From association to function at the PHACTR1 GWAS locus for coronary atherosclerosis

该提案描述了一个为期五年的学术职业发展培训计划

This proposal describes a five-year training program for career development in academic cardiovascular medicine for Dr. Rajat Gupta. Dr. Gupta is an Instructor at Harvard Medical School and prior trainee of the NIH-sponsored T32 training grant at Brigham and Women's Hospital (BWH). He has completed clinical training in Cardiovascular Medicine and Internal Medicine through American Board of Internal Medicine. He is now embarking on a research and career development program under the co-mentorship of Drs. Sekar Kathiresan and Kiran Musunuru at the Broad Institute and BWH. Both mentors are leaders in the field of cardiovascular genetics, have a track record of working together and mentorship, and are enthusiastic about supporting Dr. Gupta's training and independence in functional genomics and endothelial cell biology. Dr. Gupta's career development plan includes educational resources at Harvard Medical School, the Broad Institute, and the expertise of three leading vascular biologists (Dr. Peter Libby, Dr. Charles Lowenstein, and Dr. Thomas Michel) as advisory committee members to foster his development as an independent vascular biology researcher with training in functional genomics. Additional career development support is provided by the Brigham and Women's Hospital Division of Cardiovascular Medicine, where the principle investigator will serve as attending physician during the period of funding. He has developed a clear timeline for publication of his work in peer-reviewed journals, presentations at national meetings, and plans for the development of independent research projects and funding. Dr. Gupta is interested in discovering novel non-lipid determinants of coronary artery disease and myocardial infarction. He has previously contributed to genome-wide association studies (GWAS), studied the novel loci associated with CAD/MI, and is now focused on a group of variants at the 6p24 locus. His preliminary data establishes that at least one single nucleotide polymorphism regulates expression of the nearby PHACTR1 gene, and loss of PHACTR1 function in induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) has profound effects on endothelial cell migration, adhesion, and von Willebrand factor expression. The research proposed in this application will build on Dr. Gupta's preliminary data to test the hypothesis that DNA variants at the 6p24 locus affect risk for CAD/MI through changes in expression of PHACTR1 and altered endothelial function. The specific aims of the research proposed in this application are to (1) identify which DNA variants in the 6p24 locus causally contribute to risk of CAD/MI (2) determine the role of PHACTR1 in endothelial function using gene-edited iPSC-ECs and (3) determine the role of PHACTR1 in murine atherosclerosis using knockout mice. Success should result in precise definition of a novel causal gene and how it influences the pathogenesis of CAD/MI, as well as providing a potential new target for the treatment and prevention of CAD/MI.