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

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): This proposal describes a five-year training program for mentored 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) and a Sarnoff Fellow. 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 collaboration and mentorship, and are enthusiastic about supporting Dr. Gupta's training and independence in functional genomics and vascular 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 the genetics of coronary artery disease. Hands-on training in genome-editing technology and histopathologic assessment of atherosclerosis will be supported by the Senior Advisory Committee and expert collaborators in these areas. Additional career development support is provided by the BWH Division of Cardiovascular Medicine, where the PI will serve as attending physician, and the Broad Institute Cardiometabolic Group. He has developed a clear timeline for publication of his work, presentations at national meetings, and the development of independent research projects and funding. Dr. Gupta has worked to identify non-lipid genetic determinants of coronary artery disease and myocardial infarction (CAD/MI). With an international consortium of collaborators he has contributed to the identification of over 50 loci associated with CAD/MI, many of which have an effect on vascular biology. Dr. Gupta has identified 6p24 as one such interesting locus for functional analysis, and has published data identifying the causal variant (rs9349379) and causal gene-phosphatase and actin regulator 1 (PHACTR1). PHACTR1 is expressed in vascular tissue, and preliminary data show an important role in endothelial cell function. Dr. Gupta's primary goals are to determine 1) the importance of the causal variant, rs9349379, on gene expression using edited induced pluripotent stem cells, 2) the role of PHACTR1 in atherosclerosis- relevant endothelial cell function, and 3) the role of PHACTR1 in atherosclerotic vascular disease. Towards these goals Dr. Gupta will utilize innovative approaches such as genome editing in induced pluripotent stem cells and primary vascular cell lines, confocal and live-cell microscopy of endothelial cell migration, and in vivo histopathological assessment of atherosclerosis in a PHACTR1 knockout mouse. Going forward, Dr. Gupta will use these skills and to build a career as an independent, academic physician scientist.