Genetics of Vascular Remodeling

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DESCRIPTION (provided by applicant): This proposal describes a five-year program for the development of an academic career in cardiovascular genomics. I have completed a clinical cardiology fellowship and three years of postdoctoral training at the NIH. I now will expand my scientific skills in molecular, statistical and epidemiologic principles necessary for the analysis and interpretation of bias-free studies of genomic associations, through the genomic analysis of a complex cardiovascular disease. Over the course of this award, I plan to transition to independence and build upon work completed as a fellow, to investigate the genetic basis of vascular remodeling. The research proposed for the mentored phase will take place in the exceptional environment of the National Human Genome Research Institute Division of Intramural Research. Dr. Elizabeth Nabel, a recognized leader in molecular genetics and vascular biology, and Dr. Aravinda Chakravarti, a leading expert in the genetics of complex cardiovascular traits, will mentor my scientific development. In addition, an advisory committee of highly accomplished genomic scientists will provide scientific and career guidance. The research plan integrates career development goals in 3 Specific Aims to: (1) test the hypothesis that vascular remodeling in response to arterial injury is, in part, genetically determined, by mapping the genetics of in-stent restenosis (ISR); (2) test the hypothesis that sequence variation in candidate susceptibility genes for ISR alters gene expression of these genes and other genes in related biologic pathways; and (3) test the hypothesis that candidate genes for ISR, as determinants of vascular injury responses, are associated with atherosclerosis, which is also characterized by adverse vascular remodeling. Aim 1 will be conducted during the mentored phase of this Award, to provide me with advanced training in genetic analysis of human subjects, with the goal of defining candidate susceptibility genes in the complex vascular disease, ISR. After transitioning to a faculty position with an independent laboratory, I plan to conduct the research proposed in Aims 2 and 3 using skills acquired during fellowship training to gather sufficient preliminary data during this phase to apply for further R01 funding. This program will develop the skills required to investigate the genetics of complex cardiovascular disease as an independent scientist. My goal is to become tenured faculty in a Division of Cardiology at an academic health center where my research will focus on cardiovascular genomics.