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

• 批准号: 9298804
• 负责人: RAJAT M GUPTA
• 金额: $ 17.23万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-03 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9298804
• 关键词: 6p24; Adhesions; Advisory Committees; Affect; Alleles; American; Apolipoprotein E; Atherosclerosis; Biology; Blood Vessels; CRISPR/Cas technology; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Line; Cell-Cell Adhesion; Cellular biology; Chromosomes; Chromosomes, Human, Pair 6; Clinical; Committee Members; Coronary Arteriosclerosis; DNA; Data; Development; Development Plans; Disease; Endothelial Cells; Endothelium; Fostering; Foundations; Funding; Genes; Genetic; Genomics; Genotype; Grant; Hospitals; Human; Human Chromosomes; Human Genetics; Institutes; Internal Medicine; Introns; Investigation; Journals; Knock-out; Knockout Mice; Link; Linkage Disequilibrium; LoxP-flanked allele; Maps; Medicine; Mentors; Mentorship; Migraine; Molecular; Mus; Myocardial Infarction; Outcome; Pathogenesis; Pathway interactions; Peer Review; Phenotype; Physicians; Play; Pluripotent Stem Cells; Positioning Attribute; Prevention; Publications; Regulation; Research; Research Personnel; Research Project Grants; Resources; Risk; Risk Factors; Role; Series; Single Nucleotide Polymorphism; Testing; TimeLine; Training; Training Programs; United States National Institutes of Health; VWF gene; Variant; Vascular Endothelium; Woman; Work; career development; cell motility; cohort; coronary artery calcification; early onset; effective therapy; functional genomics; gene function; genetic association; genome wide association study; induced pluripotent stem cell; instructor; interest; medical schools; meetings; novel; programs; research and development; success; therapeutic target; von Willebrand Factor

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.

该建议描述了一项为期五年的学术发展培训计划 Rajat Gupta博士的心血管医学。 Gupta博士是哈佛医学院的讲师和先验 NIH赞助的T32培训补助金（BWH）的T32培训补助金的实习生。他已经完成 通过美国内科委员会进行心血管医学和内科医学的临床培训。 他现在正在启动DRS的委托书下的研究和职业发展计划。塞卡 Broad Institute和BWH的Kathiresan和Kiran Musunuru。两位导师都是领导者 心血管遗传学，有共同努力和指导的记录，并且对 支持Gupta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。博士 古普塔的职业发展计划包括哈佛医学院的教育资源， 研究所以及三位领先的血管生物学家的专业知识（Peter Libby博士，Charles Lowenstein博士和 托马斯·米歇尔（Thomas Michel）博士担任咨询委员会成员，以促进他作为独立血管的发展 功能基因组学培训的生物学研究人员。其他职业发展支持由 杨百翰和妇女医院心血管医学部门，主要研究员将在那里 在资金期间担任医师。他已经制定了明确的时间表来发布 他在同行评审期刊上的工作，在国家会议上的演讲以及制定计划 独立的研究项目和资金。 古普塔博士有兴趣发现新型的冠状动脉疾病的非脂质决定因素和 心肌梗塞。他以前曾为全基因组关联研究（GWAS）做出了贡献，研究了 与CAD/MI相关的新颖基因座，现在专注于6P24基因座的一组变体。他的 初步数据表明，至少一种单核苷酸多态性调节了 附近的PHACTR1基因，以及诱导多能干细胞衍生的内皮中PHACTR1功能的丧失 细胞（IPSC-EC）对内皮细胞迁移，粘附和von Willebrand因子具有深远影响 表达。本申请中提出的研究将基于Gupta博士的初步数据，以测试 假设6p24基因座的DNA变体通过改变的表达会影响CAD/MI的风险 PHACTR1和内皮功能改变。本应用程序提出的研究的具体目的是 （1）确定6p24基因座中哪些DNA变体有效地有助于CAD/MI的风险（2）确定作用 使用基因编辑的IPSC-EC在内皮功能中的PHACTR1和（3）确定PHACTR1在 鼠动脉粥样硬化使用基因敲除小鼠。成功应该导致新的因果基因的精确定义 以及它如何影响CAD/MI的发病机理，并为治疗提供了潜在的新目标 和预防CAD/MI。