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: 9263835
• 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/9263835
• 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; Chromosomes, Human, Pair 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; Human Genome; 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; Resources; Risk; Risk Factors; Role; Sampling; Scientist; Series; Serum; Stem cells; Techniques; Technology; TimeLine; Tissues; Training; Training Programs; United States National Institutes of Health; VWF gene; Validation; Variant; Woman; Work; base; career; career development; cell motility; chemokine; 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; success

 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)：本建议书描述了为Rajat Gupta博士提供的为期五年的学术心血管医学指导职业发展培训计划。古普塔博士是哈佛医学院的讲师，也是美国国立卫生研究院资助的布里格姆妇女医院(BWH)T32培训基金的前学员，也是Sarnoff研究员。他通过美国内科委员会完成了心血管内科和内科的临床培训。他现在正在布罗德研究所和BWH的Sekar Kathiresan博士和Kiran Musunuru博士的共同指导下开始一个研究和职业发展项目。这两位导师都是心血管遗传学领域的领导者，有着合作和指导的记录，并热衷于支持古普塔博士在功能基因组学和血管生物学方面的培训和独立性。古普塔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(彼得·利比博士、查尔斯·洛文斯坦博士和托马斯·米歇尔博士)作为咨询委员会成员的专业知识，以促进他作为一名接受过冠状动脉疾病遗传学培训的独立血管生物学研究员的发展。高级咨询委员会和这些领域的专家合作者将支持关于基因组编辑技术和动脉粥样硬化的组织病理学评估的实践培训。BWH心血管内科将提供额外的职业发展支持，PI将在那里担任主治医生，以及博德研究所心脏代谢小组。他制定了一个明确的时间表，用于出版他的工作、在全国会议上发表演讲以及发展独立研究项目和资金。古普塔博士致力于识别冠状动脉疾病和心肌梗死(CAD/MI)的非脂类遗传决定因素。他与一个国际合作者联盟合作，为识别50多个与CAD/MI相关的基因座做出了贡献，其中许多基因座对血管生物学有影响。古普塔博士已经确定6p24是用于功能分析的一个有趣的基因座，并发表了确定因果变异(Rs9349379)和因果基因-磷酸酶和肌动蛋白调节因子1(PHACTR1)的数据。PHACTR1在血管组织中表达，初步数据显示PHACTR1在内皮细胞功能中起重要作用。古普塔博士的主要目标是确定1)因果变异rs9349379对使用编辑的诱导多能干细胞进行基因表达的重要性，2)PHACTR1在动脉粥样硬化相关内皮细胞功能中的作用，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，古普塔博士将利用创新的方法，如诱导多能干细胞和原代血管细胞系的基因组编辑，内皮细胞迁移的共聚焦和活细胞显微镜，以及PHACTR1基因敲除小鼠动脉粥样硬化的体内组织病理学评估。展望未来，古普塔博士将利用这些技能，作为一名独立的、学术性质的内科科学家建立自己的职业生涯。