This proposal describes a 5 - year training program for the development of an academic career in Laboratory Medicine. The PI has completed Residency training in Pathology and a Fellowship in Hemostasis Medicine at Emory University, and now proposes to expand his scientific skills through a unique integration of interdepartmental and inter-institutional resources that will promote a command of quantitative trait genetics and functional genomics as applied to thrombotic disease. Dr. Warren, an internationally recognized genetics investigator, will mentor the PI's scientific development. He is Chairmen of the Department of Genetics and has trained numerous postdoctoral fellows and graduate students. Dr. Lollar, Professor of Hematology, and Dr. John Blangero, Professor of Genetics will co-mentor the PI throughout this program. Dr. Lollar is a leading authority on f-IX structure/function while Dr. Blangero, the lead scientist of the GAIT Project, the only population-based family thrombosis study, and developer of the state-of-the-art statistical genetics software package SOLAR, both of which will be used in this research proposal. To enhance training the program enlists the expertise of Dr. T.J. Murphy, Professor of Pharmacology, land Dr. Stephanie Sherman, Professor of Genetics. Dr. Murphy developed the retroviral vectors that will be used in the analysis of f-IX gene expression. Dr Sherman, one of the top genetic epidemiologists in the country, has agreed to provide the PI with formal and informal training in statistical genetics and genetic epidemiology. In addition, an advisory committee of highly regarded medical scientists will provide scientific and career advice. The research will principally explore how f-IX genetic polymorphisms influence population variation in thrombosis risk by modulating f-IX expression levels and/or catalytic activity. We have identified most of the common f-IX polymorphisms and are the only lab in the U.S. with access to the genomic DNAs of the GAIT Project. Using an integrated experimental plan that incorporates molecular, biochemical, cellular and genetic approaches, the functional consequences of human f-IX genetic variation will be investigated and correlated with clinical parameters defined within the GAIT cohort. This will be the first comprehensive analysis of how such genetic variation impacts age-dependent and -independent thrombosis risk. By supporting such customized programs, which incorporate expertise from diverse resources at Emory and from outside institutions, the Pathology Department is an ideal setting for training physician-scientists and will provide an environment that enhances the PI's potential of developing into an independent investigator in thrombosis genetics.
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