Final Annual Report - Yale School of Medicine VBT...ANNUAL REPORT 2005 – 2006 2 PROGRAM OPERATIONS VBT Steering Committee The Steering Committee serves as the principal advisory

YALE UNIVERSITY SCHOOL OF MEDICINE

Interdepartmental Program in Vascular Biology and Transplantation

Annual Report 2005 - 2006

VASCULAR BIOLOGY AND TRANSPLANTATION ANNUAL REPORT 2005 – 2006

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TABLE OF CONTENTS

Message from the Director ....................................................................................................1 Program Operations...............................................................................................................2

VBT Steering Committee ................................................................................................2 Administrative Operations..............................................................................................2 Program Faculty Membership ........................................................................................3

Program Activities..................................................................................................................4 Seminar Series.................................................................................................................4 Retreat ..............................................................................................................................4

Yale-Cambridge Program in Cardiovascular Disease.........................................................5 Research Accomplishments..................................................................................................5 Interactions With Industry ...................................................................................................40 Fund Raising and Development ..........................................................................................40 Plans for the Coming Year...................................................................................................40 Appendices

The Fifth Annual VBT/IPCT Retreat.............................................................................1-1 The Fourth Annual Meeting of the Joint Yale-Cambridge Program in ....................2-1

Cardiovascular Research On the Cover: Alterations in tight junctions in control (left) vs ICAM-1-transduced microvascular endothelial cells visualized with anti-ZO-1 antibody and DAPI counter staining. Deconvolution microscopy at 63X magnification. Photograph courtesy of Dr. Martin Kluger.


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Interdepartmental Program in Vascular Biology and Transplantation Annual Report 2005 – 2006 Message from the Director: The 2005-2006 academic year was an active one for the VBT Program. Firstly, the program was significantly expanded in size as three new faculty were recruited to Yale: Laura Niklason in Anesthesiology and Biomedical Engineering, Dan Wu in Pharmacology, and Bing Su in Immunobiology. Several additional faculty currently at Yale also joined VBT: Diane Krause in Laboratory Medicine and Pathology, Tarek Fahmy in Biomedical Engineering, and Edward Snyder in Laboratory Medicine. In addition, Laura Niklason and Jack Elias (Internal Medicine) joined the VBT steering committee, replacing departing members Fadi Lakkis and Steven Segal. Secondly, the Program was prominently featured in several medical school activities: Dr. Pober presented the history and operations of VBT at the first Chairs’ Retreat in October, 2005; the VBT annual retreat was held in November, 2005, with Robert Langer (MIT) as our keynote speaker; Dr. Saltzman organized a Dean’s Workshop on tissue engineering featuring many VBT faculty in April, 2006; and Dr. Pober organized a Medical Alumni weekend program based on VBT research in May, 2006. Thirdly, the VBT program organized several multi-investigator applications for research funding: Dr. Pober’s program project on graft arteriosclerosis was submitted for renewal in October, 2005, and was successful; Dr. Niklason organized and submitted a preliminary application for a Roadmap grant for Interdisciplinary Research, combining vascular biology, tissue engineering and vascular surgery/medicine in April, 2006; and Dr. Sessa resubmitted his PPG on peripheral vascular disease in June, 2006. VBT investigators also have begun investigations and clinical trials work, led by Marc Lorber, George Tellides and Frank Giordano. Fourthly, this year marked the inauguration of the Yale-Boehringer Ingelheim Pharmaceuticals Inc Research Alliance in Cardiovascular Diseases and Immunology, organized by VBT. Fifthly, VBT continued its role in organizing the Joint Yale-Cambridge Program in Cardiovascular Research, hosting 14 faculty from Cambridge at Yale in August, 2005. Finally, VBT organized the planning for the new Amistad Research Building, scheduled for occupancy in April, 2007, bringing together VBT’s vascular biology and tissue engineering efforts into one site. In short, has been a very busy and productive year.


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PROGRAM OPERATIONS VBT Steering Committee The Steering Committee serves as the principal advisory and leadership group for the program for the program. As noted above, Drs Elias and Niklason have joined the group, replacing Drs Steven Segal and Fadi Lakkis who resigned from the Steering Committee as they have left Yale. The current membership of the Steering Committee is listed in Table 1. Administrative Operations Dr. Sessa assumed his new note as Deputy Director of VBT on July 1, 2005, and will replace Dr. Pober as Director on July 1, 2007. Mr. Joseph Smentek, the Program Administrator, left Yale in June, 2006, and has been replaced by Ms. Carol Muzzey. The Program continues to be served by the Basic Science Business Office, now headed by Mr. Jordan Shapiro, and accounting is provided by Ms. Meriam Worzella.

Table 1. VBT Steering Committee Jeffrey R. Bender, M.D., Professor of Internal Medicine (Cadiovascular Medicine) and Immunobiology Alfred L.M. Bothwell, Ph.D., Professor of Immunobiology Jack A. Elias, M.D., Zedwitz Professor of Medicine and Section Chief, Pulmonary and Critical Care Medicine Marc I. Lorber, M.D., Professor and Section Chief of Surgery (Organ Transplantation and Immunology) Joseph A. Madri, M.D., Ph.D., Professor of Pathology Laura Niklason, M.D., Ph.D., Associate Professor of Anesthesiology and Biomedical Engineering Jordan S. Pober, M.D., Ph.D., Professor of Pathology, Immunobiology and Dermatology Nancy H. Ruddle, Ph.D., John Rodman Paul Professor & Director of Graduate Studies, Epidemiology/Public Health, Professor of Immunobiology W. Mark Saltzman, Ph.D., Professor of Chemical and Biomedical Engineering, Chair of Biomedical Engineering William C. Sessa, Ph.D., Professor and Vice Chair of Pharmacology


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Program Faculty Membership All faculties at Yale with a significant interest in vascular biology and/or transplantation are eligible to join VBT. New VBT members in academic year 2005-2006 are: Laura Niklason, M.D., Ph.D., Associate Professor of Anesthesiology & Biomedical Engineering Diane Krause, M.D., Ph.D., Associate Professor of Lab Medicine & Pathology Tarek Fahmy, Ph.D., Assistant Professor of Biomedical Engineering & Chemical Engineering Edward Snyder, M.D., Professor & Associate Chair of Clinical Affairs, Laboratory Medicine

Table 2. VBT Membership Jeffrey R. Bender, M.D., Professor of Internal Medicine (Cadiovascular Medicine) and Immunobiology Alfred L.M. Bothwell, Ph.D., Professor of Immunobiology Christopher Breuer, M.D., Assistant Professor of Surgery (Pediatrics) David Calderwood, Ph.D., Assistant Professor of Pharmacology Alan Dardik, Ph.D., M.D., Assistant Professor of Vascular Surgery Jack A. Elias, M.D., Zedwitz Professor of Medicine and Section Chief, Pulmonary and Critical Care Medicine Tarek Fahmy, Ph.D., Assistant Professor of Biomedical Engineering and Chemical Engineering Richard Flavell, Ph.D., FRS, Sterling Professor and Chairman of Immunobioligy, Investigator of Howard Hughes Medical Institute Frank J. Giordano, M.D., Associate Professor Internal Medicine (Cardiovascular Medicine) Daniel R. Goldstein, M.D., Assistant Professor Internal Medicine (Cardiovascular Medicine) Murat Gunel, M.D., Associate Professor of Neurosurgery Martin Kluger, Ph.D., Associate Research Scientist (Dermatology) Diane Krause, M.D., Ph.D., Associate Professor of Laboratory Medicine and Pathology Themis Kyriakides, Ph.D., Assistant Professor of Pathology Erin Lavik, Sc.D., Assistant Professor of Biomedical Engineering Patty J. Lee, M.D., Assistant Professor of Internal Medicine (Pulmonary) Marc I. Lorber, M.D., Professor of Surgery and Section Chief of Organ Transplantation and Immunology Joseph A. Madri, M.D., Ph.D., Professor of Pathology Laura R. Ment, M.D., Professor of Pediatrics (Neurology) Wang Min, Ph.D., Associate Professor of Pathology Laura Niklason, M.D., Ph.D., Associate Professor of Anesthesiology and Biomedical Engineering Jordan S. Pober, M.D., Ph.D., Professor of Pathology, Immunobiology and Dermatology David M. Rothstein, M.D., Associate Professor of Internal Medicine (Nephrology) Nancy H. Ruddle, Ph.D., John Rodman Paul Professor & Director of Graduate Studies, Epidemiology/Public Health, Professor of Immunobiology Kerry S. Russell, M.D., Ph.D., Assistant Professor of Medicine (Cardiovascular Medicine) Mehran M. Sadeghi, M.D., Associate Research Scientist of Internal Medicine (Cardiovascular Medicine) W. Mark Saltzman, Ph.D., Professor of Chemical and Biomedical Engineering, Chair of Biomedical Engineering William C. Sessa, Ph.D., Professor and Vice Chair of Pharmacology Albert J. Sinusas, M.D., F.A.C.C., Associate Professor of Internal Medicine (Cardiovascular Medicine) and Diagnostic Radiology Jeffrey Sklar, M.D., Ph.D., Professor of Pathology and Laboratory Medicine Edward Snyder, M.D., Professor and Associate Chair of Clinical Affairs Laboratory Medicine George Tellides, M.D., Ph.D., Associate Professor of Surgery (Cardiothoracic) Agnes Vignery, Ph.D., Associate Professor of Orthopedics


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PROGRAM ACTIVITIES Seminar Series The VBT Monday afternoon seminars continue to serve as an intellectual focus of the vascular biology community at Yale. The series also serves as a venue for assistance in the recruitment of faculty with research in vascular biology to various departments at Yale. The seminars are run by Dr. Themis Kyriakides and have maintained CME accreditation. A list of seminar speakers and their titles is shown in Table 3. Retreat The annual retreat continues to be an extremely popular activity, bringing together over one hundred scientists from the laboratories of VBT faculty members. This past year, the retreat was held on Nov 4, 2005, at the Anlyan Center. The keynote speaker was Dr. Robert Langer, University Professor, Massachusetts Institute of Technology, who spoke about his work in tissue engineering and the role of the vasculature. In addition to three sessions of platform presentations by VBT scientists, the retreat continued the poster session competition with prizes for the best posters by a graduate student and by a post-doctoral fellow. The retreat was sponsored by an unrestricted gift from Boehringer-Ingelheim Pharmaceuticals Inc. The retreat Program is listed in Appendix 1.

Table 3. VBT/IPCT 2005-2006 Seminar Series September Gang Li, Ph.D., Reader in Musculoskeletal Medicine, “Circulating Skeletal Stem Cells” October Richard Bucala, M.D., Ph.D., Professor of Internal Medicine of Rheumatology and Pathology, “Circulating Fibrocytes: Role in the Host Response and Flammatory Fibroses” Martin Kluger, Ph.D., Associate Research Scientist Dermatology, “ICAM-1 in Vascular leak and IP-10 in T Cell Recruitment: Molecular Keys to the Endothelial Gate” Louis Alexander, Ph.D., Assistant Professor of Epidemiology and Public Health, “Vascular Endothelium Mediated Enhancement of HIV Replication in T Cells” George Tellides, M.D., Ph.D., Associate Professor of Surgery, “Bystander Activation of Coronary Artery-Infiltrating T Cells” November Richard Hopkins, M.D., Chief of Division of Cardiothoracic Surgery, “From Homografts to Tissue Engineered Heart Valves” David Calderwood, Ph.D., Assistant Professor of Pharmacology, “Integrin-cytoskeleton links in integrin activation and cell migration” December Anton Bennett, Ph.D., Associate Professor of Pharmacology, “Unraveling Mechanisms of Protein Tyrosine Phosphatase Signaling in Health and Disease” David Cheresh, Ph.D., Professor of Pathology, “Regulation of Tumor Angiogenesis and Metastasis by Growth Factor and Extracellular Matrix Signals” January Wang Min, Ph.D., Associate Professor of Pathology, “Regulation of apoptosis signal-regulating kinase ASK1 in vascular and immune systems” February Jeffrey Kahn, M.D., Ph.D., Assistant Professor of Pediatrics Infectious Disease, “Association of Kawasaki’s Disease and a Novel Coronavirus” Michael Yu, Ph.D., Assistant Professor of Materials Science and Engineering, “Exploration of Collagen Mimetic Peptide’s Affinity to Natural Collagen for Sustained Drug Delivery and Scaffold Functionalization” March Di Chen, M.D., Ph.D., Assistant Professor of Orthopaedics, “Ubiquitin-Proteasome Regulation of Bone Specific Transcription Factor Runx2” John Keaney, M.D., Professor of Medicine and Pharmacology, “Redox-Sensitive Control of Vascular Phenotype” April Lawrence Young, M.D., Professor of Medicine, Section of Cardiovascular Medicine, “AMP-activated Protein Kinase Signaling Cardioprotection in the Ischemic Heart” May Mark Taubman, M.D., Professor of Medicine Cardiology Unit, “The role of circulating tissue factor in the regulation of thrombosis and cardiovascular disease” Zhaoxia Sun, Ph.D., Assistant Professor of Genetics, “Zebrafish as a Model System for Kidney Development and Disease” Geoffrey Gurtner, M.D., FACS, Associate Professor of Surgery, “Endothelial Progenitor Cell Trafficking and the Complications of Aging” June Othon Iliopoulos, M.D., Assistant Professor of Medicine, “Hypoxia signaling functional analysis of molecular targets” Omaida Velazquez, M.D., Assistant Professor Vascular Surgery, “Angiogenesis, Vasculogenesis, and Wound Healing” Peter Davies, Ph.D. Robinette Foundation Professor of Cardiovascular Medicine, “Hemodynamics and cardiovascular disease: Multiscale studies of endothelial phenotype in vivo and in vitro”


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Yale-Cambridge Program in Cardiovascular Disease The research alliance with Cambridge has continued as an important activity, with 14 faculty from Cambridge visiting Yale in August, 2005 for a two day scientific meeting sponsored by a grant from British Heart Foundation. Several new and ongoing research collaborations to basic and clinical science have developed from this association. The program for this retreat is listed in Appendix 2. A visit by Yale VBT members to Cambridge is scheduled for September, 2006. Yale-Boehringer-Ingelheim Pharmaceuticals Inc Research Alliance This program, launched in September, 2005, fosters the development of collaborative research in cardiovascular and immunological diseases. The Yale aspects of the program are managed by the VBT staff. Drs Pober, Sessa, and Richard Flavell serve on the Joint Steering Committee overseeing the program. VBT faculty with sponsored research collaborators in the first year of the alliance include Drs. Frank Giordano, Jordan Pober and Agnes Vignery. Tissue Engineering Group This biweekly forum, sponsored by VBT and organized by Dr. Themis Kyriakides, brings together investigators from Yale Medical School and Yale’s central campus to exchange updates on research in progress and to foster new research collaborations. Meetings started in the fall of 2005 and served as a launching pad for the VBT sponsored NIH Roadmap application, led by Dr. Niklason, for interdisciplinary research in tissue engineering, vascular biology, and vascular surgery/medicine. RESEARCH ACCOMPLISHMENTS A central part of VBT’s missions is to foster new basic, clinical and translational research in vascular biology with special (but at exclusive) emphasis on organ replacement therapies. A joint clinical study with Cambridge investigators, led by Dr. John Bradley was begun, enrolling patients at Addenbrookes Hospital to investigate the pathogenesis of excessive cardiovascular mortality in renal transplant recipients. A parallel study at Yale, headed by Dr. Marc Lorber, funded by Wyeth, is waiting IRB approval before enrollment may begin. Dr. George Tellides has become P.I. of a clinical trial to improve revascularization of ischemic hearts by use of a organized tissue graft. Dr. Frank Giordano has planned several interventional studies using the cardiac catheterization lab at Yale. Several multi-investigators grant applications for VBT investigators were organized and submitted in the past academic year, including the successful renewal and expansion of Dr. Pober’s program project on graft arteriosclerosis, a new program project headed by Dr. Sessa on peripheral vascular disease, and a Roadmap interdisciplinary research grant headed by Dr. Niklason. The accomplishments of individual VBT faculty are reported on the following pages.


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Jeffrey R. Bender, M.D. Professor, Internal Medicine (Cardiovascular Medicine) and Immunobiology Leukocyte-endothelial cell (EC) interactions are thought to play a role in a variety of pathological processes including inflammation, allograft rejection, and atherosclerosis. As the contiguous barrier to circulating immunocompetent cells in vascularized allografts, donor endothelium is a major stimulator and target of alloimmune responses by recipient lymphocytes, resulting in graft rejection, one form of which is transplant coronary arteriosclerosis. Furthermore, non-transplant atherosclerosis is now recognized as a multifactorial complex process that bears many similarities to chronic inflammatory conditions as demonstrated by the focal accumulation of leukocytes. The gender/hormonal influences on the development of atherosclerosis may be manifested in alterations in these inflammatory components. Metabolic perturbations that accompany insulin resistance and the metabolic syndrome in humans may also direct inflammatory changes that effect endothelial dysfunction. The efforts of my laboratory are directed at defining cellular and molecular mechanisms that govern leukocyte-EC interactions and endothelial dysfunction, and to test these molecular discoveries in animal vascular pathology models. More specifically, there are three major areas of investigation: (1) molecular mechanisms of cell-cell adhesion; (2) leukocyte- and lipid- mediated vascular activation and injury; and (3) influence of ovarian steroid hormones on endothelial activation. Within the last year, we have defined and accomplished the following: (1) the Rho family GTPases Rac1 and 2 mediate leukocyte integrin-triggered stabilization of transcripts encoding proinflammatory cytokines in mononuclear leukocytes, and angiogenic factors in macrophages; (2) MAP kinase-mediated modulation of the critical mRNA-binding and stabilizing protein HuR is required for these integrin-mediated effects; (3) T cell- and macrophage-specific HuR gene-deleted animals have been generated to utilize in transplant and tissue ischemia models; (4) an estrogen receptor (ER) α splice form, ER46, preferentially expressed in the endothelium, has been successfully purified from plasma membranes in recombinant form with prokaryotic expression systems; (5) molecular interaction domains for ER46 and the associated tyrosine kinase c-Src have been identified; (6) free fatty acids induce a form of "angiogenic factor resistance" in endothelial cells; and (7) in collaboration with Mehran Sadeghi, vascular activation and remodeling has been imaged in mouse models, targeting β3 integrins. Zhang, J., Krassilnikova, S., Gharaei, A.A., Fassaie, H.R., Esmailzadeh, L., Asadi, A.,

Edwards, D.S., Harris, T.D., Azure, M., Tellides, G., Sinusas, A., Zaret, B., Bender, J.R., Sadeghi, M.: αvβ3 targeted detection of arteriopathy in transplanted human coronary arteries: an autoradiographic study. FASEB J. 19:1857-1859, 2005.

Fabbri, M., Di Meglio, S., Gagliani, M.C., Consonni, E., Molteni, R., Bender, J.R., Tacchetti, C., Pardi, R.: Dynamic partitioning into lipid rafts controls the endo-exocytic cycle of the alphaL/beta2 integrin, LFA-1, during leukocyte chemotaxis. Mol Biol Cell. 116:5793-5803, 2005.

Kim, K-H., Bender, J.R.: Rapid, Estrogen Receptor-mediated Signaling in Vascular Cells: Why is the Endothelium So Special? Science (STKE). pe28, 1-4, 2005.

Mehra, V., Ramgolam, V., Bender, J.R.: Inflammatory Mechanisms in Vascular Disease. Drug Discovery Today: Molecular Mechanisms, 2:77-84, 2005.

Mehra, V., Ramgolam, V. Bender, J.R.: Cytokines and Cardiovascular Disease. J. Leukocyte Biol., 78:805-818:2005.

Wang, J., Collinge, M., Ramgolam, V. Ayalon, A., Xinhao, C.F., Pardi, R., Bender, J.R.: LFA-1-Dependent HuR Nuclear Export and Cytokine mRNA Stabilization in T Cell Activation.. J. Immunol. 176(4):2105-2113, 2006.

Savio, M., Rotondo, G., Rossetti, G., Bender, J.R., Pardi, R. A novel alternatively spliced constitutive photomorphogenic-1 (COP-1) product stabilizes UV stress-induced c-Jun by inhibiting COP1. Oncogene, in press.


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Alfred L.M. Bothwell, Ph.D. Professor, Section of Immunobiology The research goals of the lab are to characterize the development and function of regulatory T cells and characterize mechanisms that affect T cell recognition and recruitment into vascular sites. In addition, our experience with synthetic microvessels has lead to a translational project to revascularize islets to treat type I diabetes. Specific accomplishments in the last year: PPARs: Peroxysome proliferated activated receptors (PPARs) represent a group of transcription factors that are critical in regulating glucose and lipid metabolism. Ligands of PPARγ inhibit metabolically induced arteriosclerosis and also prevent the development of inflammatory disorders in several experimental mouse models including EAE, asthma, rheumatic arthritis and sepsis. The role of PPARγ in graft arteriosclerosis (GA) has not been characterized. We therefore tested the in vivo effects of administration of the endogenously occurring ligand, 15 deoxy-prostaglandin-J2 (15-d-PGJ2), on vascular remodeling of human artery induced by alloreactive PBMC and the IFN-γ model. The preliminary data indicate that 15-d-PGJ2 inhibits human GA in our in vivo human arterial graft model in immunodeficient mice. Since the interactions between endothelial cells (EC) and lymphocytes initiate vascular rejection, we investigated the role of PPAR γ in these primary human cells. Activation significantly alters PPARγ expression in a cell type-dependent manner. Molecular and pharmacological approaches are combined to dissect the mechanisms of PPARγ ligand effects on the interactions between human EC, VSMC and T cells both in vitro and in vivo. Microorgan Islet Grafts: The goal of this project is to bioengineer pancreatic beta cell-containing implants for treatment of diabetes. Conditions have been developed that support the survival and function of human islets in vivo in SCID mice. Casting the islets together with EC in collagen gels effectively revascularizes the islets. Indeed, our pilot data indicate that these human islet-EC microorgans secrete human insulin into the peripheral blood of mice for periods of at least 4 months and demonstrate responsiveness to glucose in glucose tolerance tests. We are characterizing the structure/function properties of these microorgans in detail, including the microvessel structure and the stability of the microvessels with time. Since the secretion of human insulin improves over time, we will test for proliferation of beta cells and also examine whether these microorgans can cure chemically-induced diabetes in mice. We will utilize synthetic molecular scaffolds to increase the size and function and microspheres will be optimized for the delivery of factors that will promote beta cell survival and function. Publications: Horowitz, M.C., Bothwell, A.L.M., Hesslein, D.G.T., Pflugh, D.L. and Schatz, D.G. 2005. B

cells and osteoblast and osteoclast development. Immunol. Rev. 208:141-153. Chae, W.-J., Henegariu, O., Lee, S.-K. and Bothwell, A.L.M. 2006. Mutant leucine zipper

domain impairs both dimerization and suppressive function of Foxp3 in T cells. Proc. Natl. Acad. Sci. USA 103:9631-9636.

Nakayama, Y., Stabach, P., Maher, S.E., Mahajan, M., Masiar, P.,Liao, C., Zhang, X., Ye, Z.-j., Tuck, D., Bothwell, A.L.M., Newburger, P.E. and Weissman, S.M. 2006. A limited number of genes are involved in the differentiation of germinal center B cells. J. Cell. Biochem. DOI: 10.1002/jcb.20952. (June 22, 2006).

Kawikova, I., Leckman, J.F., Kronig, H., Katsovich, L., Bessen, D., Ghebremichael, M. and Bothwell, A.L.M. (2006). Decreased number of regulatory T cells suggests impaired immune tolerance in children with Tourette Syndrome: A preliminary study. Biol. Psychiatry, in press.


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Christopher Breuer, M.D. Assistant Professor of Surgery The primary research interest of the Breuer lab is the development of an improved vascular graft using tissue engineering principles. We have created an autologous vascular conduit constructed from bone marrow derived vascular progenitor cells seeded onto a biodegradable tubular scaffold and evaluated the function and growth potential of this graft when used as a venous interposition graft in a juvenile lamb model. The primary clinical application for this research is the development of a vascular conduit for use in pediatric cardiothoracic surgical applications such as the Fontan procedure. Specific accomplishments in the last year: American Pediatric Surgery Association Foundation Research Scholar Lecture 2005 American Surgical Association Foundation Research Scholar 2005-2007 NIH-NHLBI K08 Research Grant 2006-2010 GCRC Clinical Research Feasibility Fund Recipient 2006 NIH-NHLBI P01 (PI: Pober) Breuer co-investigator Publications: Kakisis Y., Liapis C., Breuer C.K., Sumpio B. Artificial blood vessels: the holy grail of

peripheral vascular surgery. J Vasc Surg. 41, 349-54, 2005 Goyal A, Wang Y, Su H, Dobrucki LW, Brennan M, Fong P, Dardik A, Tellides G, Sinuses A,

Pober J, Saltzman WM, Breuer CK. Development of a model system for preliminary evaluation of tissue engineered vascular conduits. J Pediatr Surg. 41: 787-91, 2006

Roh JD, Brennan MP, Lopez-Soler RI, Fong PM, Goyal A, Dardik A, Breuer CK. Construction of an autologous tissue engineered venous conduit from bone marrow derived vascular progenitor cells: optimization of cell harvest and seeding techniques. J Pediatr Surg accepted for publication 2006

Fong PM, Goyal A, Brennan MP, Park J, Moss RL, Saltzman MW, Breuer CK. Development of PTH eluting microspheres for the treatment of hypoparathryoidism J Surg Res accepted for publication 2006.

Lopez-Soler RI, Brennan MP, Goyal A, Wang Y, Fong P, Sinusas A, Dardik A, Breuer CK. Development of a model system for evaluation of small caliber tissue engineered arterial grafts. Accepted for publication J Surg Res 2006.


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David A. Calderwood, Ph.D. Assistant Professor, Department of Pharmacology My lab investigates integrin adhesion receptors and their links to the actin cytoskeleton. Cell-cell and cell-substratum adhesion is mediated by the binding of integrin extracellular domains to diverse protein ligands, however, cellular control of these adhesive interactions and their translation into dynamic cellular responses, such as cell spreading or migration, requires the integrin cytoplasmic tails. These short tails bind to intracellular ligands that connect the receptors to signaling pathways and cytoskeletal networks. Thus, by binding both extracellular and intracellular ligands, integrins provide a link for the bidirectional transmission of mechanical force and biochemical signals across the plasma membrane. One important, rapid and reversible mechanism for regulating integrin function is by increasing integrin affinity for extracellular ligands, a process termed integrin activation. Tight regulation of integrin activation is essential because it controls cell adhesion, migration, and assembly of an extracellular matrix. Hence integrin activation is a critical step in angiogenesis, embryonic development, cardiac function, the immune response and tumor cell metastasis. The work in my lab is currently focused around 3 major observations; 1) Binding of the actin cross-linking protein filamin to integrin β subunit cytoplasmic tails regulates cell migration. We have now characterized this interaction at the structural level and revealed several mechanisms that are likely to control integrin-filamin interactions. The significance of these different regulatory processes and their roles in controlling cell adhesion and migration will now be assessed 2) Binding of the cytoskeletal protein talin to integrin β subunit cytoplasmic domains, via a PTB-domain-NPLY interaction, is a key step in integrin activation. We have recently shown that competition between filamin and talin for binding to integrins can modulate integrin activation. Furthermore, while we find that binding of talin is necessary and sufficient for activation of the platelet integrin αIIbβ3, an additional β1 tail binding protein co-operates with talin to activate β1 integrins. A major goal for the coming year will be to identify this additional activating factor. 3) PTB-domains are general integrin β tail binding motifs. The significance of the binding of other PTB-domain containing proteins and how they impact the binding of talin and filamin to integrins is currently being investigated. Publications: Kiema, T., Lad, Y., Jiang, P., Oxley, C. L., Baldassarre, M., Wegener, K. L., Campbell, I. D.,

Ylänne, J., and Calderwood, D. A. (2006) The molecular basis of filamin binding to integrins and competition with talin. Mol. Cell 21, 337–347.

Han, J., Lim, C. J., Watanabe, N., Soriani, A., Ratnikov, B., Calderwood, D. A., Puzon-McLaughlin, W., Lafuente, E. M., Boussiotis, V. A., Shattil, S. J., and Ginsberg, M. H. (2006) Reconstructing and Deconstructing Agonist-induced Activation of Integrin αIIbβ3 (Platelet GPIIb-IIIa). Current Biology (In Press)

Monniaux, D., Huet-Calderwood, C., Le Bellego, F., Fabre, S., Monge, P. and Calderwood, D. A. (2006) Integrins in Ovary. Semin. Reprod. Med. (In Press)

Bouaouina, M., Lad, Y., and Calderwood, D. A. Another β1 tail-binding factor cooperates with the PTB-like domain of talin to activate β1 integrins. Submitted


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Alan Dardik, M.D., Ph.D. Assistant Professor of Surgery (Vascular Surgery) The Dardik laboratory continues to study the healing and function of blood vessels and synthetic blood vessel substitutes, such as used in patients having vascular bypass surgery, and with particular attention given to the role of aging in host responses. Our model of vein graft arterialization in the aged rat continues to be developed; collaborations with the Sessa and Kyrakides labs are in place to further analyze the model for eNOS, caveolae, and MMP activity. In addition, collaboration with the Breuer and Tellides labs will study the role of rapamycin in inhibiting the accelerated neointimal thickening seen in this model. We have begun to examine the effects of aging in a similar model, carotid angioplasty. The responses of smooth muscle cells to laminar shear stress continues to be examined and provides an in vitro model that may be applicable to tissue engineered vascular grafts. The effects of aging on carotid aneurysm formation, as well as hind limb angiogenesis in response to ischemia, continue to be examined. Dr. Dardik was the recipient of a Pilot and Feasibility Project Grant (U24 DK59635) from the Yale-NIH Mouse Metabolic Phenotyping Center, entitled “Development of a novel model of vascular complications in the diabetic mouse.” Dr. Dardik was also awarded an NIH Mentored Clinical Scientist Development Award (1 K08 HL079927), entitled “Flow responses to carotid angioplasty.” He also received the concurrent William J. von Liebig Award from the Lifeline Foundation / American Vascular Association, in concert with the NIH K08 award. Dr. Tamara Fitzgerald, working in Dr. Dardik’s lab, was awarded an NIH Research Fellowship Award (NRSA 1 F32 HL086086-01), entitled “Characterization of Carotid Artery Flow and the Implications of Complicated Flow in Restenosis After Therapeutic Intervention.” Publications: Asada H, Paszkowiak J, Teso D, Alvi K, Thorisson A, Frattini J, Kudo FA, Sumpio BE, Dardik

A. Sustained orbital shear stress stimulates smooth muscle cell proliferation via the ERK1/2 pathway. Journal of Vascular Surgery 42(4):772-780 (2005).

Kudo FA, Warycha B, Juran PJ, Asada H, Teso D, Aziz F, Frattini J, Sumpio BE, Nishibe T, Cha C, Dardik A. Differential responsiveness of early and late passage endothelial cells to shear stress. American Journal of Surgery 190(5):763-769 (2005).

Goyal A, Wang Y, Su H, Dobrucki LW, Brennan M, Fong P, Dardik A, Tellides G, Sinusas A, Pober JS, Saltzman WM, Breuer CK. Development of a model system for preliminary evaluation of tissue-engineered vascular conduits. Journal of Pediatric Surgery 41(4):787-91 (2006).

Lopez-Soler RI, Brennan MP, Goyal A, Wang Y, Fong P, Tellides G, Sinusas A, Dardik A, Breuer C. A mouse model for evaluation of small diameter vascular grafts. Journal of Surgical Research, in press.

Muto A, Kondo Y, Yamamoto Y, Yamada H, Washimi O, Miyauchi Y, Kudo F, Dardik A, Nishibe T. Presence of prostacyclin receptor in arteriosclerotic human femoral artery. International Angiology 25(2):175-178 (2006).

Abstracts: Westvik TS, Maloney SP, Kudo FA, Muto A, Oyama JO, Dardik A. Aged mice have impaired

angiogenesis but not mitochondrial dysfunction after severe limb ischemia. To be presented at the Surgical Forum, 92nd annual meeting of the American College of Surgeons, Chicago, IL (2006).

Maloney SP, Yakimov AO, Muto A, Tang PC, Kudo FA, Westvik TS, Oyama JO, Sessa WC, Tellides G, Dardik, Dardik A. Murine carotid aneurysms develop without down regulation of Nogo-B expression: a novel model for human thoracic aneurysms. To be presented at the Surgical Forum, 92nd annual meeting of the American College of Surgeons, Chicago, IL (2006).


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Jack A. Elias, M.D. Waldemar von Zedtwitz Professor of Medicine, Chief, Pulmonary and Critical Care Medicine The Elias Laboratory is intensely interested in chronic inflammatory, injury and remodeling responses in the lung. To optimally address these issues, the laboratory has established the techniques that allow one to express transgenes in a lung-specific fashion. In addition, the laboratory established systems that allow transgenes to be eternally regulated giving the investigator the ability to selectively express a gene at a specific point in time during development and the ability to turn a gene on and off at will. Studies in the laboratory are presently focusing on the inflammation, vascular alterations and remodeling in asthma, COPD, the pathogenesis of pulmonary fibrosis and mechanisms of cytoprotection in acute lung injury. These studies are funded by multiple NIH RO1 grants, an NIH Program Project Grant (Dr. Elias is the Principal Investigator) and multiple industrial research awards. Recent scientific highlights include: a. The demonstration that murine breast regression protein (BRP-39) and its human homologue, HcGP-39, are induced at sites of Th2 inflammation such as seen in asthma. b. The demonstration that the circulating levels of HcGP-39 are important biomarkers of asthma severity. c. The generation of BRP-39 knockout mice and their use to demonstrate that BRP plays a critical role in the pathogenesis of Th2 inflammation and IL-13-induced remodeling in the lung. d. The cloning and characterization of mouse chitotriosidase. e. The demonstration that the CCR-5 chemokine receptor plays a critical role in the pathogenesis of gamma-interferon-induced emphysema and cigarette smoke-induced emphysema. f. The demonstrations that CCR-5 and leukotrienes play a critical roles in the pathogenesis of IL-13-induced tissue inflammation and remodeling. g. The demonstration with Robert Homer MD Ph D (Pathology) that AMCase is the long sought after marker for small airway epithelium. h.The demonstration that nitric oxide plays a critical role in the pathogenesis of VEGF-induced asthma-like responses in the murine lung. i. The definition of a novel pathway of pulmonary fibrosis in the murine lung that involves Semaphorin 7A. j. The demonstration that chitin is toll-like receptor 2 ligand. k. The demonstration that angiopoietin-2 is a critical mediator of acute lung injury. Many of these findings have led to patentable intellectual property and collaborations between Yale and Pharmaceutical companies developing new pulmonary therapeutics. Publications Zheng, T., Rabach, M., Chen, N.Y., Rabach, L., Hu, X., Elias, J.A., Zhu, Z. Molecular

cloning and functional characterization of mouse chitotriosidase. Gene 357:37-46, 2005. Elias, J.A., Homer, R.J., Hamid, Q., Lee, C.G. Chitinases and chitinase-like proteins in Th2

inflammation and asthma. J. Allergy Clin. Immunol. 116:497-500, 2005. Ma, B., Kang, M-J., Lee, C.G., Chapoval, S., Liu, W., Chen, Q., Coyle, A., Lora, J.M.,

Picarella, D., Homer, R.J., Elias, J.A. Role of CCR5 in IFN-gamma-induced and cigarette smoke-induced emphysema. J. Clin. Invest. 115:3460-3472, 2005.

Homer, R.J., Elias, J.A. Airway remodeling in asthma: Therapeutic implications of mechanisms. Physiology (Bethesda) 20:28-35, 2005.

Peebles Jr., R.S., Hashimoto, K., Sheller, J.R., Moore, M.L., Morrow, J.D., Ji, S., Elias, J.A., Goleniewska, K., O’Neal, J., Mitchell, D.B., Graham, B.S., Zhou, W. Allergen-induced airway hyperresponsiveness mediated by cyclooxygenase inhibition is not dependent on 5-Lipoxygenase or IL-5, but is IL-13 dependent. J. Immunol. 175:8253-8259, 2005.


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Elias, J.A., Lee, C.G. Lipid let loose in pulmonary emphysema. Nat. Med. 11:471-472, 2005.

Lee, P.J., Zhang, X., Shan, P., Ma, B., Rincon, M., Mossman, B.T., Elias, J.A. ERK1/2 mitogen-activated protein kinase mediates IL-13-induced lung inflammation and remodeling in vivo. J. Clin. Invest. 116:163-173, 2006.

Chunn, J.L., Mohsenin, A., Young, H.W.J., Lee, C.G., Elias, J.A., Kellems, R.E., Blackburn, M.R. Partially adenosine deaminase-deficient mice develop pulmonary fibrosis in association with adenosine elevations. Am. J. Physiol. Lung Cell. Molec. Physiol. 290:L579-587, 2006.

Cho, S-J., Kang, M.J., Homer, R.J., Kang, H.R., Zhang, X., Lee, P.J., Elias, J.A., Lee, C.G. Role of early growth response (Egr-1) in IL-13-induced inflammation and remodeling. J. Biol. Chem. 281:8161-8168, 2006.

Park, H-W., Lee, J-E., Shin, E-S., Lee, J-Y., Bahn, J-W., Oh, H-B., Oh, S-Y., Cho, S-H., Moom, H-B., Min, K-U., Elias, J.A., Kim, Y-Y. Kim, Y-K. Association between genetic variations of vascular endothelial growth factor receptor 2 and atopy in the Korean population. J. Allergy Clin. Immunol. 117:774-779, 2006.

Ma, B., Blackburn, M.R., Lee, C.G., Homer, R.J., Liu, W., Flavell, R.A., Boyden, L., Lifton, R.P., Elias, J.A. Adenosine metabolism in murine strain-specific IL-4-induced inflammation, emphysema and fibrosis. J. Clin. Invest. 116:1274-1283, 2006.

Ma, B., Liu, W., Homer, R.J., Lee, P.J., Coyle, A.J., Lora, J.M., Lee, C.G., Elias, J.A. Role of CCR5 in the pathogenesis of IL-13-Induced Inflammation and Remodeling. J. Immunol. 176:4968-4978, 2006.

Bhandari, V., Elias J.A. Cytokines in tolerance to hyperoxia-induced injury in the developing and adult lung. Free Radical Biol. Med. 41:4-18, 2006.

Lee, C.G., Kang, H-R, Homer, R.J., Chupp, G. and Elias, J.A. Transgenic modeling of transforming growth factor-beta1: Role of apoptosis in fibrosis and alveolar remodeling. Proc. Amer. Thor. Soc. 3:418-423, 2006.

Homer, R.J. and Elias, J.A. Cytokines in Stockley, R.A., Rennard, S.I., Celli, B., Rabe, K. (Eds), COPD, Blackwell Publishing, Oxford 2006.

Lee, C.G. and Elias, J.A. Transgenic Models in Laurent and Shapiro (Eds.), Encyclopedia of Respiratory Medicine, London 2006.


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Tarek Fahmy, Ph.D. Assistant Professor of Biomedical Engineering, Dept. of Biomedical Engineering Our research program is focused on the construction and testing of novel biomaterials for drug and protein delivery and non-invasive imaging of immune system cells. We aim to use these materials in understanding how immune system cells such as T cells and antigen-presenting cells migrate in vivo and to affect their function by specific delivery of drug or peptides. Our program is currently active in three different areas: First, construction of artificial antigen-presenting systems that may by used for, a) detection of antigen-specific T cells, b) ex-vivo stimulation and expansion of those cells, c) delivery of drug to inhibit proliferation of those cells. A second area of research involves the design of modular nanodevices that target dendritic cells for creation of adaptable vaccine delivery vehicles. Finally, we are integrating these approaches in the design of targetable particulate systems that can be imaged by a variety of modalities such as ultrasound and magnetic resonance and that may be ultimately used for tracking the trafficking of T cells and dendritic cells in vivo. Specific accomplishments in the last year: In relation to the VBT program we have focused on engineering non-invasive imaging modalities such as ultrasound and magnetic resonance imaging in targeted biodegradable, microparticulates. Our approach uses biodegradable particulate contrast agents that are engineered with targeting ligands and made to be echogenic as well as paramagnetic, facilitating imaging of blood flow in target vessels by ultrasound and offering the potential for high resolution anatomical imaging of vessel architecture by magnetic resonance. This is critical to assessment of the success of approaches that induce vessel formation and blood perfusion in tissue after ischemic injury in vivo without the need for repetitive histology. Publications: T.Fahmy, R. Samstein, C. Harness and W.M. Saltzman, Sustained target presentation in

biodegradable polymers by surface modification with fatty acid conjugates. Biomaterials. , 26, October 2005,5727-5736

T.Fahmy, J.P.Schenck, W.M.Saltzman, A nanoscopic multivalent antigen-presenting carrier for sensitive detection and drug delivery to T cells. Submitted (Nanomedicine: Nanotechnology, Biology and Medicine).

E. Stern, S Jay, J.Bertram, B. Boese, I. Kretzschmar, D.Evans, C. Dietz,A.Flye, D. LaVan, T. Malinski, T. Fahmy & M. Reed., Electropolymerization on Lithographically Patterned Electrodes: A Novel Functionalization Technique for Protein and DNA Conjugation. Anal. Chem. In Press


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Richard A Flavell, Ph.D., FRS Sterling Professor and Chairman of Immunobiology, Investigator of Howard Hughes Medical Institute The idea that atherosclerosis is an inflammatory disease is no longer controversial. Instead, much of the current research is now focused at understanding how this inflammation is regulated. T cells are of particular interest, both due to their secretion of mediators that influence plaque development, and since their activity depends on the triggering of specific antigens that are found within the disease site. Our research is focused on regulatory mechanisms related to adaptive immunity in atherosclerosis. Kabir AMN, Cao X, Gorog DA, Tanno M, Bassi R, Bellahcene M, Quinlan RA, Davis RJ,

Flavell RA, Shattock MJ, Marber MS Antimycin. A induced cardioprotection is dependent on pre-ischaemic p38-MAPK activation but independent of MKK3. J. Mol. Cell Cardiol. 39 709-717 (2005).

DeVries-Seimon T, Li Y, Yao PM, Stone E, Wang Y, Davis RJ, Flavell R, Tabas I. Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor J. Cell Biol. 171:61-73 (2005).

Lau CM, Broughton C, Tabor AS, Akira S, Flavell RA, Mamula MJ, Christensen SR, Shlomchik MJ, Viglianti GA, Rifkin IR, Marshak-Rothstein A. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp. Med. 202:1171-1177 (2005). 590.

Gao Y, Tao J, Li MO, Zhang D, Chi H, Henegariu O, Kaech S, Davis RJ, Flavell RA, Yin Z.. JNK1 is essential for CD8+ T cell-mediated tumor immune surveillance. J. Immunol. 175:5783-5789 (2005).

Liu L, Tran E, Zhao Y, Huang Y, Flavell RA, Lu B. GADD45β and GADD45γ are critical for regulating autoimmunity. J. Exp. Med. 202:1341-1348 (2005).

Spilianakis CG, Lee GR, Flavell RA. Commentary: Twisting the Th1/Th2 immune response by RXR: Lessons from a genetic approach. Eur. J. Immunol. 35:3400-3404 (2005).

Jones E, Flavell RA. Distal enhancer elements transcribe intergenic RNA in the IL-10 family gene cluster. J. Immunol. 175:7437-7446 (2005).

al-Ramadi BK, Fernandez-Cabezudo MJ, Ullah A, El-Hasasna H, Flavell RA. CD154 is essential for protective immunity in experimental Salmonella infection: Evidence for a dial role in innate and adaptive immune responses. J. Immunol. 176:496-506 (2006).

Millet I, Wong FS, Gurr W, Zawalich W, Green EA, Flavell RA, Sherwin RS. Targeted expression of the anti-apoptotic gene CrmA to NOD pancreatic islets protects from autoimmune diabetes. J. Autoimmunity 26:7-15 (2006).

Wohlfert EA, Gorelik L, Mittler R, Flavell RA, Clark RB. Cutting Edge: Deficiency in the E3 ubiquitin ligase Cbl-b results in a multi-functional defect in T cell TGF-β sensitivity in vitro and in vivo. J. Immunol. 176:1316-1320 (2006).

Town T, Jeng D, Alexopoulou L, Tan J, Flavell RA. Microglia recognize double-stranded RNA via Toll-like receptor 3. J. Immunol. 176:1937-1942 (2006).

Rudd BD, Smit JJ, Berlin AA, Alexopoulou L, Flavell RA, Lukacs NW. Deletion of TLR3 alters the pulmonary immune environment and mucus production during RSV infection. J. Immunol. 176 1937-1942 (2006).

Lakhani SA, Masud AA, Kuida K, Porter GA Jr, Booth CJ, Mehal WZ, Inayat I, Flavell RA. Caspases 3 and 7: Key mediators of mitochondrial events of apoptosis. Science 311:847-851 (2006).

Chi H, Barry SP, Roth R, Wu JJ, Jones EA, Bennett AM, Flavell RA. Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses. Proc. Natl. Acad. Sci. USA 103:2274-2279 (2006).

Buch T, Polic B, Clausen BE, Alferink J, Weiss S, Akilli O, Chang C-H, Flavell RA, Jonjic S, Waisman A, Förster I. MHC class II expression through a hitherto unknown pathway


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supports T helper cell dependent immune responses: Implications for MHC class II delivery. Blood 107:1434-1444 (2006).

Querec T, Bennouna S, Alkan S, Laouar Y, Gorden K, Flavell R, Akira S, Ahmed R, Pulendran B. Yellow fever vaccine YF-17D activates multiple dendritic cell subsets through TLR2, 7, 8 and 9 to stimulate polyvalent immunity. J. Exp. Med. 203:413-424 (2006).

Zamboni DS, Kobayashi K, Kohlsdorf T, Ogura Y, Long EM, Vance RE, Kuida K, Flavell RA, Dietrich WF, Roy CR. Birc1e (Naip5) regulation of caspase-1 function restricts Legionella growth in macrophages. Nat. Immunol. 7:318-325 (2006).

Sutterwala F, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, Grant E, Bertin J, Coyle AE, Galan J, Askenase P, Flavell RA. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 24:317-327 (2006).

Li MO, Flavell RA. TGF-β, T-cell tolerance and immunotherapy of autoimmune diseases and cancer. Expert. Rev. Clin. Immunol. 2:257-265 (2006).

Mitchell JE, Cvetanovic M, Tibrewal N, Patel V, Colamonici OR, Li MIO, Flavell RA, Levine JS, Birge RB, Ucker DS. The presumptive phosphatidylserine receptor is dispensable for innate anti-inflammatory recognition and clearance of apoptotic cells. J. Biol. Chem. 281:5718-5725 (2006).

Ventura J-J, Hübner A, Zhang C, Flavell RA, Shokat KM, Davis RJ. Chemical genetic analysis of the time course of signal transduction by JNK. Molec. Cell 21:701-710 (2006).

Lee GR, Kim ST, Spilianakis CG, Fields PE, Flavell RA. T helper cell differentiation. Regulation by cis elements and epigenetics. Immunity 24:369-379(2006).

Li MO, Wan YY, Sanjabi S, Robertson A-KL, Flavell RA. Transforming growth factor-β regulation of immune responses. Annu. Rev. Immunol. 24:99-146 (2006).

Kriegel MA, Li MO, Sanjabi S, Wan YY, Flavell RA. Transforming growth factor-β: Recent advances on its role in immune tolerance. Curr. Rheumatol. Rep. 8:138-144 (2006).

Pan Q, Kravchenko V, Katz A, Huang S, Ii M, Mathison JC, Kobayashi K, Flavell RA, Schreiber RD, Goeddel D, Ulevitch R. NF-κB inducing kinase (NIK) regulates selected gene expression in the Nod2 signaling pathway. Infect Immun. 74:2121-2127 2006.

Inoue T, Boyle DL, Corr M, Hammaker D, Davis RJ, Flavell RA, Firestein GS. MKK3 is a pivotal pathway regulating p38 activation in inflammatory arthritis. Proc. Natl. Acad. Sci. USA. 103:5484-5489 (2006).

Spilianakis CG, Flavell RA. Managing associations between different chromosomes. Science 312:207-208 (2006).

Wu W, Misra RS, Russell JQ, Flavell RA, Rincón M, and Budd RC. Proteolytic regulation of NFATc2 and NFAT activity by caspase-3. J. Biol. Chem.. 281:10682-10690 (2006).

Du W, Wong FS, Li MO, Peng J, Qi H, Flavell RA, Sherwin R, Wen L. TGF-β signaling is required for the function of insulin-reactive T regulatory cells. J. Clin. Immunol. 116:1360-1370 (2006).

Matalova E, Sharpe PT, Lakhani SA, Roth KA, Flavell RA, Setkova J, Misek I, Tucker AS. Molar tooth development in caspase-3 deficient mice. Int. J. Develop. Biol. 50:491-497 (2006).

Ma B, Blackburn MR, Lee CG, Homer RJ, Liu W, Flavell RA, Boyden L, Lifton RP, Elias JA. Adenosine metabolism and murine strain-specific IL-4-induced inflammation, emphysema and fibrosis. J. Clin. Invest. 116:1274-83 (2006).

Doran B, Gherbesi N, Hendricks G, Flavell RA, Davis R, Gangwani L. Deficiency of the zinc finger protein ZPR1 causes neurodegeneration. PNAS 103:7471-7475 (2006)

Gitlin L, Barchet W, Gilfillan S, Cella M, Beutler B, Flavell RA, Diamond MS, Colonna M. Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc. Natl. Acad. Sci. USA 103:8459-8464 (2006).


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Le Goffic R, Balloy V, Lagranderie M, Alexopoulou L, Flavell R, Chignard M, Si-Tahar M. The Toll-like receptor (TLR)-3 contributes to influenza A virus-induced acute pneumonia. PLoS Pathogens 2:526-535 (2006).

Lara-Tejero M, Sutterwala FS, Ogura Y, Grant E, Coyle AJ, Flavell RA, Galan JE. Brief Definitive Report: Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis. J. Exp. Med. 203:1407-1412 (2006).

Canaan A, Yu X, Booth CJ, Lian J, Lazar I, Gamfi SL, Castille K, Kohya N, Nakayama Y, Liu Y-C, Eynon E, Flavell R, Weissman SM. FAT10-diubiquitin-like protein-deficient mice exhibit minimal phenotypic differences. Molec. Cell. Biol. 26:5180-5189 (2006).

Wan Y, Chi H, Xie M, Schneider MD, Flavell RA. The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival and function. Nature Immunol. 7:851-858 (2006).

Wan YY, Flavell RA. The roles for cytokines in the generation and maintenance of regulatory T cells. Immunol. Rev. 212:114-130 (2006).

Sutterwala FS, Ogura Y, Zamboni DS, Roy CR, Flavell RA. NALP3 – not just for bacteria anymore. J. Endotoxin Res. 12:251-256 (2006).

Oertelt S, Lian Z-X, Cheng C-M, Chuang Y-H, Padgett KA, He X-S, Ridgway WM, Ansari AA, Coppel RL, Li MO, Flavell RA, Kronenberg M, Mackay IR, Gershwin ME. Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-β receptor II dominant-negative mice. J. Immunol. 177:1655-1660 (2006).

Bellahcene M, Jacquet S, Cao XB, Tanno M, Haworth RS, Layland J, Kabir AM, Gaestel M, Davis RJ, Flavell RA, Shah AM, Avkiran M, Marber MS. Activation of pc8 mitogen-activated protein kinase contributes to the early cardiodepressant action of tumor necrosis factor. J. Am. Coll. Cardiol. 48:545-555 (2006).

Ogura Y, Sutterwala FS, Flavell RA. Mini Review: Inflammasome: First line of immune response to cell stress. Cell 126:659-662 (2006).


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Frank J. Giordano, M.D. Associate Professor of Medicine (Cardiovascular Medicine) The purpose of our program, and our contributions to VBT, are primarily directed to translational research. Our program combines basic science, pre-clinical, and clinical research in efforts to develop therapeutic strategies that have their genesis in Yale-based discovery. Our areas of research include: a) transcriptional gene regulation (this includes- a program in the development and clinical use of engineered zinc finger protein transcription factors, and studies of epigenetic mechanisms of cardiovascular disease); b) determinants and manipulation of angiogenesis and arteriogenesis; c) developing strategies to augment repair and adaptive remodeling of infarcted hearts (includes efforts to define determinants of stem cell homing); d) effects of oxygen and metabolite-responsive gene expression as determinants of cardiac adaptation and function; e) development of advanced delivery strategies for cardiovascular therapies; and f) development of molecular strategies to treat heart failure.

Specific accomplishments in the last year:

Over the past year we have shown that a) the endothelium is a major determinant of whole-organ glucose metabolism and that the hypoxia-inducible factor HIF-1α is a crucial determinant of this function, b) endothelium-specific deletion of the β-1 integrin gene abrogates normal developmental vascular patterning and that haploid β1 integrin deficiency leads to abnormal vascular remodeling, c) chronic HIF-1α-mediated gene expression in cardiac muscle leads to lipid accumulation, loss of function, and cardiac dedifferentiation, d) paracrine induction of adhesion complexes is a crucial factor in stem cell recruitment, and e) post-infarction exposure to leptin promotes retention of cardiac function. Our pre-clinical and translational efforts have lead to two clinical -translational studies slated to begin recruitment in 2006-2007, and funding for a large animal pre-clinical study that will form the basis for an anticipated IND submission (first quarter 2007) for a first ever post-MI gene therapy trial. We have also collaboratively developed an engineered transcriptional repressor that augments cardiac function and may be a viable treatment option for heart failure. We have initiated a cath lab-based proteomics protocol in which we will examine plasma and platelets for biomarkers of coronary disease, and have ongoing cath lab-based projects examining the cell and cholesterol crystal content of acute human coronary thrombi, and the incorporation of progenitor cells into these thrombi.

Publications: Huang Y, Lei L, Liu D, Hao Z, Jovin I, Hickey RP, Tang N, Russell III R, Johnson RS, and

Giordano FJ. Normal glucose uptake in the brain and heart requires an endothelial cell-specific HIF-1a-dependent function. 2006 PNAS (2006 In Press)

Giordano FJ. Oxygen, oxidative stress, hypoxia, and heart failure. J Clin. Invest. 2005 115:500-508

Yu J, Lei L, Liang Y, Hinh L, Hickey RP, Huang Y, Liu D, Yeh JL, Rebar E, Case C, Spratt K, Sessa WC, and Giordano FJ. An engineered Vegf-activating ZFP improves blood flow and limb salvage in advanced-age mice. Faseb J (2006 In Press)

Uemura M, Swenson ES, Gaca MD, Giordano FJ, Reiss M, Wells RG. Smad2 and Smad3 play different roles in rat hepatic stellate cell function and alpha-smooth muscle actin organization. Mol Biol Cell. 2005 Sep;16(9):4214-24.


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Daniel R. Goldstein, M.D. Assistant Professor of Medicine (Cardiovascular Medicine) My lab has two broad areas of investigation: 1) The role of innate immunity in solid organ transplantation 2) The impact of aging on innate and adaptive immunity The role of innate immunity in solid organ transplantation. Our work has demonstrated the innate immune receptors, Toll like receptors (TLRs), are critically involved in certain models of minor mismatch transplant rejection (1) and important for Th1 immune responses in fully allogeneic graft rejection (2). These manuscripts were one of the 1st descriptions of the role of TLRs in solid organ transplantation. Recently, we have investigated the role of TLRs in transplantation tolerance induction and found that TLR signaling is critical for transplantation tolerance induced by costimulatory blockade (Journal of Immunology in press). Additionally, we have shown that fragments of the extracellular matrix can activate dendritic cells and augment their alloimmune priming function on T cells (American Journal of Transplantation in press). Hence, we believe that work generated in our laboratory has been instrumental in determining the role of TLRs in acute allograft rejection and transplantation tolerance. We have also investigated the role of T cell activation in xenograft recognition. Our work demonstrated that the activation requirements of xenografts are vastly different to allografts. Specifically, we showed that T cell activation does not require the use of secondary lymphoid organs for cellular xenograft rejection (this rejection occurs in the absence of hyperacute and antibody mediate xenograft rejection) whereas allografts require the presence of draining lymph nodes (3). Impact of aging on innate and adaptive immune responses. We have investigated the impact of aging on innate and adaptive immune responses. We have specifically shown that aging intrinsically impairs the function of T cells but leaves the innate function of myeloid dendritic cells intact using both allogeneic and viral infection experimental systems (Aging Cell in press). It is our opinion that this is the 1st comprehensive description of the impact of aging on TLR immune responses in dendritic cells. This work may have very important implications for future investigation aimed at boosting immune function in older hosts. Publications: Goldstein DR, Tesar BM, Akira S, Lakkis FG. Critical role of the Toll-like receptor signal

adaptor protein MyD88 in acute allograft rejection. J. Clin. Invest. 2003;111(10):1571-1578.

Tesar BM, Zhang J, Li Q, Goldstein DR. TH1 Immune Responses to Fully MHC Mismatched Allografts are Diminished in the Absence of MyD88, a Toll Like Receptor Signal Adaptor Protein. Am J Transplant 2004: 2004;4(9):1429-1439.

Tesar, B.M., G. Chalasani, L. Smith-Diggs, F.K. Baddoura, F.G. Lakkis, and Daniel R. Goldstein. Direct antigen presentation by a xenograft induces immunity independently of secondary lymphoid organs. Journal of Immunology 2004. (173): 437-4386.


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Martin S. Kluger, Ph.D. Associate Research Scientist/Department of Dermatology Persistent expression of E-selectin on the endothelial cell (EC) surface contributes to chronic inflammatory and malignant disease. With Jordan Pober, I identified amino acid motifs in the cytoplasmic domain of E-selectin regulating persistent E-selectin surface expression. Current research aims to explain how the cytoplasmic domains of adhesion molecules such as E-selectin, ICAM-1 and VCAM regulate organization of the endothelial actin cytoskeleton and interendothelial junctions, structures important for vascular leak and leukocyte transendothelial migration. We have recently characterized a novel leak-inducing activity of ICAM-1 in microvascular EC and received new funding to examine vascular hyperpermeability in melanoma. In concert with adhesion mole-cules, chemokines expressed on the EC surface selectively recruit T cells from blood into normal and diseased tissues. In a second research area, we use an in vitro flow model of leukocyte recruitment that simulates physiological shear stress, and have demonstrated that individual adhesion molecules together with surface chemokines are sufficient for memory T cell recruitment and transendothelial migration even without global activation of EC by inflammatory cytokines. EC cultures derived from lymphatic and blood-carrying microvessels is a third research interest relating to my role as Director of the Yale Skin Disease Research Center Endothelial Cell Culture Core. Projects are in progress comparing blood and lymphatic vessel-derived EC phenotypes under cell culture conditions, as well as their distinct signaling pathways and barrier functions. Publications: Manes, T., Pober, J.S. and Kluger, M.S. 2006. IP-10 Stimulates Rapid Transendothelial

Migration of Human Effector but not Central Memory CD4+ T Cells: Requirements for Shear Stress and Adhesion Molecules. Transplantation. 82: S9-S14

Clark, P.R., Manes, T.D., Pober, J.S. and Kluger, M.S. Increased ICAM-1 expression causes endothelial cell leakiness, cytoskeletal reorganization and shape change. Accepted, J Invest Dermatol.

Ranjbaran H., Manes, T.D., Akhtar, S., Kluger, M.S., Pober, J.S., and Tellides, G. Heparin Displaces CXCR3 Ligands Sequestered in the Vasculature and Inhibits the Transendothelial Migration of T Helper Cells. Accepted, Circulation.

Invited Book Chapter - Kluger, M.S. 2004. Vascular Endothelial Cell Adhesion and Signaling during Leukocyte Recruitment. In Advances in Dermatology, (Ed., Sam Hwang) Vol. 20, pp. 163-201, N.Y., Elsevier.

Meeting Abstract - Clark, P.R., Pober, J.S. and Kluger, M.S. 2006. Characterization of an Off Target Effect of an ICAM-1 siRNA. Immunology 2006, Boston, MA.


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Diane Krause, M.D., Ph.D. Laboratory Medicine The major focus of work in my laboratory is the identification and regulation of bone marrow stem cells. Specifically, we work on 1) the molecular mechanisms that regulate early hematopoiesis and leukemogenesis, and 2) in vitro and in vivo methods for the purification bone marrow-derived stem cells, and functional characterization of their pluripotentiality.. Specific accomplishments in the last year: RBM15 at a common chromosomal rearrangement site in AMKL inhibits myeloid differentiation RBM15 is a fusion partner with MKL in the t(1;22) translocation of AML-M7. In order to understand the mechanism by which the fusion protein RBM15-MKL induces leukemia, we are first elucidating the normal function of RBM15. In the past year, we have demonstrated a role for RBM15 in myelopoiesis. RBM15 is expressed at highest levels in hematopoietic stem cells and at more moderate levels during myelopoiesis of murine cells lines and primary human cells. Inhibition of RBM15 leads to decreased proliferation and enhances myeloid differentiation. Consistent with SHARP, another member of the SPOC domain family that can affect Notch signaling, we show that RBM15 affects Notch induced Hes1 promoter activity RBM15 inhibits notch activity in nonhematopoietic cell lines, and stimulates notch in hematopoietic cell lines. We have shown that RBM15 coimmunoprecipitates with RBPJκ, a critical transcription factor in the Notch signaling pathway, via the N terminal domain of RBM15. Confirming that this interaction of the N terminal domain of RBM15 mediates the stimulation of Hes1 promoter activity in hematopoietic cells, the N terminal domain of RBM15 inhibits the ability of full length RBM15 to activate notch induced Hes1 promoter activity in hematopoietic cells. Dynamics of histone modifications during NB4 cell differentiation Epigenetic modifications and chromatin accessibility play major roles in control of gene expression, yet little is known about the dynamics of these modifications during cellular differentiation. We have examined changes in 3 histone modifications during retinoic acid (RA) induced differentiation of the human promyelocytes. Changes in Me2K4 and Me3K4 and AcK9 of histone H3 were assessed on the promoters of 4 genes, Myeloperoxidase, Defensin-α, C/EBP-β and RAR-β, chosen for their differential regulation during neutrophil differentiation. We found that in undifferentiated cells, unexpressed genes that are subsequently upregulated are primed for expression with an open chromatin structure marked by Me2K4 and AcK9. Upon differentiation, when the Defensin-α, C/EBP-β and RAR-β genes are expressed, Me2K4 and AcK9 levels increase. In contrast, Me3K4 is never present on the genes when they are silent, and is present on only 2 (Defensin-α and RAR-β, but not C/EBP-β) of the 3 genes that were upregulated with differentiation. Publications:

Guo J, Schedl A, Krause DS. Bone marrow transplantation can attenuate the progression of mesangial sclerosis. Stem Cells 24: 406-15, 2006.

Bruscia E, Price J, Cheng E, Weiner S, Caputo C, Ferreira E, Egan ME, Krause DS. Assessment of cystic fibrosis transmembrane conductance regulator (CFTR) activity in CFTR-null mice following bone marrow transplantation, PNAS 103: 2965-70, 2006.

Herzog EL, Van Arnam J, Hu B, Krause DS. Threshold of Lung Injury Required for the Appearance of Marrow Derived Lung Epithelia. Stem Cells 24: 1986-1992, 2006.


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Themis R. Kyriakides, Ph.D. Assistant Professor, Pathology The main area of my research is the elucidation of the molecular events that dictate the course of healing and especially inflammation and angiogenesis following the implantation of biomaterials and scaffolds for tissue engineering applications. Based on investigations in genetically-modified mice we have identified molecular modifiers of the foreign body response such as CCL-2 (also known as MCP-1), MMP-9 and TSP2. MCP-1 and MMP-9 are required for monocyte fusion and formation of foreign body giant cells. We have also expanded our biomaterial studies to include brain implants. Detailed investigation of monocytes undergoing fusion revealed a dramatic change in cell shape prior to fusion that was associated with the extensive formation of lamellipodia. Because the latter process depends on the activation of the small GTPase Rac1, we developed strategies to block its activation and we were successful in doing so both in vitro and in vivo. The anti-angiogenic activity of TSP-2 has been demonstrated in numerous publications. However, the mechanism of inhibition of angiogenesis has not been determined. We are utilizing an in vitro TSP-2-sensitive three-dimensional angiogenesis assay and we are currently investigating the effects of TSP-2 on endothelial cells. Our aim is to identify the signaling pathway that mediates the anti-angiogenic effect of TSP2. We have recently shown that TSP2 is critical for the recovery of blood flow in an experimental model of hindlimb ischemia predominantly through an increase in angiogenesis. We are currently examining the possible role of TSP2 in arteriogenesis and endothelial progenitor cell mobilization. Finally, we have generated TSP2-/eNOS double-null mice in order to determine the role of TSP2 in limiting ischemic recovery in eNOS-null mice. Since my arrival at Yale I have engaged in collaborative research with fellow VBT members Drs. Sessa, Breuer, Dardik, Giordano, and Vignery. With Dr. Sessa, we have generated the double-null mice and we are focusing on the function of TSP2 in ischemia. With Dr. Breuer we are collaborating on determining the immunogenicity of artificial vascular conduits. With Dr. Dardik we are focusing on the effects of aging in an interpositional vein graft model. With Dr. Giordano we are performing a detailed functional analysis of the hearts of TSP2-null mice. With Dr. Vignery we are examining the phenotype of MMP9-null mice. Specific accomplishments in the last year: We have submitted two invention disclosures, one relating to the use of the Rac1 inhibitor to prevent foreign body giant cell formation and one relating to the development of vascular grafts coated with extracellular matrix derived from TSP2-null cells. Publications: Bryers, J.D., Jarvis R.A., Lebo, J., Prudencio, A., Kyriakides, T.R., Uhrich K. Biodegradation

of poly(anhydride-esters) into non-steroidal anti-inflammatory drugs and their effect on Pseudomonas aeruginosa biofilms in vitro and on the foreign-body response in vivo. Biomaterials 27:5039-5048, 2006.

Saltzman MW, Kyriakides TR. Cell Interactions with Polymers. In Principles of Tissue Engineering, Third Edition," edited by Drs. Lanza, Langer, Vacanti. (in press)

Steven M. J, Skokos E., Laiwalla F., Kyriakides T.R. Differential susceptibility to Rac1 inhibition distinguishes biomaterial-induced foreign body giant cell formation and phagocytosis. (Submitted)


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Erin Lavik, Sc.D. Assistant Professor of Biomedical Engineering Our research focuses on creating environments that promote repair using three dimensional biodegradable polymer systems. These allow us to direct the temporal and spatial patterning of growth factors, to design specific surfaces to probe ECM interactions, and to use scaffold architecture to guide cells. We use stem cells, particularly neural stem cells (NSCs) as a model system to study the effects of different parameters on their proliferation, migration, and differentiation. Within the VBT program, we are investigating the relationship between NSCs and endothelial cells with Dr. Madri’s lab. To that end, we have developed a novel macroporous hydrogel system which permits the coculture of endothelial cells and NSCs in a three dimensional environment. Implantation of this system leads to an increase in the number of large vessels over implantation of the gel with endothelial cells alone at long time points. We published this work in PNAS in the last year. We are now continuing the work to determine if the vessels are stable for extremely long times (12 weeks) and to determine if we can use this microvessels as a neural stem cell niche. We are also translating the system to rat cells from mouse cells so that we can test this microvascular structures in models of injury. Publications: Warfvinge, K., Kiilgaard, J.F., Lavik, E.B., Scherfig, E., Langer, R., Klassen, H.J., and Young,

M.J. 2005. Retinal progenitor cell xenografts to the pig retina - Morphologic integration and cytochemical differentiation. Archives of Ophthalmology 123:1385-1393.

Ford, M.C., Bertram, J.P., Hynes, S.R., Michaud, M., Li, Q., Young, M., Segal, S.S., Madri, J.A., and Lavik, E.B. 2006. A macroporous hydrogel for the co-culture of neural progenitor and endothelial cells to form functional vascular networks in vivo. Proceedings of the National Academy of Sciences of the United States of America 103:2512-2517.

Ward, M.S., Koobehi, A., Lavik, E.B., Langer, R., and Young, M.J. accepted. Neuroprotection of retinal ganglion cells in DBA/2J mice with GDNF-loaded biodegradable microspheres. Journal of Pharmaceutical Sciences.


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Patty J. Lee, M.D. Associate Professor of Medicine/Pulmonary & Critical Care Our overall research interests are to define the mechanisms of tissue protection and cell survival during oxidant lung injury. Specifically, we have focused upon the role of the lung endothelial cell as central orchestrator of injury and repair responses during hyperoxia- or ischemia-reperfusion-induced oxidant injury. We have identified the induction of the stress protein heme oxygenase-1 (HO-1) and its reaction products, carbon monoxide and biliverdin, as important protective responses. HO-1 and its products mediate their protective effects via the mitogen-activated protein kinases (MAPKs) and STAT3 signal transduction pathways. Recently, we have extended our oxidant studies to demonstrate for the first time that TLRs plays an essential role in the survival of lung structural cells in vivo during lethal oxidant injury. These novel findings link innate immunity and oxidant stress in an important manner. Specific accomplishments in the last year: I was awarded a Career Investigator Award by the National American Lung Association to study the relationship between HO-1 and vascular endothelial growth factor in acute lung injury. Our lab has on-going collaborative studies with Dr. Wang Min to explore the role of thioredoxin in oxidant lung injury and TLR4-mediated mechanisms of endothelial protection. Our long-standing collaborations with Dr. Nicholas Morrell, University of Cambridge, has resulted in a manuscript “Bone morphogenetic protein-4 induced HO-1 via a SMAD independent, p38 MAPK dependent pathway in human pulmonary artery smooth muscle cells” (submitted). Publications: Zhang X., Shan P., Qureshi S., Homer, R., Medzithov R., Noble P.W., and Lee P.J. Cutting

edge: Toll-like receptor 4 deficiency confers susceptibility to lethal oxidant lung injury. J Immunol, 175: 4834-4838, 2005.

Scott J.R., Gray D.K., Bihari A., Badhwar A., Zhang X., Shan P.Y., Lee P.J., Chakrabarti S., Harris K.A., Potter R.F. Heme oxygenase modulates small intestine leukocyte adhesion following hindlimb ischemia/reperfusion by regulating the expression of ICAM-1. Crit Care Med, 33: 2563-2570, 2005.

Jiang D., Liang J., Fan J., Shuang Y., Suping C., Yi L.,Prestwich G.D., Mascarenhas M.M., Garg H.G., Quinn D.A., Homer R.J., Goldstein D.R., Bucala R., Lee P.J., Medzhitov R., and Noble, P.W. Regulation of lung injury and repair by toll-like receptors and hyaluronan. Nat Med, 11: 1173-1179, 2005.

Lee P.J., Zhang X., Shan P., Ma B., Lee CG, Homer RJ, Zhu Z, Rincon M, Mossman BT, and Elias, JA. ERK1/2 mitogen-activated protein kinase selectively mediates IL-13-induced lung inflammation and remodeling in vivo. J Clin Invest, 116: 163-173, 2006.

Qureshi, S.T., Zhang, X., Aberg E., Bousette N., Giaid A., Shan P., Medzhitov, R.M., and Lee P.J. Inducible activation of TLR4 confers resistance to hyperoxia-induced pulmonary apoptosis. J Immunol, 176: 4950-4958, 2006.

Zhang X., Shan P., Jiang G., Zhang S-M., Otterbein L.E., Fu X-Y., and Lee P.J. Endothelial STAT3 is essential for the protective effects of HO-1 in oxidant-induced lung injury. FASEB J, In Press, 2006.


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Marc I. Lorber, M.D. Professor of Surgery and Pathology; Section Chief, Surgery, Organ Transplantation and Immunology The Lorber laboratory has continued research in transplantation immunobiology. Our focus on remains allograft vascular injury, strategies with potential for generating long term allograft acceptance, as well as immunologic monitoring in human organ transplantation. The laboratory work builds on results using our human arterial transplant model in the SCID/bg mouse, and our close collaboration with Drs. Pober, Tellides, and Bothwell has continued. The model uses the SCID/bg mouse bearing human muscular artery, replacing the infrarenal abdominal aorta. Animals are reconstituted with allogeneic human peripheral mononuclear cells, and we alloimmune mediated injury to those human arterial segments. Other research is more transplant recipient focused, studing new immunosuppressants to prevent human allograft rejection, immunologic monitoring in clinical transplantation, as well as translational studies seeking to apply recent discoveries relevant to allograft vascular injury to the clinical transplant setting. This year, we concluded studies demonstrating amelioration of alloimmune arterial injury in the presence of the HMG coA reductase inhibitors atorvastatin and simvistatin in the SCID transplant model, and we are continuing our investigations using the PPARs. Our transplant monitoring work has focused on consequences of donor specific anti- HLA antibodies in the setting of positive anti- donor crossmatch using flow cytometry based techniques. We are also evaluating the Luminex platform for determining circulating proinflammatory cytokines as part of our translational work in allograft vascular injury. Finally, although the funding was delayed, we are now beginning investigations described in last year’s report evaluating associations between biopsy demonstrated chronic allograft nephropathy in clinical kidney transplant recipients, with vascular changes using intravascular ultrasound, flow mediated vasodilation, and inflammatory cytokines, as correlates of inflammation associated endothelial dysfunction. Publications: Lorber MI, Ponticelli C, Whelchel J, Mayer HW, Kovarik J, LI Y, Schmidli H. Therapeutic

drug monitoring for everolimus in kidney transplantation using 12-month exposure, efficacy, and safety data. Clinical Transplantation. 19: 145-151. 2005.

Lorber MI, Mulgaonkar S, Butt KHM, Elkhammas E, Mendez R, Rajagopalan PR, Kahan BD, Sollinger H, Li Y, Cretin N, Tedesco H and the B251 Study Group. Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: a 3-year randomized, multicenter, phase III study. Transplantation. 80: 244-252. 2005.

Formica RN, Friedman AL, Lorber MI, Smith JD, Eisen T, Bia MJ. A randomized trial comparing losartan to amlodipine as initial therapy for hypertension in the early post-transplant period. Nephol Dial Transplant. (in press)

Kovarik JM, Tedesco-Silva, H, Lorber, MI, Foster, C. Exposure Efficacy relationships of a fingolimod- everolimus regimen in kidney transplant patients at risk for delayed graft function. Transplant. Proc. (in Press).

Yi T, Cuchara L, Wang Y, Koh KP, Ranjbaran H, Tellides G, Pober JS and Lorber MI. Human allograft arteriopathy in a SCID mouse model is ameliorated by sirolimus and cyclosporine and correlates with Interferon-γ suppression. Transplantation. (in Press).


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Joseph A. Madri, M.D., Ph.D., Professor, Pathology Department Endothelial cells play central roles in development and maintenance of the vascular system and in the processes of inflammation and metastasis. Interactions with cell adhesion molecules, surrounding matrix, and soluble factors directs endothelial cell responses, yet little is known about these complex interactions and the mechanisms involved in signal transduction. We are investigating the roles of cell adhesion molecules, integrins, junctional associated molecules, and extracellular matrix components in modulating vascular development and behavior. Using whole conceptus and AV cushion cultures we are investigating the roles of selected adhesion molecules, growth factors and their receptors in the processes of vasculogenesis, angiogenesis and epithelial to mesenchymal transformation in the murine embryo. We are also investigating the interactions of neural progenitor cells and endothelial cells, comprising the neurovascular niche, during brain development and in response to chronic hypoxia. Lastly, we are investigating the roles of T-cell and endothelial cell proteinases and proteinase inhibitors in modulating T-cell transendothelial migration and their roles in initiating and maintaining the inflammatory response in murine models of autoimmune disease and in several tissue culture models. A multi-disciplinary approach is used which includes the use of knockout & transgenic animals, tissue and embryo culture model systems of cell adhesion, migration and angiogenesis and a variety of biophysical, biochemical, molecular and cell biological methods. Specifically, we have developed and employed 2 and 3-dimensional co-culture methods and in vivo implantation models in our studies of neural stem cell-endothelial cell interactions. We have also elucidated a role for PECAM-1 as a modulator of GSK-3β activity in the regulation of β−catenin degradation. Publications: Nath A.K., Madri J.A., The Roles of Nitric Oxide in Murine Cardiovascular Development,

Develop. Biol., 292(1):25-33, 2006. Ford, M.C., Bertram, J.P., Hynes, S.R., Michaud, M., Li, Q., Young, M., Segal, S.S., Madri,

J.A., Lavik, E.B., A novel macroporous hydrogel for the culture of neural progenitor and endothelial cells to form functional vascular networks in vivo, Proc. Natl. Acad. Sci. (USA), 103 (8):2512-2517, 2006.

Biswas, P., Canosa, S., Schoenfeld, D.S., Schoenfeld, J., Li, P., Cheas, L.C., Zhang, J., Cordova, A., Sumpio, B.E., and Madri, J.A., PECAM-1 Affects GSK-3β -mediated b-catenin Phosphorylation and Degradation. Amer. J. Pathol., 169 (1):314-324, 2006.


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Laura R. Ment, M.D. Professor, Departments of Pediatrics and Neurology; Associate Dean for Admissions Preterm birth results in significant disability, and the Neonatal Brain Research Group studies injury and recovery in the developing brain in preclinical, clinical and genetic studies. The “Adaptive Mechanisms of Developing Brain” program project work group (NS 35476) examines neuropathologic, behavioral and molecular mechanisms in a clinically-relevant model for preterm birth, murine chronic sublethal hypoxemia. Magnetic resonance imaging studies employing diffusion tensor imaging techniques are correlated with behavioral changes and cDNA microarray approaches are employed to understand the interaction of the environment and the genome. These preclinical studies are the result of our longstanding clinical trial, the “Multicenter Randomized Indomethacin IVH Prevention Trial,” (NS 27116), which has demonstrated that indomethacin not only prevents injury to the developing brain but that it is also associated with neurocognitive improvement – in male prematurely-born subjects only. Specific accomplishments in the last year Dr. Ment has been involved in both clinical and translational research at Yale for over twenty five years. She is a member of the NANDS Council of the National Institute of Neurological Disorders and Stroke and was recently named chair of the Clinical Trials Subcommittee for NINDS. Publications: Fagel DM, Ganit YM, Silbereis J, Ebbitt T, Stewart WB, Zhang H, Ment LR, Vaccarino FM.

Cortical neurogenesis enhanced by chronic perinatal hypoxia. Exp Neurol, 2006. Ment LR, Allan WA, Makuch RW, Vohr B. Grade 3 – 4 IVH and Bayley scores predict

outcome at age 12 years. PEDIATRICS, 2005;116:1597 - 8. Bhandari V, Zhang H, Ment LR, Gruen JR. Familial and genetic susceptibility to major

neonatal morbidities in preterm twins. PEDIATRICS 2006:117:1901 – 6. Ment LR, Peterson BS, et al. A functional MRI study of the long term influences of early

indomethacin exposure on language processing in prematurely born children. PEDIATRICS, 2006, in press.

Ment LR, Peterson BS, Vohr B, Allan W, Schneider KC, Lacadie C, Katz KH, Maller-Kesselman J, Pugh K, Duncan CC, Makuch RW, Constable RT. Cortical recruitment patterns in prematurely-born children compared to controls during a passive listening fMRI task. J Pediatr, in press, 2006.

Bizzarro M, Hussain N, Jonsson B, Feng R, Ment LR, Gruen JR, Zhang H, Bhandari V. The genetic susceptibility to retinopathy of prematurity. PEDIATRICS, 2006, in press.


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Wang Min, Ph.D. Associate Professor, Pathology The primary goal in my laboratory is to dissect signal pathways during inflammatory responses and develop therapeutic targets for treatment of vascular diseases. In the past year, we have shifted our focus from dissecting in vitro signaling in cultured endothelial cells (EC) to defining the in vivo function of several critical signaling molecules in mouse models. In vivo function of Bmx/Etk in ischemia-mediated arteriogenesis and angiogenesis. Peripheral arterial disease is a common disease found in 10-25% of patients over the age of 55 years and its occurrence and severity are strongly correlated with other cardiovascular risk factors that lead to coronary artery disease and stroke such as hyperlipidemia, smoking and endothelial dysfunction. In collaboration with Drs. William C. Sessa and Albert Sinusas in the VBT program, we use both mice with a genetic deletion of Bmx (Bmx-KO) and transgenic mice expressing a constitutively active form of Bmx under the endothelial Tie-2 enhancer/promoter (Bmx-SK-Tg) to study the role of Bmx in ischemia-mediated arteriogenesis/angiogenesis. Our study provides the first demonstration that Bmx in endothelium and bone marrow plays a critical role in arteriogenesis/angiogenesis in vivo. This work is in press in J. Clin. Invest. In vivo function of TNFR1 and TNFR2 in ischemia-mediated arteriogenesis and angiogenesis. We have also analyzed the phenotypic differences between TNFR1-KO and TNFR2-KO mice in an ischemic hindlimb model. Our data clearly demonstrate differential functions of TNFR1 and TNFR2 signaling in ischemia-mediated arteriogenesis/angiogenesis. A manuscript resulted from this work is now under revision for acceptance by Am. J. Pathol. for publication. SOCS1 in graft arteriosclerosis. This is a new project as a part of Dr. Jordan Pober’s Program Project (Chronic DTH and IFN-g in human graft arteriosclerosis) to determine the mechanism by which IFN-γ and TNF synergistically reduce NO bioavailability in EC. Our data suggest that SOCS1, a member of suppressor of cytokine signaling protein family, is a critical mediator of IFN-γ and TNF-induced EC dysfunction. Specifically, we show that SOCS1 genetically deficient mice or EC from such mice are hypersensitive to TNF leading to enhanced TNF-induced ASK1-JNK signaling. Publications: He Y, Luo Y, Tang S, Rajantie I, Salven P, Heil M, Zhang R, Luo D, Li X, Chi H, Yu J,

Carmeliet P, Schaper W, Sinusas AJ, Sessa WC, Alitalo K, Min W (2006) Critical function of Bmx/Etk in ischemia-mediated arteriogenesis and angiogenesis, J. Clin. Invest., 116:in press.

He, Y., Zhang, W., Zhang, R., Zhang, H., Min, W. (2006) SOCS1 inhibits TNF-induced ASK1-JNK inflammatory signaling by mediating ASK1 degradation. J. Biol. Chem. 281(9), 5559-66.


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Laura Elizabeth Niklason M.D., Ph.D. Associate Professor, Departments of Anesthesia and Biomedical Engineering Concise description of research program(s): Dr. Niklason’s research program encompasses topics in vascular biology and cardiovascular tissue engineering. Specifically, Dr. Niklason is a world-recognized expert in the engineering of implantable arteries that are grown from autologous cells. Using biomimetic pulsatile bioreactor systems, Niklason has shown the feasibility of culturing and implanting arteries in a range of species, including bovine, porcine and canine. In addition, Niklason has shown the importance of human donor and vascular cell age on the ability of cells to reconstitute vessels in vitro, and has dissected the role of cellular replicative lifespan in this process. Currently, Niklason’s group is exploring the utility of adult, marrow-derived human stem cells as building blocks for engineered vascular tissues. In addition to this research focus, Niklason has several other areas of active investigation. Projects in vascularized cardiac and lung tissue engineering are getting underway. In addition, understanding the fundamental remodeling and mechanical aspects of cerebral vasospasm that accompanies subarachnoid hemorrhage is an ongoing area of investigation. Lastly, Niklason is continuing to work on the topic of cellular lifespan extension and cellular aging. Specific accomplishments in the last year: (In relation to the VBT Program): Niklason arrived at Yale from Duke University in January of 2006, as Associate Professor. Prior to that, she held faculty positions at Duke for over 7 years. Since her arrival at Yale, Niklason has worked to establish new scientific interactions with Yale faculty, particularly in VBT. Currently, Niklason is establishing projects with Dr. Sessa concerning the potential role of NOGO in vascular regeneration, and with Dr. Pober on the differentiation of vascular phenotypes from circulating and marrow-derived stem cells. In addition, in April of 2006 Dr. Niklason submitted an X02 application in response to an NIH Roadmap Initiative. Entitled “Engineering the Vasculature: Next Generation Therapeutics”, this application includes some 24 faculty members and described Yale’s plan to from a Consortium for Vascular Engineering. This Consortium will encompass a range of research projects, core laboratories, and a pre-doctoral training program, all of which will work synergistically to improve our understanding of vascular disease and its treatment. Publications: Poh M., Boyer M., Solan A., Dahl S.L., Pedrotty D., Banik S.S., McKee J.A., Klinger R.Y.,

Counter C.M., Niklason L.E. 2005. Blood vessels engineered from human cells. Lancet 365: 2122-2124.

Dahl, S.L.M., Rucker, R.B., Niklason, L.E. 2005. Effects of Copper and Cross-Linking on the Extracellular Matrix of Tissue-Engineered Arteries. Cell Transplantation 14:861-868.

Dahl, S.L.M., Chen, Z., Solan, A.D., Brockbank, K.G.M., Niklason, L.E., Song, Y.C. 2006. Feasibility of vitrification as a storage methods for tissue engineered blood vessels. Tissue Engineering 12: 291-300; 2006.

Klinger, R.Y., Blum, J.L., Hearn, B., Lebow, B., Niklason, L.E. 2006. Relevance and Safety of Telomerase for Human Tissue Engineering, Proceedings of the National Academy of Sciences of the United States of America (Track II) 103: 2500-2505.

Gong, Z., Niklason, L.E. 2006. Blood vessels engineered from human cells. Trends in Cardiovascular Medicine 16: 153-156


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Jordan S. Pober, M.D., Ph.D. Professor of Pathology, Immunobiology and Dermatology and Director, Interdepartmental Program in Vascular Biology and Transplantation The Pober lab studies the role(s) of blood vessel cells, especially vascular endothelial cells, in protective and pathological immune responses. Specific areas of interest are: (a) the role of endothelial cells as antigen presenting cells, (b) the role of endothelial cells in the recruitment of effector and effector memory T cells, (c) the responses of endothelial cells to T cells and their products, and (d) the use of endothelial cells to repair or replace (through tissue engineering) end stage organs. Specific accomplishments in the last year are the demonstration that human allograft injury and rejection can be mediated by interactions between host memory T cells and graft endothelial cells; that only effector memory T cells can transmigrate across endothelial cell monolayers in response to the chemokine IP-10; that TNF effects on human kidney endothelial cells may be regulated by differential expressions of TNF receptors type 1 and type 2; and that human peripheral blood contains progenitors for endothelial cells that may be differentiated in vitro into mature endothelial cells capable of vascularizing synthetic skin grafts. All three sets of observations have clinical relevance for the translational mission of VBT. Publications: Al-Lamki RS, Wang J, Vandenabeele P, Bradley JA, Thiru S, Luo D, Min W, Pober JS,

Bradley JR. 2005 TNFR1- and TNFR2- mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury. FASEB J. 19:1637-1645.

Shaio S, McNiff J.M., Pober J.S. 2005 Memory T cells and their costimulators in human allograft injury. J Immunol. 175:4886-4896.

Manes TD, Pober JS, Kluger MS. 2006 Endothelial Cell-T Lymphocyte Interactions: IP-10 stimulates rapid transendothelial migration of human effector but not central memory CD4+ T cells: requirements for shear stress and adhesion molecules. Transplantation. 82:S9-S14.

Wilson JH, Paturzo FX, Johnson LK, Carreiro MP, Hixson DC, Mennone A, Boyer JL, Pober JS, Harding MJ. 2006 Rat hepatocyte engraftment in severe combined immunodeficient x beige mice using mouse-specific anti-fas antibody. Xentransplantation. 13:53-62.

Shepherd BR, Enis DR, Wang F, Suarez’ Y, Pober JS, Schechner JS. 2006 Vascularizationand engraftment of a human skin equivalent using circulating progenitor cell-derived endothelial cells. FASEB J. 20:1739-1741.

LaGier AJ and Pober JS. 2006 Immune accessory functions of human endothelial cells are modified by overexpression of B7-H1 (PDL1). Human Immunology. (in press).

Goyal A, Wang Y, Su H, Dobrucki LW, Brennan M, Fong P, Dardik A, Tellides G, Sinusas A, Pober JS, et al. 2006 Development of a model system for preliminary evaluation of tissue-engineered vascular conduits. J Pediatr Surg. 41;787-791.

Ranjbaran H, Wang Y, Manes TD, Yakimov AO, Akhtar S, Kluger MS, Pober JS, Tellides G. 2006 Heparin displaces IP-10, I-TAC, and Mig sequestered in the vasculature and inhibits the transendothelial migration and arterial recruitment of T cells. Circulation. (in press).


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David M. Rothstein, M.D. Associate Professor of Internal Medicine (Nephrology) A deeper understanding of how the immune system is regulated will ultimately allow the design of more rational strategies for immunosuppression and the induction of tolerance. We are studying the CD45 protein tyrosine phosphates, a family of transmembrane molecules that are critically involved in regulating T cell activation. We have shown that several doses of an antibody targeting the higher Mr isoforms of CD45 (anti-CD45RB) prevents rejection of islet cell allografts in mice. Moreover, anti-CD45RB-based therapies are extremely potent and can, for example, induce permanent survival of skin grafts across highly immunogenic murine strain combinations. Importantly, data from our collaborators indicates that a short-course of anti-CD45 may also induce long-term survival of rental allografts in monkeys, making this novel therapeutic approach very attractive for therapy in humans. Although much is known about CD45, little is known about how anti-CD45 might induce tolerance. Our studies indicate a novel mechanism of action. We have shown that effective mAbs induce a shift in CD45 isoform expression on T cells towards the lower Mr (CD45RBLo) isoforms. This is associated with augmented expression CTLA-4, a potent down regulatory molecule. The ability to specifically upregulate CTLA-4 without inducing overt T cell activation represents a practical means of harnessing this inhibitory pathway to promote tolerance. New data suggests that CTLA-4 is expressed on newly induced regulatory T cells that play a critical role in the tolerogenic activity of CD45. As such, we are now determining the biochemical pathways by which CD45 cross-linking leads to upregulation of CTLA-4 and how CTLA-4 upregulation itself promotes tolerance. We are using transgenic mice expressing a Foxp3-reporter to determine the exact effects of other tolerogenic agents on regulatory T cell generation. Finally, new work is focused on the role of CD45 on transplant-specific activation of the innate immune system. Publications: Sho M, Kishimoto K, Harada H, Livak M, Sanchez-Fueyo A, Yamada A, Zheng XX, Strom

TB. Basadonna G, Sayegh MH and Rothstein DM. Requirements For Induction And Maintenance of Peripheral Tolerance In Stringent Allograft Models. 2005. Proc Natl Acad Sci USA. Track II. 102:13230-35.

Salvalaggio PR*, Camirand G*, Ariyan CE, Deng S, Rogozinski L, Basadonna GP, Rothstein DM. Antigen Exposure during Enhanced CTLA-4 Expression Promotes Allograft Tolerance In Vivo. J Immunol. 2006 176:2292-8. *Contributed Equally.

Stephan L, Pichavant C, Bouchentouf M, Mills P, Camirand, G., Tagmouti S, Rothstein, DM, and Tremblay, JP. Induction Of Tolerance Across Fully Mismatched Barriers By A Non Myeloablative Treatment Excluding Antibodies Or Irradiation Use. 2006. Cell Transplant. In Press.

Manuscripts Submitted: Ariyan, C., Dohi T., Millet I., Plescia J., Salvalaggio P., Rothstein DM., Altieri D., Basadonna

G. Anti-apoptotic gene therapy with Survivin protects islets of Langerhans from cell death. Submitted.

Chae W-J, Rogozinski L, Frederick C. Rodriguez FC, Qin L, Rothstein DM, Lee S-K, and Bothwell ALM. Continued Expression of Foxp3 is Required to Maintain Functional Differentiation of CD25+Treg In Mice. Under Revision. J. Immunology Cutting Edge.


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Nancy H. Ruddle, Ph.D. John Rodman Paul Professor/ Epidemiology and Public Health and Immunobiology My research is concerned with cell trafficking in inflammation and lymphoid organ development. Several models are used. Experimental autoimmune encephalomyelitis is a mouse model of multiple sclerosis. We use myelin oligodendrocyte glycoprotein (MOG) to induce an inflammatory, demyelinating, paralytic disease. By varying a single amino acid in MOG, we can induce a change in pathogenic mechanism from one mediated by inflammatory T cells and cytokines to one mediated by antibodies . In both cases, antibodies are produced. We have been able to distinguish pathogenic from non-pathogenic antibodies. We have shown that at crucial difference lies in their ability to distinguish glycosylated MOG from non-glycosylated MOG . Current studies are aimed at adapting these studies to human MS patients. Another aspect of our work involves high endothelial venules (HEVs), specialized blood vessels that allow the egress of naïve lymphocytes into lymph nodes. We have studied HEV regulation in canonical secondary lymphoid organs and “tertiary lymphoid organs,” ectopic lymphoid accumulations arising in situations of chronic inflammation. More recently, we have begun to study lymphatic vessels, an additional crucial lymphoid organ vascular system. Specific accomplishments in the last year: 1. The demonstration that we can distinguish between pathogenic and non pathogenic myelin oligodendrocyte glycoprotein antibodies. We have shown that only pathogenic antibodies transfer disease, recognize glycosylated epitopes and perturb oligodendrocyte physiology (Publication 1). 2. The demonstration that high endothelial venules and lymphatic vessels are in synchrony after immunization. This process is regulated by B Cells and the LTβ receptor (Publication 3) 3. The development of techniques to evaluate murine lymphatic vessel structure and function using fluorescent dendrimers and magnetic resonance imaging (Collaboration with Tarek Fahmy) We have been fortunate to compete successfully for a pilot grant from the Yale Skin Diseases Research Center and to obtain a postdoctoral fellowship form the Lymphatic Research Foundation to support this new aspect of our work. 4. The demonstration that tertiary lymphoid tissues generate effector and memory T cells that lead to allograft rejection. Skin from RIPLTα mice that exhibit lymphoid accumulations in the skin was transplanted to allogeneic mice that lack lymph nodes. This was able to generate an immune response and rejection both to that skin and skin from a mouse that shared its histocompatibility antigens. Submitted to Nature Medicine Publications: Marta, C.B., Oliver, A.R., Sweet, R.A., Pfeiffer, S.E., and Ruddle, N.H. 2005. Pathogenic

myelin oligodendrocyte glycoprotein antibodies recognize glycosylated epitopes and perturb oligodendrocyte physiology. Proc Natl Acad Sci U S A 102:13992-13997.

Drayton, D.L., Liao, S., Mounzer, R.H., and Ruddle, N.H. 2006. Lymphoid organ development: from ontogeny to neogenesis. Nat Immunol 7:344-353.

Liao, S., and Ruddle, N.H. 2006. Synchrony of high endothelial venules and lymphatic vessels revealed by immunization. J Immunol 177:3369-3379.


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Kerry S. Russell, M.D., Ph.D. Assistant Professor of Medicine, Section of Cardiovascular Medicine, Department of Internal Medicine Our research broadly encompasses 2 common themes in cardiovascular medicine: preservation of cardiac function and promotion of angiogenesis. We have chosen to focus on 2 major targets in the cardiovascular system that could potentially be manipulated to achieve the goals of myocyte preservation and angiogenesis. The first of these targets is the neuregulin/erbB ligand/receptor system. Evidence for the importance of this signaling system in the heart comes from clinical data showing that interruption of this system (e.g. using Herceptin in breast cancer patients) leads to depression of cardiac function, ultimately leading to heart failure in some patients. Our work over the past year has shown that activation of this signaling system can protect cardiac myocytes against injury in response to ischemia and can promote angiogenesis. The second target under investigation is the IL-6/STAT3 signaling cascade. Clinical data has revealed a paradoxical relationship between detrimental and protective effects of several “pro-inflammatory” cytokine pathways, including that of IL-6, in patients with heart failure. Our data suggests that one particular downstream target of IL-6 signaling, the STAT3 protein, may be important for the cardioprotective effects of IL-6. We hope that unraveling the details of this signaling pathway will provide novel targets to protect the heart in the setting of ischemic or inflammatory injury. Specific accomplishments in the last year: Understanding how the neuregulin/erbB system functions in the highly clinically relevant model of ischemia/hypoxia forms the basis of our recently funded NIH R01. Both of the projects described above have involved early in vitro work to define the potential of these specific targets for further work. Simultaneously, we have undertaken development of complex transgenic models to allow both tissue selective and inducible alteration of the expression of our target molecules. We are now taking this work to the next phase in which these animal models will be used to test the effects of activation or suppression of target molecule expression in response to various injuries. In addition to our own research efforts, we hope to establish a core to provide comprehensive hemodynamic and functional analysis of multiple small animal models of cardiovascular disease. With this goal in mind, our group has begun to coalesce our individual expertise in these areas to build such a core facility and plan for future needs for success. We have applied for an NIH Shared Instrumentation Grant to obtain state-of-the-art imaging and hemodynamic equipment to supplement our current individual hemodynamic apparatuses and clinical echocardiography machine (also obtained through an NIH SIG). Publications: Park SY, Cho YR, Finck BN, Kim HJ, Higashimori T, Hong EG, Lee MK, Danton C, Deshmukh

S, Cline GW, Wu JJ, Bennett AM, Rothermel B, Kalinowski A, Russell KS, Kim YB, Kelly DP, Kim JK. Cardiac-specific overexpression of peroxisome proliferator-activated receptor-{alpha} causes insulin resistance in heart and liver. Diabetes. 2005;54:2514-24.

Park SY, Cho YR, Kim HJ, Higashimori T, Danton C, Lee MK, Dey A, Rothermel B, Kim YB, Kalinowski A, Russell KS, Kim JK. Unraveling the temporal pattern of diet-induced insulin resistance in individual organs and cardiac dysfunction in C57BL/6 mice. Diabetes. 2005;54:3530-40.


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Mehran M. Sadeghi, M.D. Assistant Professor of Medicine (Cardiovascular Medicine) The main goal of our laboratory research is to develop novel molecular imaging approaches for cardiovascular disease, with a focus on the vascular system, including vascular remodeling. Vascular remodeling is a common feature of a broad spectrum of vasculopathies, from atherosclerosis to graft arteriosclerosis. For each process studied, we identify specific imaging targets based on pathophysiology or genomic and proteomic screening, develop novel ligands for imaging or use existing radiotracers, establish various small animal models, and use a dedicated hybrid microSPECT/CT small animal imaging system to image the process in vivo. Better understanding of the pathophysiology and vascular biology is an integral part the research in the laboratory. Over the past year we have focused on three pathological processes, namely injury-induced vascular remodeling, graft arteriosclerosis and aneurysm. We continued our work on αvβ3integrin activation as a target for imaging the proliferative process in vascular remodeling, and demonstrated the suitability of αvβ3-targeted tracers for imaging graft arteriosclerosis. We extended our work to assess matrix metalloproteinase activation as target for detection of vascular remodeling in response to injury and aneurysm formation. MicroSPECT/CT imaging was optimized for detection of murine carotid remodeling. In parallel, we continued our work on better characterization of a potentially novel target, endothelial and smooth muscle derived neuropilin-like protein (ESDN) identified in previous years through cDNA array analysis. We established the pattern of ESDN expression in graft arteriosclerosis in vivo, demonstrating little ESDN expression in normal arteries and high levels of expression during the course of vascular remodeling which parallels cell proliferation. Hua J, Dobrucki LW, , Sadeghi MM, Zhang, J, Bourke BN Cavaliere P, Song J, Chow C,

Jahanshad N, Van Royen N, Buschmann I, Madri JA, Mendizabel M, and Sinusas AJ. “Non-invasive Imaging of Angiogenesis with a 99mTc-labeled Peptide Targeted at αvβ3 Integrin Following Murine Hindlimb Angiogenesis”. Circulation, 2005, 111:3255-3260.

Piao D, Sadeghi MM, Zhang J, Chen Y, Sinusas AJ, and Zhu Q. “A hybrid positron detection and optical coherence tomography system: Design, calibration and experimental validation with rabbit atherosclerotic models.” Journal of Biomedical Optics, 2005, 2005, 10(4):044010.

Zhang J, Krassilnikova S, Gharaei AA, Rastegar Fassaei H, Esmailzadeh L, Asadi A, Danesh FR, Edwards DS, Harris TD, Azure M, Rodriguez ER, Tellides G, Sinusas AJ, Zaret BL, Bender JR, and Sadeghi MM. “αvβ3-targeted imaging of arteriopathy in transplanted human coronary arteries” FASEB Journal, 2005, 19(13):1857-9.

Zeng L, Xu H, Eng E, Chew T, Sadeghi MM, Adler S, Kanwar YS, and Danesh FR. “VEGF-Induced Endothelial Cell Hyperpermeability Is Mediated by Myosin Regulatory Light Chain Phosphorylation: Modulatory Effects of Statins” FASEB Journal, 2005, 19(13):1845-7.

Sadeghi MM. “The pathobiology of the vessel wall; implications for imaging.” Journal of Nuclear Cardiology, 2006, 13(3):402-414.

Sadeghi MM and Bender, JR. “Activated αvβ3 integrin targeting in injury-induced vascular remodeling.” Trends in Cardiovascular Medicine, in press

Xu H, Zeng L, Peng H, Chen S, Jones J, Chew T, Sadeghi MM, Kanwar YS, and Danesh FR. “HMG-CoA reductase inhibitor, simvastatin mitigates VEGF-induced “inside-out” signaling to extracellular matrix by preventing RhoA activation.” American Journal of Physiology Renal Physiology, 2006, doi:10.1152/ajprenal.00092.2006.


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W. Mark Saltzman, Ph.D. Goizueta Foundation Professor of Chemical and Biomedical Engineering/Chair of Biomedical Engineering Our laboratory is creating new technology, based on the use of biocompatible polymeric materials, for the controlled delivery of drugs, proteins, and genes. We also develop and study new polymeric materials that influence the growth and assembly of tissues. Our research projects in the area of tissue engineering are the most relevant to the VBT program. Tissue engineering is a new field of inquiry, defined about 15 years ago. In our view tissue engineering involves the use of synthetic polymers as scaffolds for cell transplantation, in which the properties of the scaffold are tuned to encourage the formation or regeneration of tissue structure and function. Importantly, tissue engineering involves a combination of disciplines to achieve new therapies and, in some cases, entirely new approaches to therapy. Specific accomplishments in the last year: We have been particularly interested in developing methods for transplantation of neo-tissues—combinations of cells and synthetic materials that are assembled ex vivo. In the past year, we have made progress in three areas that are important in this overall effort. First, we have used electrospinning techniques to make synthetic polymer meshes with fibers that are much less than 1 micron and therefore mimic the natural extracellular matrix dimensions. We have developed a variety of approaches for modifying the surface of these fibers, allowing us to tune them for attach and growth of different cell populations. Second, in collaboration with Christopher Breuer, we have developed a variety of microparticle controlled release systems that are useful in tissue engineering, including systems that release parathyroid hormone, osteopontin, and rapamycin. Third, we have developed controlled release systems for VEGF and are using these in collaboration with Jordan Pober, to optimize the delivery of VEGF in the context of endothelial cell transplantation for treatment of ischemia. Publications: Goyal A, Wang Y, Su H, Dobrucki LW, Brennan M, Fong P, Dardik A, Tellides G, Sinuses A,

Pober J, Saltzman WM, Breuer CK. Development of a Model System for Preliminary Evaluation of Tissue Engineered Vascular Conduits. Journal of Pediatric Surgery 41:787-791 (2006).

Shen H, Hu YY, and Saltzman WM. DNA Diffusion in Mucus: effect of size, topology and charge of DNAs, Biophysical Journal 91:639-644 (2006).

Neeves KB, Lo CT, Foley CP, Saltzman WM, and Olbricht WL. Fabrication and characterization of microfluidic probes for convection enhanced drug delivery. Journal of Controlled Release 111:252-262 (2006).

Keegan ME, Royce SM, Fahmy T, and Saltzman WM. In vitro evaluation of biodegradable microspheres with surface-bound ligands, Journal of Controlled Release 110: 574-580 (2006).


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William C. Sessa, Ph.D. Professor and Vice-Chair, Department of Pharmacology, Deputy Director, Interdepartmental Program in Vascular Biology and Transplantation Our laboratory is very interested in regulation of post-natal angiogenesis and arteriogenesis in health and disease. Specific accomplishments in the last year: (In relation to the VBT Program) In the past year, we have made successful inroads into understanding the role of plasma membrane microdomains termed caveolae in mechanotransduction of blood vessels. We have developed a novel mouse model re-expressing the coat protein for caveolae, caveolin-1, back into the endothelium of mice globally deficient in caveolin-1 and have shown that the endothelial expression of this gene is critical for flow mediated vasodilation and structural remodeling of blood vessels. An additional interest of the lab is to elucidate the role of Nogo in vascular remodeling and we have taken a significant step in the right direction by cloning a unique receptor for Nogo-B. In addition, we have collaborated with groups at Yale and abroad examining the role of Nogo-B in human vascular disease and have submitted a manuscript describing the loss of Nogo-B in severe stenotic atherosclerotic lesions in man. Finally, we have identified five new palmitoyltransferase enzymes that are expressed in endothelial cells that palmitoylate eNOS. These may be new targets for anti-angiogenic therapy. Publications: Yu, J., Bergaya, S., Murata, T., Alp, I.F., Bauer, M.P., Lin, M.I., Drab, M., Kurzchalia, T.V.,

Stan, R.V. and Sessa, W.C. Direct evidence for the role of caveolin-1 and caveolae in mechanotransduction and remodeling of blood vessels. J Clinical Investigation, 116:1284-91 (2006).

Hatakayama, Pappas, P.J., Hobson, I., Boric, M.P., Sessa, W.C. and Duran, W.N. Endothelial nitric oxide synthase regulates microvascular hyperpermeability in vivo. J. Physiology, 574:275-81 (2006).

Miao, R.Q., Gao, Y., Harrison, K.D., Prendergast, J., Acevedo, L.M., Yu, J., Hu, F., Strittmatter, S.M. and Sessa, W.C. Identification of a receptor necessary for Nogo-B stimulated chemotaxis and morphogenesis of endothelial cells. Proc Natl Acad Sci (U S A) 103:10997-11002 (2006).

Fernandez-Hernando, C., Fukata, M., Bernatcez, P.N., Fukata, Y., Lin, M.I., Bredt, D.S. and Sessa, W.C. Identification of Golgi localized acyltransferases that palmitoylate and regulate endothelial nitric oxide synthase. J. Cell Biology, 174(3):369-77 (2006).

Bhandari, V., Choo-Wing, R., Chapoval, S., Lee, C.G., Tang, C., Kim, Y.K., Ma, B., Baluk, P., Lin, M.I., McDonald, D.M., Homer, R.J., Sessa, W.C. and Elias, J.A. Essential role of nitric oxide in VEGF-induced, asthma-like angiogenic, inflammatory, mucous and physiologic responses in the lung. Proc Natl Acad Sci (U S A) 103:11021-11026 (2006).

Phung, T., Ziv, K., Dabydeen, D., Riveros, G., Shiolima, I., Nagy, J., Lin, M.I., Walsh, K., Dvorak, A.M., Briscoe, D. M., Neeman, M., Sessa, W.C., Dvorak, H.F., and Benjamin, L.E. Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell, 10:159-170, (2006).


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Albert J. Sinusas, M.D., FACC, FAHA Professor of Medicine and Diagnostic Radiology During the last year we opened a dedicated Small Animal Molecular Imaging Center located in the basement of LCI building at Yale University. In this facility we operate a microSPECT/CT imaging system as a shared resource for many investigators at the Yale University and other outside Universities and Medical Institutions. This facility has the capacity for targeted SPECT radiotracer production, animal housing and preparation including microsurgery and hemodynamic monitoring, as well as imaging. A separate radiochemistry laboratory was also established adjacent to the large animal imaging facility (BML), capable of synthesizing SPECT radiopharmaceuticals, and performing radioactive HPLC. These facilities are available for use by investigators participating in the PPG, and are integral for the imaging project. Published manuscripts 05-06 related to PPG: Piao D, Sadeghi M, Zhang J, Chen Y, Sinusas AJ, Zhu Q. A hybrid positron detection and

optical coherence tomography system: Design, calibration and experimental validation with rabbit atherosclerotic models. J Biomed Opt 10(4):044010 (July/August) 2005.

Li S, Dobrucki WL, Sinusas AJ, Liu YH. A new method for SPECT quantification of targeted radiotracers uptake in the myocardium. Proceeding of Medical Image Computing and Computer-Assisted Intervention (MICCAI), LNCS 3750, 8(Pt 2):684-691, 2005

Papademetris X, Dione DP, Dobrucki LW, Staib LH, Sinusas AJ. Articulated Rigid Registration for Serial Lower-Limb Mouse Imaging. Proceedings of Medical Image Computing and Computer-Assisted Intervention, MICCAI LNCS 3750, 8(Pt 2):919-926, 2005

Jackowski M, Papademetris X, Dobrucki LW, Sinusas AJ, Staib LH. Characterizing vascular connectivity from microCT images. Proceedings of Medical Image Computing and Computer-Assisted Intervention, MICCAI, LNCS 3750, 8(Pt 2):701-708, 2005

Zhang J, Krassilnikova S, Gharaei AA, Fassaei HR, Esmailzadeh L, Asadi A, Edwards DS, Harris TD, Azure M, Tellides G, Sinusas AJ, Zaret BL, Bender JR, Sadeghi MM. Alphavbeta3-Targeted detection of arteriopathy in transplanted human coronary arteries: an autoradiographic study. The FASEB Journal (express article 10.1096/fj.05-4130fje) Published online September 8, 2005

Su H, Spinale FG, Dobrucki LW, Song J, Hua J, Sweterlitsch S, Dione DP, Cavaliere P, Chow C, Bourke BN, Hu X, Azure M, Yalamanchili P, Liu R, Cheesman EH, Robinson S, Edwards DS, Sinusas AJ. Non-invasive Targeted Imaging of Matrix Metalloproteinase Activation in a Murine Model of Post-Infarct Remodeling. Circulation 112:3157-3167, 2005

Lindsey ML, Escobar GP, Dobrucki WL, Goshorn DK, Bouges S, Mingoia JT, McClister DM, Jr., Su H, Gannon J, MacGillivray C, Lee RT, Sinusas AJ, Spinale FG. Matrix Metalloproteinase-9 Gene Deletion Facilitates Angiogenesis Following Myocardial Infarction. Am J Physiol:Heart & Circ Phys 290:232-9 2006

Goyal A, Wang Y, Su H, Dobrucki LW, Brennan M, Fong P, Dardik A, Tellides G, Sinusas AJ, Pober JS, Saltzman WM, Breuer CK. Development of model system for preliminary evaluation of tissue-engineered vascular conduits. J Ped Surg 41:787-791, 2006


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Edward L. Snyder, M.D. Professor Laboratory Medicine and Associate Chair of Clinical Affairs The Apheresis/Elutriation/Cell Processing Core Facility will play a critical role in the Vascular Biology and Transplant Program. The Cell Processing Core Laboratory is designed to support the needs of the VBT Program users who are performing basic science and clinical research involving mononuclear and other cell types, by providing four specific functions. First, the Apheresis section of the Cell Processing Core Laboratory will procure and provide both patient and normal donor specimens in support of research projects. These samples, obtained under IRB approved protocols from fresh specimens, will be available to VBT membership. Second the Elutriation section of the VBT Core Laboratory can provide cell purification services in the form of elutriation technology using closed system devices to ensure safety and sterility of the cellular product. Third, the main Cell Processing Core provides large-scale processing capabilities in support of specific research studies involving human MNCs as well as CD34 positive and other cell types. Included within this section is the development of new cell selection and culturing techniques to support the novel cell therapy protocols, as well as the pre-clinical validation of research procedures. The VBT Core resource provides the critical instrumentation and technical expertise in cell processing and cryopreservation, needed for the in vitro use of cells, or infusion of cells into animals. Fourth, the Apheresis/Elutriation/Cell Processing VBT Core Facility will maintain compliance with institutional, NIH, FDA, AABB and FACT guidelines, and will ensure that the protocols can be safely and effectively applied. Included with this objective will be training new investigators in compliance and Quality Control issues. Thus, this resource provides access to cell collection, selection, purification, processing and culturing technologies, as well as services and scientific consultation to enhance the productivity of the VBT members. This technically sophisticated resource is critical to the Vascular Biology and Transplantation Section’s research progress. Publications: Snyder EL, Raife T, Lin L., et al. Recovery and life span of 111-indium-radiolabeled platelets

treated with pathogen inactivation with amotosalen HCL (S-59) and UV light. Transfusion 2004;44:1732-40.

McCullough J, Vesole DH, Benjamin RJ, Slichter S, Pineda A, Snyder EL, et al. Therapeutic efficacy and safety of platelets treated with a photochemical process for pathogen inactivation: the SPRINT Trial. Blood 2004;104:1534-41

Snyder EL. Evaluation of stored Platelets. International Forum. Vox Sang 2004;86:222-223 Snyder EL, McCullough J, Slichter SJ, Strauss RG, Lopez-Plaza I, Lin J-S, Corash L and

Conlan MG for the SPRINT Study Group. Clinical Safety of Platelets Photochemically Treated with Amotosalen HCl and Ultraviolet A Light for Pathogen Inactivation: The SPRINT Trial. Transfusion 2005;45:1864-75

Snyder EL, Haley NR. Cord blood units for adult transplantation. Transfusion 2005;45:829-31

AuBuchon JP, Snyder EL.The rationale for a standardized approach to assessment of platelet kinetics. Transfusion 2006;(in press)

Slichter SJ, Baril L, Corda T, Dincecco D, Bolgiano D, MK Jones, Christoffel T, Corson J, Snyder EL. Viability and function of 8-day stored Haemonetics apheresis platelets. Transfusion 2006;(in press).

Murphy S, Snyder EL, Cable R, et al. Platelet dose consistency and its effect on the number of platelet transfusions for support of thrombocytopenia. An analysis of the SPRINT Trial of platelets photochemically treated with amotosalen HCL and ultraviolet A light. Transfusion 2006;in press.


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George Tellides, M.D., Ph.D. Professor of Surgery (Cardiothoracic) Our primary research interest is immune-mediated vascular injury and remodeling focusing on the regulation of interferon-γ production by artery-infiltrating T cells and on the mechanisms of interferon-γ responses in vascular smooth muscle cells resulting in arteriosclerosis. Studies of inflammatory vascular disease are performed on clinical specimens and experimental models of allograft and xenograft arteriosclerosis, coronary artery atherosclerosis, aortic aneurysm, and vein graft neointimal hyperplasia. Specific accomplishments in the last year: Competitive renewal of program project grant with other members of VBT. Six lab trainees entered or returned to residency training programs this year, hopefully to become physician-scientists of the future. Publications: Burns WR, Wang Y, Tang PC, Ranjbaran H, Iakimov A, Kim J, Cuffy M, Bai Y, Pober JS,

Tellides G. Recruitment of CXCR3 and CCR5 T Cells and Production of Interferon-gamma-Inducible Chemokines in Rejecting Human Arteries. Am J Transplant 2005;5:1226-1236.

Nasr IW, Wang Y, Gao G, Deng S, Diggs L, Rothstein DM, Tellides G, Lakkis FG, Dai Z. Testicular Immune Privilege Promotes Transplantation Tolerance by Altering the Balance between Memory and Regulatory T Cells. J Immunol 2005;174:6161-6168.

Tang PC, Coady MA, Lovoulos C, Dardik A, Aslan M, Elefteriades JA, Tellides G. Hyperplastic Cellular Remodeling of the Media in Ascending Thoracic Aortic Aneurysms. Circulation 2005;112:1098-1105.

Tang PC, Yakimov AO, Teesdale MA, Coady MA, Dardik A, Elefteriades JA, Tellides G. Transmural inflammation by interferon-gamma-producing T cells correlates with outward vascular remodeling and intimal expansion of ascending thoracic aortic aneurysms. FASEB J 2005;19:1528-1530.

Zhang J, Krassilnikova S, Gharaei AA, Rastegar Fassaei H, Esmailzadeh L, Edwards DS, Harris TD, Azure M, Tellides G, Sinusas AJ, Zaret BL, Bender JR, Sadeghi MM. Avb3-targeted imaging of arteriopathy in transplanted human coronary arteries. FASEB J 2005;19:1857-1859.

Davies RR, Gallo A, Coady MA, Tellides G, Botta DM, Burke B, Coe MP, Kopf GS, Elefteriades JA. Novel measurement of relative aortic size predicts rupture of thoracic aortic aneurysms. Ann Thorac Surg 2006;81:169-177.

Yi T, Cuchara L, Wang Y, Koh KP, Ranjbaran H, Tellides G, Pober JS, Lorber MI. Human Allograft Arterial Injury Is Ameliorated by Sirolimus and Cyclosporine and Correlates with Suppression of Interferon-gamma. Transplantation 2006;81:559-566.

Chung C, Chin S, Chin M, Tellides G, Narayan D. Pectoralis major hemiosseous flap for paradoxical respiration. Plast Reconstr Surg 2006;117:2102-2103.

Goyal A, Wang Y, Su H, Dobrucki LW, Brennan M, Fong P, Dardik A, Tellides G, Sinusas A, Pober JS, Saltzman WM, Breuer CK. Development of a model system for preliminary evaluation of tissue-engineered vascular conduits. J Pediatr Surg 2006;41:787-791.

Rosner D, Stoneman V, Littlewood T, McCarthy N, Figg N, Wang Y, Tellides G, Bennett M. Interferon-gamma Induces Fas Trafficking and Sensitization to Apoptosis in Vascular Smooth Muscle Cells via a PI3K- and Akt-Dependent Mechanism. Am J Pathol. 2006;168:2054-2063.


39

Agnès Vignery, DDS, Ph.D. Associate Professor of Orthopaedics and Rehabilitation Research in our laboratory focuses on osteoporosis, a disease that is at the cross road of the immune, vascular and nervous system. Our main line of investigation regards the differentiation of osteoclasts, which resorb bone, and giant cells, which resorb foreign bodies, with particular emphasis on the molecular mechanisms of fusion of their mononucleate precursor cells that belong to the monocyte-macrophage lineage. The molecular mechanisms used by macor-phages to fuse and form osteoclasts and giant cells have been a long standing and major focus of investigation in our laboratory. Most recently, we have initiated a new line of investigation, which focuses on the targeted induction of new bone to specific sites of the skeleton. Macrophages seed all tissues and can fuse with themselves to differentiate into multinucleate osteoclasts, in bone, or giant cells, in chronic inflammatory reactions and cancer. Although osteoclasts and giant cells play a central role in these diseases, the molecular mechanisms that are responsible for the fusion of macrophages remain poorly understood. With regard to the Boehringer Ingelheim (BIPI) Alliance with the VBT, we have been fortunate to be granted support from BIPI to collaborate on the identification of new molecular targets that are required for the fusion of macrophages. Last year, we initiated a collaborative effort with Themis Kyriakides and Joseph Madri, members of the VBT, on the role of MMP-9 in osteoclast differentiation, and its impact on bone remodeling and homeostasis. As per the induction and targeting of new bone to specific sites of the skeleton, our results are preliminary but encouraging. We have submitted our data for publication, and filed two patents, in 2004 and 2005, on the methodology and concept of targeted formation of new bone. These studies have been, in part, a collaborative effort with Mark Saltzman and his group, also members of the VBT. Conferences: In the summer of 2005, I submitted a proposal for a new Gordon Research Conference (GRC) entitled “ cell-cell fusion”. That proposal was approved by the GRC Board of Directors in the fall of 2005 and the conference scheduled to take place July 1-6, 2007 in New London, NH: http://www.grc.uri.edu/programs/2007/cellcell.htm. I will co-chair that new GRC with Dr Diana Myles, from UC Davis. In recent years, Macrophages have emerged as important players in tissue homeostasis and repair across research fields and medical specialties. Indeed, a new Keystone Symposium dedicated to Macrophages is scheduled for in April 2007: https://www.keystonesymposia.org/Meetings/ViewMeetings. cfm? MeetingID =853. will deliver the closing lecture on “Macrophage Fusion” at that meeting. Publications: Vignery A. Macrophage fusion: the making of osteoclasts and giant cells. J Exp Med 202:

337-340, 2005 Vignery A. La fusion des macrophages: partenaires des cellules somatiques et cancéreuses

Médecine/ Sciences (Paris). 21(12):1070-1075, 2005 van den Berg TK, van Beek EM, Buhring HJ, Colonna M, Hamaguchi M, Howard CJ, Kasuga

M, Liu Y, Matozaki T, Neel BG, Parkos CA, Sano S, Vignery A, Vivier E, Wright M, Zawatzky R, Barclay AN. A nomenclature for signal regulatory protein family members. J Immunol. 175(12):7788-7789, 2005

Cui W, Zhang Ke J, Zhang Q, Ke H-Z, Chalouni C, Vignery A. The intracellular domain of CD44 promotes the fusion of macrophages. 2006 Blood 107:796-805 [Epub 2005 Sep 29]

Zhang Q, Cuartas E, Mehta N, Gilligan J, Ke H-Z, Saltzman W M, Kotas M, Ma M, Rajan S, Chalouni C, Carlson J, Vignery A. PTH promotes the formation of lamellar bone at targeted skeletal sites after marrow ablation in rats. Submitted.


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INTERACTIONS WITH INDUSTRY This past academic year marked the interactions of our research alliance with Boehringer-Ingelheim Pharmaceuticals Inc. This relationship is non-exclusive and is focused on specific projects of mutual interest Wyeth-Ayest has provided funding for a clinical study of cardiovascular disease in renal transplant patients headed by Dr. Lorber. Patient enrollment will begin once final approvals are received from the IRB. VBT leaders continue to actively seek out additional sponsors for program-based research. FUND RAISING AND DEVELOPMENT VBT is working with the Development Office and assisted in preparation of a “white paper” for the pending Yale Central campaign. Support is being actively sought for shared equipment to be used in The Amistad building. PLANS FOR THE COMING YEAR The major task for VBT this coming year will be the relocation of the program to the Amistad building, allowing us to consolidate our vascular biology and transplantation research with our tissue engineering efforts in one common site. The Amistad building will also allow us to integrate our newly expected recruits, Dan Wu and Bing Su, with the existing faculty, and will provide new opportunities to develop interaction with Yale’s new programs in Stem Cell Biology and in Human and Translational Immunology. A second initiative for the coming year will be the launch of a formal effort in translational medicine headed by Frank Giordano. Finally, the coming academic year will provide an opportunity to achieve a transition in leadership as Bill Sessa will replace Jordan Pober as VBT’s director on July 1, 2007.


1-1

Appendix 1

The Fifth Annual VBT/IPCT Retreat


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2-1

Appendix 2

Yale-Cambridge Program


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Scientific Program Cambridge-Yale Meeting BCMM 206 August 8th and 9th Monday AM SESSION I: Preclinical Transplantation and Tissue Engineering 9:00 Jordan Pober and John Bradley

“Welcome and Introduction” 9:10 Mark Saltzman

“Polymers and Drug Delivery Systems for Cell Transplantation” 9:30 Chris Breuer

“Tissue Engineered Vascular Conduits” 9:50 Themis Kyriakides

“Molecular Regulation of Inflammation and Angiogenesis in Tissue-Engineered Scaffolds”

10:10 Jordan Pober “Microvessel Constructs”

10:30-11:00 Break 11:00 Joe Madri

“Interactions of Neural Stem Cells and Brain Endothelial Cells” 11:20 Su Metcalfe

“Is Regulatory Immune Tolerance Linked to Stemness?” 11:40 Frank Giordano

“The Potential of Designed DNA Binding Proteins for Gene Correction, Tissue Healing,

and Tissue Engineering” 12:00 Paul Lehner “Novel Receptors for HSP70” 12:20-1:30 Lunch in BCMM 208 Monday PM SESSION II: Clinical Vascular Biology and Transplant 1:30 Ian Wilkinson

“Arterial Stiffness and Inflammation” 1:50 Steve Pfau

“The Interferon-γ Axis in Coronary Atherosclerosis” 2:10 Rafia Al-lamki

“Differential TNF receptor expression in Inflammation and Ischemia” 2:30 Mehran Sadeghi

“Imaging Vascular Remodeling in Graft Arteriopathy” 2:50-3:20 Break 3:20 Chris Watson

“Cambridge Trials in Renal Transplant Recipients” 3:40 Marc Lorber

“Yale Trials in Renal Transplant Recipients


2-3

4:00 Tony Booth “Cholesterol Lowering and Vascular Function in Inflammatory Conditions”

4:20 Stu Katz “Pilot Studies on Vascular Inflammation and Endothelium-Dependent Dilation”

4:40 Ken Smith “Expression Profiling in Vasculitis”

5:00 Thomas Dengler “Vasculopathy and Endothelial Progenitors”

5:30 Recess 5:30-6:15 Yale-Cambridge Clinical Trials Group Subcommittee Meeting 6:30 Dinner Tuesday SESSION III: Basic and Pre-Clinical Vascular Biology 9:00 Bill Sessa

"Role of eNOS in Arteriogenesis and Remodeling" 9:20 John Bradley

“Death Receptor 3 in Renal Injury” 9:40 Wang Min

“Mitochondrial Thioredoxin in Endothelial Cell Function” 10:00 Cathy Shanahan

“Smooth Muscle Cells, Vesicle Release, and Calcification” 10:20-10:50 Break 10:50 Alan Dardik

“Aging and Vein Graft Arterialization” 11:10 Trevor Littlewood

“Role of Apoptosis in Atherosclerosis” 11:30 Jack Elias

“VEGF in the Pathogenesis of Asthma” 11:50 Steve Charnock-Jones

“Placental Response to Oxidative Stress” 12:10 Marty Kluger

“TNF-mediated Vascular Leak” 12:30 Jeff Bender

“Estrogen and Vascular Function” 12:50-2:00 Lunch in BCMM 208 2:00-3:00 Wrap Up

Documents

Final Annual Report - Yale School of Medicine VBT...ANNUAL REPORT 2005 – 2006 2 PROGRAM OPERATIONS VBT Steering Committee The Steering Committee serves as the principal advisory