO variants are associated with obesity in the Chinese and Malay populations in Singapore. Diabetes 57(10): 2851-7. (2008)

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Ng Unoki H, Takahashi A, Kawaguchi T, Hara K, Horikoshi M, Andersen G, Ng DPK, Holmkvist J, Borch-Johnsen K, Jrgensen T, Sandbk A, Lauritzen T, Hansen T, Nurbaya S, Tsunoda T, Kubo M, Babazono T, Hirose H, Hayashi M, Iwamoto Y, Kashiwagi A, Kaku K, Kawamori R, Tai ES, Pedersen O, Kamatani N, Kadowaki T, Kikkawa R, Nakamura Y, Maeda S. SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nature Genetics 40 (9): 1098-102. (2008)

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Einarsdottir K, Darabi H, Li Y, Low YL, Li YQ, Bonnard C, Sjolander A, Czene K, Wedren S, Liu ET, Hall P, Humphreys K, Liu J. ESR1 and EGF genetic variation in relation to breast cancer risk and survival. Breast Cancer Research Feb 14;10(1): R15. (2008)

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Garcia-Closas M, Hall P, Nevanlinna H, Pooley K, Morrison J et al. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genetics 4(4): e1000054. (2008)

Contact Details Professor Chia Kee Seng Centre for Molecular Epidemiology Yong Loo Lin School of Medicine National University of Singapore c/o Department of Community, Occupational and Family Medicine Blk MD3, 16 Medical Drive, Singapore 117597Tel: (65) 6516 4971

Fax : (65) 6779 1489 Email : cofcks@nus.edu.sg Website : http://www.med.nus.edu.sg/cof/cme.html

Expression Microarrays

Neurobiology/AgeingAge-related neurodegenerative diseases (especially Alzheimers and Parkinsons disease) and stroke are increasingly consuming larger amounts of Singapores healthcare budget and the social burden weighs on the community. NUS has therefore made ageing and age-related diseases, especially neurodegenerative diseases, a major focus area. The Neurobiology/Ageing Programme consists of a broad-based group of investigators who conduct inter-disciplinary research in neurobiology. Members are drawn from a range of departments within and outside NUS.

Key Objectives To develop NUS as a world-class hub in Neurobiology and Ageing Research To act as a focus for the recruitment of talented academic staff members, researchers and postgraduates To pay special attention to neurological problems of relevance to Singapore and Asia

Research Areas Assessment of neurodegeneration (Combining cognitive, chemical, and imaging approaches) Origins of vascular dysfunction in Singapore Predictors of stroke and dementia Diet, environmental toxins, and neurodegenerative disease Cell adhesion, cell migration and axonal guidance Neuronal stem cells Neuronal lipidomics Proteasomal dysfunction, mitochondrial defects and oxidative damage in neurodegeneration Neuroprotective strategies Protein phosphorylation, protein folding and neurodegeneration Nematode and murine models for human ageing Cognitive neuroscienceImmunofluorescent micrograph of Nogo -A expression found on the cell body and processes of hippocampal neurons in culture. Neuronal Nogo-A may serve intrinsic guidance functions during regeneration.

Neurobiology/AgeingRecent Research Developments Formulation of a unifying hypothesis of neurodegeneration Discovery of foetal cells in the mothers brain Discovery of new risk factors for stroke and prediction of stroke outcome Elucidation of the role of H2S in neurodegeneration Discovery of a mechanism by which hypercholesterolaemia can cause neurodegeneration Cloning and expression of a novel nerve growth factor from the spitting cobra Establishment of an animal model for researching diabetic neuropathy Identification of novel agents that increase longevity in nematodes Discovery of novel physiological locations and functions of amyloid precursor protein (APP) (patent filed) RNomics and Genomics of stroke Neuroprotectants against focal ischemia (patents filed) Determination of the first NMR structure of Nogo-60 and design of a structured and buffer-soluble Nogo54 Structural characterization of all three Nogo proteins5 4 3 2 Selected Recent Publications 1 Voronov SV, Frere SG, Giovedi S, Pollina EA, Schmidt C, Wenk MR, Antonarakis SE, Arancio O, Davisson MT, Gardiner K, De Camilli P, and Di Paolo G (2008). Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down syndrome. Proc Natl Acad Sci U S A 105(27), 9415-9420 Ma, QH, T Futagawa, WL Yang, XD Jiang, L Zeng, D Takeda, RX Xu, D Bagnard, M Schachner, AJ Furley, D Karagogeos, K Watanabe, GS Dawe and Z Xiao, "A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis". NATURE CELL BIOLOGY, 10, no. 3 (2008): 283-294. (IF 2007 = 17.623) Hongjie Yuan, Katie M. Vance, Candice E. Junge, Matthew T. Geballe, James P. Snyder, John R. Hepler, Manuel Yepes, Chian-Ming Low, and Stephen F. Traynelis. The serine protease plasmin cleaves the amino-terminal domain of the NR2A subunit to relieve zinc inhibition of the N-methyl-Daspartate receptors. J. Biol. Chem., Feb 2009; doi:10.1074/ jbc.M805123200 Chee Wilder-Smith EP, Seet RS, Lim EC (2006). Diagnosing carpal tunnel syndromeclinical criteria and ancillary tests. Nature: Clinical Practice Neurology. 2:366-374 Chuah LYM and Chee MWL. Cholinergic Augmentation Modulates Visual Task Performance in Sleep-Deprived Young Adults. J Neurosci (2008); 28:11369 -11377 Halliwell B. Oxidative stress and neurodegeneration; where are we now? J Neurochem 97: 1634-58. (2006)Wang C, Lu R, Ouyang X, Ho MW, Chia W, Yu F, Lim KL. Drosophila overexpressing parkin R275W mutant exhibits dopaminergic neuron degeneration and mitochondrial abnormalities. J Neurosci 27: 8563-70. (2007) Liao P, Yu D, Li G, Yong TF, Soon JL, Chua YL, Soong TW. A Smooth Muscle Cav1.2 Calcium Channel Splice Variant Underlies Hyperpolarized Window Current and Enhanced State-dependent Inhibition by Nifedipine. J Biol Chem 282: 35133-42. (2007)

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Contact Details Professor Barry Halliwell Deputy President (Research & Technology) National University of Singapore University Hall, Lee Kong Chian Wing, UHL #05-02GTel : (65) 6516 3247

Fax : (65) 6775 2207 Email : bchbh@nus.edu.sg Website : http://www.lsi.nus.edu.sg/research.shtml

Tissue EngineeringThe NUS Tissue Engineering Programme (NUSTEP) is a multidisciplinary programme that aims to develop core competencies and to create innovations in cell and construct technologies for effective integration of living systems for clinical therapies. The goal is to establish a globally competitive programme in tissue engineering with significant research outcomes that will result in international recognition for high quality research with clinical and industrial applications.

Key Objectives To engage basic scientists and clinicians in the strategic development of translational research in Tissue Engineering To develop strong partnerships with research institutes, both locally and abroad to develop a world-class program in Tissue Engineering To create a conducive environment for education and training of research manpower To develop industrial outreach programs in the field of Tissue Engineering To raise the global profile of the Programme by participating in International Conferences To establish cGMP / cGTP shared core facilities in NUHS for translational research 3 Translational Research: design and development of relevant animal models and the application of various imaging, modeling and assessment modalities to monitor tissue regeneration and functionality. Over the few years NUSTEP has developed these strategic technologies particularly for musculoskeletal tissues regeneration, such as bone, cartilage, tendon, ligament and skin, as well as the development of suitable collagen matrices to support tissue regeneration. Currently, new initiatives in the field of cardiovascular tissue engineering and cancer research are being explored to exploit these strategic technologies and expertise.

Research StrategyTo develop strategic technologies crucial to tissue engineering and regenerative medicine, these areas are as follows: 1 Stem Cell Science: discoveries of new knowledge and greater understanding of embryonic and adult stem cells in regenerative medicine applications and the development of cell therapies for repair and regeneration Biomimetic Scaffold Technologies: design and development of novel biocompatible and biofunctional constructs for tissue engineering applications. Biofunctionalisation includes the use of regulatory biomolecules and control delivery systems.

Pharmacologially induced blood vessel growth in zebrafish embryos (arrows)

Research InfrastructureFacilities in NUSTEP include the following: BSL2 Cleanrooms Bio-Imaging Lab Tissue Modulation Lab Biomaterials and Scaffold Fabrication Lab Histology Lab Microscopy Lab General Labs for Principal Investigators and their teams

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Tissue EngineeringResearch Projects1 Generating a High Quality Immortal MesenchymalSelected Recent Publications 1 Fan H, Liu H, Wong EJ, Toh SL, Goh JC. In vivo study of anterior cruciate ligament regeneration using mesenchymal stem cells and silk scaffold. Biomaterials 29(23):3324-37. (Aug 2008) Fan HB, Liu HF, Toh SL, Goh J. Enhanced differentiation of mesenchymal stem cells co- cultured with ligament fibroblasts on gelatin/silk fibroin hybrid scaffold. Biomaterials 29(8):1017-1027. (Mar 2008) Liu H, Fan H, Wang Y, Toh SL, Goh J. The interaction between a combined knitted silk scaffold and microporous silk sponge with human mesenchymal stem cells for ligament tissue engineering. Biomaterials 29(6):662-674. (Feb 2008) Liu HF, Fan HB, Toh SL, Goh J. A comparison of rabbit mesenchymal stem cells and anterior cruciate ligament fibroblasts responses on combined silk scaffolds. Biomaterials 29(10):144353. (April 2008) Fan H, Liu H, Wang Y, Toh SL, Goh J. Development of a silk reinforced gelatin/silk fibroin hybrid scaffold for ligament tissue engineering. Cell Transplantation. 17(12): 1443-53 (2008) Yang Z, Sui L, Toh WS, Lee EH, Cao T. Stage-Dependent Effect of TGF-1 on Chondrogenic Differentiation of Human Embryonic Stem Cells. Stem Cells and Development 18(6). (2009) See EY, Toh SL, Goh JC. Technique to accurately quantify collagen content in hyperconfluent cell culture. Journal of Molecular Histology 39(6):643-7. (Dec 2008) Raghunath M, Sy Wong Y, Farooq M, Ge R. Pharmacologically induced angiogenesis in transgenic zebrafish. Biochemistry and Biophysics Research Communications 378(4):766-71. (Jan 2009) Harve KS, Vigneshwar R, Rajagopalan R, Raghunath M. Macromolecular crowding in vitro as means of emulating cellular interiors: When less might be more. Proceedings of the National Academy of Sciences of the United States of America. 105(51):E119. (Dec 2008) Chen, Z. C. C.; Ekaputra, A. K.; Gauthaman, K.; Adaikan, P. G.; Yu, H.; Hutmacher, D. W., In vitro and in vivo analysis of coelectrospun scaffolds made of medical grade poly(-caprolactone) and porcine collagen. Journal of Biomaterials Science- Polymer Edition 19 (5): 693-707. (2008)

S4em Cell Line for Chondrogenesis. 2 Modeling grosth plate function with bone marrow derived mesenchymal stem cells to develop improved treatments for growth plate defects in children. 3 Development and characterization of xeno-/serumfree ledium fgr tha enhancement of human bone marrow mesenchymal cells ex vivo expansion suitable for efficient clinical cellular therapy. 4 CNP-modified alginate for cell-based cartilage tissue engineering. 5 Development of a Functional Tissue-Engineered Bone-Ligament-Bone Grafp with ovel Fixation Device to Bone Tunnels for ACL Reconstruction. 6 GeneratingTranslational Study of Autologous Bone Marrow stem cell in TGF-beta 1 loaded fumarate based hydrogel for chondral defect repairing. 7 Tri-phasic sil+/stem cell based bone ligament bone construct in the repair of medial collateral ligament if rabbits. 8 Control release of recombinant (human bone morphogene4ic protein type 2 from heparin conjugated multilayered alginate microbeads to enhance new bone formation in spine fusion. 9 Imaging of transplanted bone marrow derived stem cells (BMSCs) by MRI in chondral defect, meniscus iNjury and diabetic neuropath. 10 Self-vascularizing implant sensors A pilot study 11 Platform technologies for stem cell culture for translational applications in human healthcare.

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Recent Achievement Prof Lee Eng Hin has won the National Outstanding Clinician Mentor Award in 2008.

Contact Details Associate Professor James Goh Cho Hong Department of Orthopaedic Surgery Yong Loo Lin School of Medicine National University of Singapore DSO (Kent Ridge) Building Level 4 27 Medical Drive, Singapore 117510 Tel : (65) 6516 5259 Fax : (65) 6776 5322 Email : dosgohj@nus.edu.sg Website : http://www.ols.nus.edu.sg/nustep/

Bone marrow derived mesenchymal stem cell

High magnification image showing chondrocytes and the

calcified cartilage

Cord Lining Mesenchymal Cells

Cell sheet-scaffold constructs