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

这份提案描述了一项为期五年的学术生涯发展培训计划 给拉贾特·古普塔医生的心血管药物。古普塔博士是哈佛医学院的讲师， 美国国立卫生研究院资助的布里格姆妇女医院(BWH)T32培训基金的实习生。他已经完成了 通过美国内科委员会进行心血管内科和内科临床培训。 他现在正在Sekar博士的共同指导下开始一个研究和职业发展计划 Kathiresan和Kiran Musunuru在博德研究所和BWH。这两位导师都是该领域的领导者 心血管遗传学，有共同工作和指导的记录，并对 支持古普塔博士在功能基因组学和内皮细胞生物学方面的培训和独立性。Dr。 古普塔的职业发展计划包括哈佛医学院的教育资源 该研究所拥有三位顶尖血管生物学家(Peter Libby博士、Charles Lowenstein博士和 Thomas Michel博士)作为咨询委员会成员，以促进他作为独立血管的发展 受过功能基因组学训练的生物研究员。额外的职业发展支持由 布里格姆妇女医院心血管内科，首席调查员将在那里 在资助期间担任主治医生。他已经为出版制定了一个明确的时间表 他在同行评议期刊上的工作，在全国会议上的演讲，以及发展 独立研究项目和资金。 古普塔博士对发现冠状动脉疾病的新的非脂类决定因素和 心肌梗死。他之前参与了全基因组关联研究(GWAS)，研究了 与CAD/MI相关的新基因座，目前主要集中在6p24基因座上的一组变异上。他的 初步数据证实，至少有一个单核苷酸多态调节着 PHACTR1基因附近及诱导多能干细胞来源的内皮细胞中PHACTR1功能的丧失 细胞(IPSC-ECs)对内皮细胞的迁移、黏附和von Willebrand因子有深远的影响 表情。这项申请中提出的研究将基于古普塔博士的初步数据来测试 假设6p24基因座的DNA变异通过改变6p24基因的表达来影响CAD/MI的风险 PHACTR1和内皮功能改变。在本申请中提出的研究的具体目标是 要(1)确定6p24基因座上的哪些DNA变异与冠心病/心肌梗死的风险相关(2)确定其作用 利用基因编辑的IPSC-ECs研究PHACTR1在内皮功能中的作用和(3)确定PHACTR1在 利用基因敲除小鼠建立小鼠动脉粥样硬化模型。成功应该导致对新的因果基因的准确定义 以及它如何影响CAD/MI的发病机制，以及为治疗提供一个潜在的新靶点 预防冠心病/心肌梗死。

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.