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：
9919442
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/9919442
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 genomic locus 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.

描述（由申请人提供）：本提案描述了 Rajat Gupta 博士在学术心血管医学领域指导职业发展的五年培训计划。Gupta 博士是哈佛医学院的讲师，也是 NIH 资助的 T32 培训的前实习生。他获得了布莱根妇女医院 (BWH) 的资助，并成为萨诺夫研究员。他已通过美国内科医学委员会完成了心血管医学和内科的临床培训，目前正在开展一项研究和职业发展计划。 Broad 研究所和 BWH 的 Sekar Kathiresan 博士和 Kiran Musunuru 博士的共同导师，两位导师都是心血管遗传学领域的领导者，拥有合作和指导的记录，并热衷于支持 Gupta 博士的培训和独立性。 Gupta 博士的职业发展计划包括哈佛医学院、布罗德研究所的教育资源以及三位领先的血管生物学家（Peter Libby 博士、Charles Lowenstein 博士和托马斯·米歇尔（Thomas Michel）博士作为顾问委员会成员，通过冠状动脉疾病遗传学方面的培训，促进他作为独立血管生物学研究员的发展，并得到高级顾问的支持。这些领域的委员会和专家合作者由 BWH 心血管医学部门提供额外的职业发展支持，其中 PI 将担任主治医师，并且 Broad 研究所心脏代谢小组制定了明确的出版物出版时间表。 Gupta 博士与一个国际合作者联盟致力于确定冠状动脉疾病和心肌梗塞 (CAD/MI) 的非脂质遗传决定因素。已帮助鉴定了 50 多个与 CAD/MI 相关的基因座，其中许多基因座对血管生物学有影响。Gupta 博士已将 6p24 确定为这样一个有趣的功能分析基因座，并发表了识别因果关系的数据。变体 (rs9349379) 和因果基因磷酸酶和肌动蛋白调节因子 1 (PHACTR1) 在血管组织中表达，初步数据显示在内皮细胞功能中发挥重要作用。Gupta 博士的主要目标是确定 1) 的重要性。因果变异，rs9349379，使用编辑的诱导多能干细胞进行基因表达，2) PHACTR1 在动脉粥样硬化相关的内皮细胞功能，以及 3) PHACTR1 在动脉粥样硬化性血管疾病中的作用为了实现这些目标，Gupta 博士将利用创新方法，例如诱导多能干细胞和原代血管细胞系的基因组编辑、共聚焦和活细胞显微镜。展望未来，Gupta 博士将研究 PHACTR1 敲除小鼠的内皮细胞迁移以及动脉粥样硬化的体内组织病理学评估。使用这些技能并建立作为一名独立的学术医师科学家的职业生涯。