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.

该提案描述了一个为期五年的学术职业发展培训计划 Rajat Gupta 医生的心血管医学。 Gupta 博士是哈佛医学院的讲师 布莱根妇女医院 (BWH) 的 NIH 赞助的 T32 培训补助金的实习生。他已经完成了 通过美国内科医学委员会进行心血管医学和内科临床培训。 他现在正在博士的共同指导下开展研究和职业发展计划。塞卡 布罗德研究所 (Broad Institute) 和 BWH 的 Kathiresan 和 Kiran Musunuru。两位导师都是该领域的领军人物 心血管遗传学，有合作和指导的记录，并且热衷于 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、布罗德医学院的教育资源 研究所，以及三位领先的血管生物学家（Peter Libby 博士、Charles Lowenstein 博士和 Thomas Michel 博士）作为顾问委员会成员，促进他作为独立血管学家的发展 接受过功能基因组学培训的生物学研究员。额外的职业发展支持由 布莱根妇女医院心血管医学科，首席研究员将在那里 资助期间担任主治医师。他制定了明确的出版时间表 他在同行评审期刊上的工作、在国家会议上的演讲以及发展计划 独立研究项目和资助。 Gupta 博士对发现冠状动脉疾病的新型非脂质决定因素感兴趣 心肌梗塞。他之前曾为全基因组关联研究（GWAS）做出过贡献，研究了 与 CAD/MI 相关的新基因座，现在重点关注 6p24 基因座上的一组变异。他的 初步数据表明至少一种单核苷酸多态性调节 附近的 PHACTR1 基因，以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-EC) 对内皮细胞迁移、粘附和冯维勒布兰德因子具有深远影响 表达。本申请中提出的研究将基于 Gupta 博士的初步数据来测试 假设 6p24 位点的 DNA 变异通过表达的变化影响 CAD/MI 的风险 PHACTR1 和改变的内皮功能。本申请中提出的研究的具体目标是 (1) 确定 6p24 位点中的哪些 DNA 变异会导致 CAD/MI 风险 (2) 确定作用 使用基因编辑的 iPSC-EC 检测 PHACTR1 对内皮功能的影响，以及 (3) 确定 PHACTR1 在 使用基因敲除小鼠进行小鼠动脉粥样硬化研究。成功应该导致新的因果基因的精确定义 及其如何影响 CAD/MI 的发病机制，并为治疗提供潜在的新靶点 和预防 CAD/MI。