Awarded: Jan 01, 2008
$9,000,000 over 5 to 7 years
In 2008, six outstanding physician-scientists at the mid-career level each received grants of $1.5 million to be used over five to seven years.
Sunil K. Ahuja, M.D.
University of Texas Health Science Center at San Antonio
"Immunogenetic Rheostats of HIV-1 Transmission, Keys for Vaccine Development"
Marcus Altfeld, M.D., Ph.D.
Massachusetts General Hospital/Harvard Medical School
"Innate Immunity in HIV-1 Infection"
Jayakrishna Ambati, M.D.
University of Kentucky College of Medicine
"Short Non-Interfering RNAs as Novel Therapies for Age-related Macular Degeneration"
Arul M. Chinnaiyan, M.D., Ph.D.
University of Michigan
"Searching for Recurrent Gene Fusions and Translocations in Common Solid Tumors"
Terrie Inder, M.D., Ph.D.
Washington University in St. Louis/St. Louis Children's Hospital
"Understanding Brain Injury and Development in at Risk Infants to Improve Outcomes"
Eric Vilain, M.D., Ph.D.
University of California, Los Angeles
"Disorders of Sex Development"
Sunil K. Ahuja, M.D.
University of Texas Health Science Center at San Antonio
"Immunogenetic Rheostats of HIV-1 Transmission, Keys for Vaccine Development"
Sunil K. Ahuja, M.D., is professor of medicine, and of microbiology and immunology, and biochemistry at the University of Texas Health Science Center at San Antonio, TX He is also a Staff Physician at the South Texas Veterans Health Care System (STVHCS), San Antonio, TX. He also serves as the Director for the Veterans Administration Center for AIDS and HIV infection. Dr. Ahuja's laboratory uses genetic tools to determine biological pathways and genes therein that influence HIV-AIDS pathogenesis, lupus and other diseases.
Dr. Ahuja received his medical school training at the Armed Forces Medical College, Pune, India and subsequently completed his residency and chief residency in Internal Medicine at SUNY Downstate, New York. He completed fellowship training in infectious diseases at the National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). He received additional research training at the Laboratory of Host Defenses at NIAID, NIH.
Dr. Ahuja is an elected member of the American Society for Clinical Investigation and the Association of American Physicians. He is a recipient of the Elizabeth Glaser Scientist Award from the Elizabeth Glaser Pediatric AIDS Foundation, and the Burroughs Wellcome Clinical Scientist Award in Translational Research. Dr. Ahuja's research is also supported by the NIH, including a MERIT award and through a Veterans Administration MERIT award.
Abstract:
Immunogenetic Rheostats of HIV-1 Transmission, Keys for Vaccine Development
Not all subjects are equally susceptible to acquiring HIV infection and once infected, individuals differ in their rate of progression to AIDS. There is increasing evidence that intersubject differences in HIV-AIDS susceptibility are in part dictated by genetic changes. Dr. Ahuja will investigate host genes that influence variable HIV-AIDS susceptibility and this information will help provide insights into the correlates of protection and, in turn this might help in the design and evaluation of HIV vaccines.
Marcus Altfeld, M.D., Ph.D.
Massachusetts General Hospital/Harvard Medical School
"Innate Immunity in HIV-1 Infection"
Dr. Altfeld is the Director of the Program for Innate Immunity at the Partners AIDS Research Center (PARC) and the Department of Infectious Diseases at the Massachusetts General Hospital in Boston, and is an Associate Professor at Harvard Medical School. He received his M.D./Ph.D. from the University of Cologne in Germany in 1997, and subsequently worked as a Resident in the Department of Medicine at the University of Bonn. After receiving his Diploma in Tropical Medicine and Hygiene (DTM&H) at the London School of Hygiene and Tropical Medicine, he joined PARC as a research fellow in 1999, and became a member of the faculty in 2001.
Dr. Altfeld's research is directed towards the characterization of innate and adaptive immunity in viral infections, with focus on acute HIV-1 and Influenza infection. The aim of this research is to understand the correlates of protective immunity in viral infections, and in particular, how the initial activation of the innate immune system by pathogens shapes the quality of the adaptive immunity.
The long term goal is to harness innate immunity for the development of protective vaccines. Dr. Altfeld's laboratory maintains close collaborations with the HIV-1 Pathogenesis Program at the Nelson Mandela School of Medicine, University of KwaZulu Natal, in Durban, South Africa; and the Department of Infectious Diseases at the Tangdu Hospital, 4th Military Medical School, in Xi'an, China, where he also serves as a Visiting Professor.
Dr. Altfeld is as a member of the American Association of Clinical Investigation, the NIH Plan for HIV-1 Related Research Etiology and Pathogenesis Planning Group (FY 2006-2009), the Harvard University Center for AIDS Research Executive Committee, and the Harvard Medical School Immunology Graduate Program.
Abstract:
Innate Immunity in HIV-1 Infection
Current efforts to develop an HIV-1 vaccine have failed, and basic research beyond traditionally studied adaptive HIV-1-specific immunity is required to identify the immune correlates of protection against HIV-1. The first line of defense against infections consists of a highly organized innate immune response, and the aims of the proposed research program are to define the mechanisms by which the innate immune system senses HIV-1, contributes to the control of viral replication, and influences the function of the subsequently developing adaptive immune response.
In response to the identified needs to facilitate translation of advances in the understanding of the human innate immune system's involvement in the control of HIV-1 infection into clinical practice, Dr. Altfeld has built an Innate Immunity Program between MGH in Boston and the University of KwaZulu-Natal in Durban, South Africa. The program is aimed at training physician-scientists in the evolving field of innate viral immunity, and at translating laboratory research advances into clinical trials that will evaluate interventions targeting the innate immune system to enhance anti-HIV immunity.
The specific hypotheses addressed in this research program are:
- HIV-1 can be directly recognized by receptors of the innate immune system;
- Innate effector cells, in particular NK cells, directly mediate control of HIV-1 replication;
- The innate immune system shapes the function of adaptive HIV-1 immunity, and the virus directly interferes with this process, resulting in T cell dysfunction; and
- Innate immunity can be modulated in humans to enhance the antiviral activity of HIV-1-specific adaptive immunity. The ultimate goal of this program is the rational development of protective HIV-1 vaccines that exploit the antiviral activity of innate immunity.
The Doris Duke award will also support research training for medical students and young physician-scientists to work with Dr. Altfeld and his team both at Harvard Medical School and at the University of KwaZulu-Natal in Durban, South Africa.
Jayakrishna Ambati, M.D.
University of Kentucky College of Medicine
"Short Non-Interfering RNAs as Novel Therapies for Age-related Macular Degeneration"
Dr. Ambati is Professor of Ophthalmology & Visual Sciences and Professor of Physiology at the University of Kentucky School of Medicine. He serves as Vice Chair of the Department of Ophthalmology & Visual Sciences and holds the Dr. E. Vernon Smith & Eloise C. Smith Endowed Chair in Macular Degeneration Research. Dr. Ambati was born and raised in India, the elder son of Prof. A. Muralimohan Rao, an Indian Institute of Technology-educated mathematician, and Gomathi Rao, a scholar in Tamil literature. He secured his electrical engineering degree at The Johns Hopkins University at the age of 17, and M.D. (magna cum laude) from SUNY Health Science Center at Brooklyn. Following ophthalmology residency at the University of Rochester and retina fellowship at Harvard Medical School, he joined the University of Kentucky in 2001.
Dr. Ambati seeks to identify the molecular mechanisms underlying the development of age-related macular degeneration (AMD), which affects 10 million Americans, and to develop novel therapeutics to prevent and treat this blinding condition. His laboratory has made fundamental discoveries about AMD pathogenesis and the immune pathways that trigger both the atrophic and neovascular forms of this disease. They also discovered an unexpected intersection of small interfering RNA (siRNA) activity, an anti-viral immune receptor, and blood vessel growth that has profound implications for clinical application of siRNA therapeutics. In collaboration with his brother, Dr. Balamurali Ambati, a cornea surgeon and vascular biologist, he answered one of the foremost questions in vascular biology: how does the cornea remain avascular? His laboratory has published several articles in such journals as Nature, Nature Medicine, and the New England Journal of Medicine, and is supported by the National Eye Institute of NIH.
Dr. Ambati is a Clinical Scholar in Translational Research of the Burroughs Wellcome Fund. He received the Physician Scientist Award and the Lew R. Wasserman Merit Award from Research to Prevent Blindness, the Dennis W. Jahnigen Career Development Award from The American Geriatrics Society, and a Career Development Award from The Foundation Fighting Blindness. The University of Kentucky awarded Dr. Ambati the Albert D. and Elizabeth H. Kirwan Memorial Prize and named him a University Research Professor. He is on the Editorial Board of Investigative Ophthalmology & Visual Science and has been elected a member of the American Society for Clinical Investigation. He lives with his wife Kameshwari, an IIT-educated chemist, and their daughters Meenakshi and Vidya Lakshmi in Lexington, Kentucky.
Abstract:
Short Non-Interfering RNAs as Novel Therapies for Age-related Macular Degeneration
Age-related macular degeneration (AMD), is the leading of blindness among the elderly in most industrialized nations, and affects as many Americans as all cancers combined. It results in vision loss either through invasion of abnormal blood vessels into the retina (choroidal neovascularization) or via death of retinal cells (geographic atrophy). Dr. Ambati's laboratory has identified a critical role for toll-like receptor-3 (TLR3), an anti-viral immune receptor that recognized double stranded RNAs, in both geographic atrophy and choroidal neovascularization. The aim of this project is to develop therapeutics for both forms of the disease by either activating or inhibiting TLR3. In tandem, Dr. Ambati seeks to train a new generation of physician-scientists with translational interests in angiogenesis research.
Arul M. Chinnaiyan, M.D., Ph.D.
University of Michigan
"Searching for Recurrent Gene Fusions and Translocations in Common Solid Tumors"
Dr. Chinnaiyan is a Howard Hughes Medical Institute Investigator, the S.P. Hicks Endowed Professor of Pathology and Professor of Pathology and Urology at the University of Michigan Medical School, and is also a member of the Comprehensive Cancer Center and Bioinformatics Program. In 2007, he was named the Director of a new initiative at the University called the Michigan Center for Translational Pathology (MCTP), the goal of which is to develop new molecular tests and therapeutics for human disease with a primary focus on cancer. Dr. Chinnaiyan is a board certified Clinical Pathologist and currently serves as Director of the Division of Pathology Research Informatics and Director of Cancer Bioinformatics.
In addition to receiving his undergraduate degree and medical training at Michigan, he received his Ph.D. in Pathology and has made seminal contributions to the understanding of the molecular mechanisms of how cells die (a process called apoptosis). Dr. Chinnaiyan has received a number of awards including the Basic Science Research Award awarded by the University of Michigan Medical School Dean's Office, the AMGEN Outstanding Investigator Award, the Pew Biomedical Scholar Award, the Burroughs Welcome Foundation Award in Clinical Translational Research, the 2006 Benjamin Castleman Award, the 2007 Ramzi Cotran Young Investigator Award and was recently appointed as an Investigator of the Howard Hughes Medical Institute. Dr. Chinnaiyan was also elected as a member of the American Society of Clinical Investigation.
Dr. Chinnaiyan's laboratory has focused on functional genomic, proteomic and bioinformatics approaches to study cancer for the purposes of understanding cancer biology as well as to discover clinical biomarkers. He and his collaborators have characterized a number of biomarkers of prostate cancer including AMACR, EZH2 and hepsin. AMACR is being used clinically across the country in the assessment of cancer in prostate needle biopsies.
The landmark study thus far from Dr. Chinnaiyan's laboratory is the discovery of TMPRSS2-ETS gene fusions prostate cancer. TMPRSS2-ETS gene fusions are specific markers of prostate cancer as well as presumably function as rational targets for this disease. This finding potentially redefines the molecular basis of prostate cancer as well as other common epithelial cancers. The team involved with these studies recently was awarded the 2007 AACR Team Science Award. His laboratory is currently looking for ways to target this gene fusion as well as discover similar gene fusions in other common epithelial tumors such as those derived from the breast, lung, and colon. His laboratory also developed the popular cancer profiling bioinformatics resource called Oncomine (www.oncomine.org) which is freely available to the academic community (hosting nearly 10,000 registered users from over 30 countries).
Abstract:
Searching for Recurrent Gene Fusions and Translocations in Common Solid Tumors
The goal of this project is to launch a new effort in the Chinnaiyan laboratory to comprehensively and systematically scour common human solid tumors for the presence of recurrent gene arrangements known as gene fusions. Once a recurrent gene fusion is identified, it becomes a prime candidate for being a specific biomarker for a tumor type as well as a rational therapeutic target. The Chinnaiyan lab currently has an established program to discover these gene fusions in prostate cancer. We will develop a translational scientist training program to establish gene fusion discovery efforts in breast cancer, melanoma, lung cancer, ovarian cancer, and bladder cancer, among others.
To accomplish our goal, we will need to develop and orchestrate novel, high-throughput technologies to search the genome of hundreds of tumors. High-throughput screening allows a researcher to quickly conduct millions of biochemical, genetic or pharmacological tests. Through this process one can quickly identify genes which modulate a particular biomolecular pathway. The ultimate goal is to translate the findings into the clinical impact of developing a prognostic biomarker or therapeutic target.
Terrie Inder, M.D., Ph.D.
Washington University in St. Louis/St. Louis Children's Hospital
"Understanding Brain Injury and Development in at Risk Infants to Improve Outcomes"
Dr. Inder is an Associate Professor of Pediatrics, Neurology, and Radiology as well as Neonatal Clinician at St. Louis Children's Hospital, Washington University. She is noted as author, lecturer, and researcher in the field of the newborn brain. She was born and educated in New Zealand. She graduated with her Bachelor in Medicine and Bachelor in Surgery from the University of Otago, Dunedin, New Zealand as the top graduate in her class.
Dr. Inder completed her Residency in Pediatrics and Fellowship in Newborn Medicine in New Zealand as well as her Ph.D. in "Free Radical Mediated Injury in the Newborn" before undertaking a second residency in child neurology at Children's Hospital in Boston.
She now leads an internationally recognized research team defining the timing of brain injury in premature and term born babies developing new technologies and interventions to improve long- term outcomes in high-risk infants. An increasing number of at-risk preterm and sick term born infants survive with high rates of neurodevelopmental disability.
In order to apply rational neuroprotective strategies her laboratory aims to define the timing and nature of injury at which to target such interventions as well as the impact of such injury on subsequent cerebral development. This is achieved with a large number of parallel clinical studies in a large 80 bed neonatal intensive care unit based at St. Louis Children's Hospital utilizing bedside technologies such as electroencephalography, optical tomography alongside advanced state of the art magnetic resonance imaging techniques in both the preterm and term born at risk infant. A multidisciplinary team of neonatal attendings, neurologists, radiologists, fellows, M.D./Ph.D. students, occupational therapists, research assistants and research nurses contribute to studies such as the impact of hypothermia and seizures on the injured brain, nature and timing of injury in the preterm brain, the impact of reservoir drainage in post-hemorrhagic hydrocephalus and the potential neuroprotective effect of maternal pomegranate. Dr. Inder is supported by the NIH with multiple R01 awards and is devoted to the training of the next generation of clinical investigators in her field.
Abstract:
Understanding Brain Injury and Development in at Risk Infants to Improve Outcomes
Preterm birth is a major public-health challenge because of its increasing incidence combined with frequent occurrence of subsequent behavioral, neurological, and psychiatric challenges faced by surviving infants. To date, the underlying mechanisms responsible for the poor outcomes in these infants remain poorly understood. Neural progenitor or stem cells (NPCs) are known to reside in two regions of the developing brain— the subventricular zone (SVZ) and the hippocampus with the ability to produce new brain cells including neurons, astrocytes and oligodendrocytes in vivo and in vitro. This raises the potential of their role in recovery following brain injury. This potential may be even greater in the immature brain of an infant but has not yet been evaluated.
Thus, we propose to apply complementary magnetic resonance (MR) imaging approaches to detect and quantify the presence of the progenitor or native stem cell region within the preterm infant from shortly after birth until discharge from the hospital several months later. This will be carried out alongside complimentary advanced structural MR imaging to evaluate brain injury and development. The study design with repeated MR imaging of the infants throughout the infant's course in the intensive care unit will allow characterization of the relationship of this region to both structural abnormalities and compensatory changes in response to early brain injury, perinatal exposures and intensive care therapies. The presence and extent of the progenitor cell region will also be related to neurodevelopmental outcomes in early childhood. If successful, the proposed studies will engender a deeper understanding of the innate neural recovery in the immature brain with in-vivo MR biomarkers of NPC region and its impact on subsequent regional brain structure and neurodevelopmental outcome. These data will assist in providing new understanding of neural recovery and strategies for improving outcomes in preterm infants. In addition, the MR techniques will be capable of being applied in-vivo to any infants at-risk of brain injury or altered brain development.
Eric Vilain, M.D., Ph.D.
University of California, Los Angeles
"Disorders of Sex Development"
Eric Vilain, M.D., Ph.D. was born in Paris, France, and earned his M.D. from the Paris Children's Hospital Necker, his Ph.D. from the Pasteur Institute in Paris, France, then completed a post-doctoral fellowship in Medical Genetics at the University of California, Los Angeles. He is Professor of Human Genetics, Pediatrics and Urology in the David Geffen School of Medicine at UCLA, the Chief of Medical Genetics in the Department of Pediatrics and the Director of the Center for Gender-Based Biology.
Dr. Vilain's laboratory explores the genetics of sexual development, focusing on the molecular mechanisms of gonad development, as well as on the genetic determinants of brain sexual differentiation. He has identified a large number of mutations in sex-determining genes, developed animal models with atypical sexual development, and identified genes differentially expressed between male and female fetal mouse brains.
Dr. Vilain currently works at three projects: the genetics of Disorders of Sex Development (intersexuality), the genetics of sexual orientation and gender identity, and the biological bases of sex differences in susceptibility to diseases, particularly for Parkinson's disease and hypertension. His research program has been continuously supported by several grants from the NIH, and he has published extensively in the field of sexual development. He is a Fellow of the American College of Medical Genetics, and a member of numerous professional committees, including those related to the care of intersex individuals.
Abstract:
Disorders of Sex Development
Disorders of sex development (DSD) encompass a very large spectrum of phenotypes, from minor malformations of the genitalia (hypospadias, cryptorchidism, hypertrophy of the clitoris) to sexual ambiguity. Taken altogether, these anomalies have an estimated frequency of 0.5% to 1%. Understanding the pathophysiology of disorders of sex development has clinical consequences in terms of fertility (most patients are sterile), cancer (most patients carry a higher risk of gonadal tumor) and sexual dysfunction (most patients suffer from sexuality issues).
Recently, the debate about the management of intersex patients has intensified over issues of gender assignment and the indication for early genital surgery. Yet the scientific data on patient outcome have remained poor. The main obstacles to the optimal management of intersex patients has been a combination of lack of controlled outcome data and the lack of understanding of their pathophysiology, which prevents precise diagnostic categorization of patients.