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Costi Sifri, M.D., University of Virginia Health Sciences Center. Todd A. Fehniger, M.D., ..... postdoctoral fellowship in neuroimaging and genetics under the ..... HIV-1 vpr causes DNA damage in human proximal tubule cells: insights into the mechanism of. HIV-associated ...... strated that DOC and DEX trans-repressed inflam- ...

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2009 Meeting of Medical Fellows, Research Scholars, and Physician-Scientist Early Career Awardees Research Training Fellowships for Medical Students HHMI-NIH Research Scholars Program Physician-Scientist Early Career Award Program and Abstracts May 17–20, 2009 Office of Grants and Special Programs 3 Introduction 4 Program Schedule 8 Keynote Speaker 9 2008 Early Career Awardees’ Biographies 15 Physician-Scientist Career Panel Members’ Biographies 16 Schedule of Presentations 29 Abstracts of Presentations 103 Howard Hughes Medical Institute Tr ustees Officers Grants and Special Programs 104 Participants 109 Index of Presentation Times 113 HHMI Conference Center Map HHMI Home Page www.hhmi.org Grants and Special Programs www.hhmi.org/grants HHMI Scientists and Research www.hhmi.org/research HHMI News www.hhmi.org/news GrantsNet www.grantsnet.org Cover: Tissues of the developing heart respond to a coordinated series of extracellular signals to form the many distinct anatomical features of the mature organ. Disruption of these signaling networks contributes to congenital heart disease, the most common class of birth defects. Among these signals, vascular endothelial growth factor (VEGF) family members are critically important; however, their specific temporal roles remain incompletely defined. Using chemical-induced expression of VEGF inhibitors in trans- genic mouse embryos, we have characterized time windows during which VEGF has three distinct functions during heart develop- ment. One of these functions is to coordinate cell survival to sup- port ventricle septation, as expression of an inhibitor of VEGF signaling (VEGFR2T) at embryonic day 11.5 (E11.5) prevents endothelialization of the ventricles and causes apoptosis specifically within the interventricular septum. These results provide a frame- work to understand how perturbations of VEGF signaling con- tribute to congenital heart defects. The cover image shows immunofluorescent staining of the inter- ventricular septum of a heart from an E13.5 embryo in which VEGF signaling has been blocked by the expression of VEGFR2T. Smooth muscle actin stains myocardial cells (red), PECAM stains endothelial cells (blue), and active caspase-3 stains apoptotic cells (green). Nuclei (grey) are stained with Hoechst. See abstract on page 35. (Courtesy of Gene Kew Ma, HHMI Medical Fellow, Department of Medicine, Stanford University School of Medicine. Mentor: Ching- Pin Chang, M.D., Ph.D.) INTRODUCTION Another way for you to continue your associa-Welcome to the 2009 Meeting of Medical Fellows, tion with HHMI and fellow trainees is through Research Scholars, and Physician-Scientist Early the HHMI Alumni Network, which comprisesCareer Awardees of the Howard Hughes Medical current and former awardees. Local networks haveInstitute. We are very pleased that participants been established in Boston, Northern California,from both HHMI medical education programs will Washington, D.C./Baltimore, Southern California,be sharing their research and expertise in this one North Carolina, Chicago, Michigan, the Pacificmeeting and will be joined by the 2008 awardees of Northwest, Texas, Cleveland, and New York City.our Physician-Scientist Early Career Award program. We invite you to become involved in the HHMIIn 1985, HHMI launched the HHMI-NIH alumni group nearest you and affiliate with newResearch Scholars Program in partnership with the groups as you move about the country during yourNational Institutes of Health to provide outstand- training and early career. ing students from U.S. medical schools with the This meeting is held each spring so that you canopportunity to receive a year of research training present your research and exchange ideas. We haveat NIH. Then, in 1989, HHMI established the grown accustomed to high-quality work from ourResearch Training Fellowships for Medical Students awardees, and this year’s presentations, as judged byProgram to provide a similar group of students the abstracts, will be no exception. We congratulatewith research training in leading academic research you on your scientific accomplishments and devel-laboratories beyond NIH. Recent years have seen opment, and we want to convey our appreciation the expansion of both of the programs to include to your mentors and preceptors, whose guidance isdental and veterinary students, and we welcome clearly evident.their participation. In speaking with numerous alumni of ourThe Physician-Scientist Early Career Awards medical education programs, we are impressed byprovide five years of research support to selected the pivotal effect that this research opportunity hasalumni of the HHMI Research Training Fellowships had on their career development. We hope that youand HHMI-NIH Research Scholars Program as will view your HHMI research experience similarlythey begin their independent academic careers. The and that you will pursue further research and, ulti-awardees will be giving oral presentations, partici- mately, rewarding careers as physician-scientists.pating in a career panel discussion on Monday Finally, we are interested in your comments andevening, and co-chairing presentation sessions with suggestions regarding both this meeting and thethe Medical Fellows and Research Scholars. Medical Fellows, Research Scholars, and Physician-Since the inception of the research training and Scientist Early Career Award programs in general.development programs, HHMI has supported more Please direct your feedback to your respectivethan 2,000 Medical Fellows and Research Scholars, program as follows: Medical Fellows Program toand 52 Early Career Awardees. This year, 74 Medical Melanie Daub at medfellows@hhmi.org; ResearchFellows, 49 Research Scholars, and 18 Early Scholars Program to Min Lee at research_scholarsCareer Awardees will be presenting their research. @hhmi.org; and Physician-Scientist Early CareerThis book contains the schedule and abstracts of Award to Anh-Chi Le at earlycareer@hhmi.org.their presentations. We look forward to hearing about your researchWe are delighted to have Richard P. Lifton, M.D., and to following your careers in the years ahead.Ph.D., as our honored speaker this year. Dr. Lifton is an HHMI investigator, chairman of the Depart- Robert Tjian, Ph.D., Presidentment of Genetics, Sterling Professor of Genetics and Internal Medicine, and director of the Yale Peter J. Bruns, Ph.D., Vice PresidentCenter for Human Genetics and Genomics at Yale Grants and Special ProgramsSchool of Medicine. He will discuss his laboratory’s research using genetic approaches to identify the William R. Galey, Ph.D., Directorgenes and pathways that contribute to common Graduate and Medical Education Programshuman diseases, including cardiovascular, renal, and bone disease. We hope that the meeting will not only be a time for sharing and learning, but also a time for you to get to know your future physician-scientist colleagues better. In keeping with this objective, we have provided several informal opportunities for you to interact and network with each other. 3 PROGRAM SCHEDULE 2009 MEETING OF MEDICAL FELLOWS, RESEARCH SCHOLARS, AND PHYSICIAN-SCIENTIST EARLY CAREER AWARDEES HHMI HEADQUARTERS AND CONFERENCE CENTER, CHEVY CHASE, MARYLAND Sunday, May 17, 2009 5:30–6:00 p.m. Welcoming Reception, Research Scholars and Medical Fellows, Great Hall 5:30–7:00 p.m. Dinner, Early Career Awardees, Rathskeller 6:00–7:00 p.m. Dinner, Research Scholars and Medical Fellows, Dining Room 7:00 p.m. Opening Remarks, Auditorium William R. Galey, Ph.D., Director, Graduate and Medical Education Programs Howard Hughes Medical Institute Welcoming Remarks Peter J. Bruns, Ph.D., Vice President, Grants and Special Programs Howard Hughes Medical Institute Early Career Awardees Introductions Panel Discussion: Pathway to Becoming a Physician-Scientist Moderator: William R. Galey, Ph.D. Early Career Awardee Panelists: Ari Green, M.D., University of California, San Francisco, School of Medicine Regina LaRocque, M.D., Massachusetts General Hospital Eduardo Méndez, M.D., University of Washington Medical Center Mark Onaitis, M.D., Duke University School of Medicine Rathskeller open until 10:30 p.m. 4 PROGRAM SCHEDULE Monday, May 18, 2009 8:00 a.m. Breakfast, Dining Room 9:00–10:30 a.m. Platform Presentations Biomedical Engineering, Biochemistry, and Bioinformatics, Room D-124 Molecular and Cancer Biology, Room D-125 Cancer Biology I, Auditorium 10:30–10:45 a.m. Break, Great Hall 10:45 a.m.– 12:30 p.m. Platform Presentations Immunology and Developmental Biology I, Room D-124 Vascular and Cell Biology, Room D-125 Cancer Biology II, Auditorium 12:30 p.m. Lunch, Dining Room and Rathskeller 1:30–2:45 p.m. Early Career Awardees’ Plenary Presentations, Auditorium John T. Chang, M.D., University of Pennsylvania School of Medicine Yvonne R. Chan, M.D., Univittsburgh School of M Costi Sifri, M.D., University of Virginia Health Sciences Center Todd A. Fehniger, M.D., Ph.D., Washington University School of Medicine 2:45–3:00 p.m. Break, Great Hall 3:00–4:00 p.m. Poster Session A, Atrium 4:00–5:00 p.m. Poster Session B, Atrium 5:00–5:30 p.m. Reception, Atrium 5:30–7:00 p.m. Dinner, Dining Room 7:00 p.m. Keynote Speaker, Auditorium Richard P. Lifton, M.D., Ph.D., Investigator, Howard Hughes Medical Institute; Chairman of the Department of Genetics, Sterling Professor of Genetics and Internal Medicine, Director of the Yale Center for Human Genetics and Genomics, Yale School of Medicine Rathskeller open until 10:30 p.m. Program Schedule 5 PROGRAM SCHEDULE Tuesday, May 19, 2009 7:45 a.m. Breakfast, Dining Room 8:45–10:15 a.m. Platform Presentations Infectious Disease, Room D-124 Cell and Developmental Biology, Room D-125 Stem Cell Biology, Auditorium 10:15–10:30 a.m. Break, Great Hall 10:30 a.m.– Noon Platform Presentations Immunology III, Room D-124 Neuroscience I, Room D-125 Genetics, Auditorium Noon Lunch, Research Scholars and Medical Fellows, Dining Room Noon Lunch and Workshop, Early Career Awardees, Rathskeller 1:30–2:30 p.m. Panel Discussion: Balancing Career and Family, Auditorium Moderators: Matthew Goldstein, Medical Fellow Mari Johanna Tokita, Research Scholar Physician-Scientist Panelists: Donald L. Gilbert, M.D., M.S., Cincinnati Children’s Hospital Medical Center William Matsui, M.D., Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine Christine Seroogy, M.D., University of Wisconsin–Madison School of Medicine and Public Health Jennifer U. Sung, M.D., M.B.A., Wilmer Eye Institute, Johns Hopkins University 2:45 p.m. Depart for Social/Networking Event 3:00–4:30 p.m. Social/Networking Event, National Naval Medical Center 5:00 p.m. Return to HHMI Headquarters Reception, Great Hall 5:30–6:30 p.m. Dinner, Dining Room 6:30–7:30 p.m. Poster Session C, Atrium 7:30–8:30 p.m. Poster Session D, Atrium Dessert, Atrium Rathskeller open until 10:30 p.m. 6 2009 Meeting of Medical Fellows, Research Scholars, and Physician-Scientist Early Career Awardees PROGRAM SCHEDULE Wednesday, May 20, 2009 8:15 a.m. Breakfast, Dining Room 9:15–10:45 a.m. Platform Presentations Epidemiology and Genetics, Room D-124 Neuroscience II, Room D-125 10:45 a.m. Medical Fellows’ Assembly, Auditorium 10:45–11:00 a.m. Research Scholars’ and Early Career Awardees’ Break, Great Hall 11:00 a.m. Recognition Ceremony, Auditorium Opening Remarks William R. Galey, Ph.D. Director, Graduate and Medical Education Programs Howard Hughes Medical Institute Remarks Peter J. Bruns, Ph.D. Vice President, Grants and Special Programs Howard Hughes Medical Institute President’s Remarks Robert Tjian, Ph.D. President Howard Hughes Medical Institute Presentation of Fellows’ Certificates Noon Lunch, Dining Room and Rathskeller 1:30 p.m. Adjournment Program Schedule 7 KEYNOTE SPEAKER Extreme Outliers as Models of Dr. Lifton is an HHMI Common Human Disease investigator, Chairman of the Department of RICHARD P. L IFTON, M.D., PH.D. Genetics, Sterling Professor of Genetics and InternalInvestigator, Howard Hughes Medical Institute; Medicine, and Director Chairman of the Department of Genetics, Sterling of the Yale Center forProfessor of Genetics and Internal Medicine, Director of the Yale Center for Human Genetics Human Genetics and and Genomics, Yale School of Medicine Genomics at Yale School of Medicine. He received his ■ We have used the investigation of extreme out- Ph.D. in biochemistry liers in the human population to identify genes and from Stanford University pathways that contribute to risk of cardiovascular, and an M.D. from Stanford University School of renal, and bone disease. A major focus of our work Medicine. Dr. Lifton completed a residency and chief has been on hypertension, a trait that affects more residency in internal medicine at the Brigham and than a billion people worldwide. This trait has vari- Women’s Hospital. His laboratory has used human ge- ously been proposed to be a primary consequence netics and genomics to identify causes of heart, kidney, of abnormalities in diverse organ systems. Our in- and bone disease. By investigating thousands of families vestigation of thousands of patients from around from around the world, his group has identified more the world has identified renal salt handling as a than 25 human disease genes. These include key genes principal determinant of long-term blood pressure and pathways that are critical to the risk of hyperten- homeostasis in humans. Mutations that increase net sion, stroke, heart attack, and osteoporosis. These renal salt reabsorption raise blood pressure, whereas studies have provided new diagnostic and therapeutic mutations that reduce salt reabsorption lower blood approaches to these diseases, which affect more than pressure. These mutations identify the elements 1 billion people worldwide. Dr. Lifton’s honors include that mediate and regulate the salt-handling path- election to the National Academy of Sciences and the way, including a novel gene family, the Wnk ki- Institute of Medicine, and he was awarded the 2008 nases, which we have shown regulate the balance Wiley Prize in Biomedical Sciences. between salt reabsorption and potassium secretion. New sequencing technologies support identification of rare variants with large effects. These findings have provided insight into both rare and common forms of blood pressure variation, have modified therapeutic approaches, and have identified new targets with the potential of having larger beneficial and fewer adverse effects. 8 Paul Fetters 2008 EARLY CAREER AWARDEES’ BIOGRAPHIES ■ Yvonne R. Chan, M.D., is an assistant professor fellow in the laboratory of Dr. Steven Reiner, he of medicine in the Division of Pulmonary, Allergy, found that T cells divide asymmetrically when con- and Critical Care Medicine (PACCM) at the fronting microbial pathogens. The discovery of asymmetric T cell division was recognized as one ofUniversity of Pittsburgh. She also regularly attends on the university’s Medical Intensive Care Unit and the journal Science’s Top 10 Breakthroughs of 2007. Pulmonary Transplant services. Dr. Chan partici- Dr. Chang’s research focuses on the differentiation pated in the HHMI Medical Fellows Program in of T lymphocytes during immune responses against 1997–1998 and is a recipient microbial pathogens and during autoimmunity. of the HHMI Continued ■ Hyung J. Chun, M.D., is an instructor at StanfordSupport Award. She received University School of Medicine. He received his un-her M.D. from Harvard dergraduate degree in biochemical sciences fromMedical School in the Harvard University. He subsequently received hisHealth Sciences and Tech- M.D. from the Johns Hopkins University School nology Program in 2001. of Medicine, during which time he participated in She finished her clinical the HHMI-NIH Researchtraining in internal medicine Scholars Program from 1999at Mount Auburn Hospital to 2001, working in the in Cambridge, Massachusetts, in 2004 and went on laboratory of Dr. Michaelto graduate from pulmonary and critical care fellow- Lenardo. His work led to ship at the University of Pittsburgh in 2007. Con- the identification of a novelcurrently, she completed postdoctoral research human mutation in the training in pulmonary host defense and lung im- caspase-8 gene, which leadsmunology under the mentorship of Dr. Jay Kolls at to an inherited immunodefi-Children’s Hospital of Pittsburgh and Dr. Prabir ciency syndrome. His re-Ray in the Division of PACCM. Dr. Chan’s research search also characterized a novel role for caspase-8focuses on innate defense against bacterial pneumo- in immune activation. He continued his medicalnias. Most recently, she has studied lipocalin 2, an training in internal medicine and cardiovascularantimicrobial protein, and its mechanism of induc- medicine at the Stanford University School oftion in bacterial infection. Her current studies in- Medicine. Dr. Chun’s current research focuses onvolve characterization of the host signaling response the role of G protein-coupled receptors in the vas-to lipocalin 2. In addition, her projects include culature. He is interested in characterization of thecharacterization of host inflammatory immune re- apelin-APJ signaling pathway, which he has recentlysponses in chronic bacterial infection and coloniza- identified to have an important role in protectingtion in cystic fibrosis (CF). This bedside-to-bench against vascular injury in rodent models of athero-translational study characterizes human lung T sclerosis and aneurysms. cells, isolated from lung explants obtained from CF patients undergoing transplant. Dr. Chan’s ■ To dd A. Fehniger, M.D., Ph.D., is an assistant pro- research characterizes the T cell response to chro- fessor of medicine at the Washington University in nic colonizers in CF, such as Pseudomonas and St. Louis School of Medicine. He was introduced Aspergillus, in an effort to identify culprit immuno- to basic and translational re- logical mechanisms responsible for the lung dam- search as an HHMI Medical age seen in late-stage CF. Fellow in 1996–1997 study- ■ John T . Chang, M.D., is an instructor of medicine ing natural killer cell modu- lation in AIDS-malignancyin the Division of Gastroenterology at the Univer- patients receiving low-dosesity of Pennsylvania. He obtained his B.S. degree in biological sciences from Stanford University and his interleukin-2 therapy. He re- M.D. from Temple University. During medical ceived his Ph.D. in 2000 school, he undertook re- and his M.D. in 2002 from search training as an HHMI- Ohio State University, where NIH Research Scholar from he studied the role of cytokine-cytokine receptor 1997 to 1999 in the labora- signals in natural killer cell development and func- tory of Dr. Ethan Shevach. tion. From 2002 to 2008, he completed a clinical He completed a residency in residency in internal medicine and fellowship train- ing in medical oncology at the Washington Uni-internal medicine and a fel- versity in St. Louis School of Medicine. As alowship in gastroenterology at the University of Pennsyl- postdoctoral fellow from 2005 to 2008, his studies vania. While a postdoctoral focused on the cytotoxic effector mechanisms 9