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

PHACTR1 GWAS 位点与冠状动脉粥样硬化的关联和功能

基本信息

批准号：
10004934
负责人：
RAJAT M GUPTA
金额：
$ 16.88万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004934
关键词：
6p24 Actin-Binding Protein Actins Advisory Committees Affect Alleles American Apolipoprotein E Area Atherosclerosis Biological Biological Assay Biology Blood Vessels CRISPR/Cas technology Cardiovascular Diseases Cardiovascular system Cause of Death Cell Adhesion Molecules Cell Line Cell physiology Cells Cellular Assay Chromosome 6 Clinical Collaborations Committee Members Coronary Arteriosclerosis Coronary artery Data Development Development Plans Disease Endothelial Cells Endothelium Fostering Foundations Functional disorder Funding Gene Expression Genes Genetic Genetic Determinism Genetic study Genotype Goals Grant Histologic Histology Hospitals Human Human Chromosomes Human Genetics Individual Institutes Internal Medicine International Knock-out Knockout Mice Lead Learning Link Lipids Location Medicine Mentors Mentorship Methods Modeling Mus Myocardial Infarction Neurons Pathway interactions Phenotype Phosphoric Monoester Hydrolases Physicians Positioning Attribute Prevention Program Development Publications Publishing Regulation Research Research Personnel Research Project Grants Risk Risk Factors Role Sampling Scientist Series Serum Techniques Technology TimeLine Tissues Training Training Programs United States National Institutes of Health VWF gene Validation Variant Woman Work base cardiometabolism career career development causal variant cell motility chemokine education resources effective therapy experimental study functional genomics gene function genetic association genetic regulatory protein genetic variant genome editing genome wide association study genome-wide in vivo induced pluripotent stem cell innovation instructor live cell microscopy loss of function medical schools meetings migration new therapeutic target novel public health relevance research and development risk variant skills stem cells success

项目摘要

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.