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：
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
项目类别：
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

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（由应用程序提供）：该提案描述了一项为期五年的培训计划，用于为Rajat Gupta博士提供学术心血管医学的指导职业发展。 Gupta博士是哈佛医学院的讲师，也是Brigham and妇女医院（BWH）的NIH赞助的T32培训补助金的先前培训人员和Sarnoff研究员。他通过美国内科委员会完成了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。 Broad Institute和BWH的Sekar Kathirens和Kiran Musunuru。两位导师都是心血管遗传学领域的领导者，具有协作和心态的记录，并热衷于支持Gupta博士在功能基因组学和血管生物学方面的培训和独立性。 Gupta博士的职业发展计划包括哈佛医学院，广泛研究所的教育资源，以及三位领先的血管生物学家（Peter Libby博士，Charles Lowenstein博士和Thomas Michel博士）的专业知识作为咨询委员会成员，以促进他作为一名独立的血管生物学研究人员的发展，并在培训遗传学的冠状动脉疾病中培训。基因组编辑技术和动脉粥样硬化的组织病理学评估的动手培训将得到这些领域的高级咨询委员会和专家合作者的支持。心血管医学的BWH部门提供了额外的职业发展支持，PI将在该部门作为医师和广泛的研究所心脏代谢组。他已经制定了一个明确的时间表来发表他的工作，在国家会议上的演讲以及独立研究项目和资金的发展。 Gupta博士致力于鉴定冠状动脉疾病和心肌梗塞（CAD/MI）的非脂质遗传决定剂。在国际合作者的联盟中，他为识别与CAD/MI相关的50多个基因座做出了贡献，其中许多对血管生物学产生了影响。 Gupta博士已将6P24识别为功能分析的有趣基因座，并发布了识别因果变体（RS9349379）和因果基因磷酸酶和肌动蛋白调节剂1（PHACTR1）的数据。 PHACTR1在血管组织中表达，初步数据在内皮细胞功能中表现出重要作用。 Gupta博士的主要目标是确定1）利用编辑诱导的多能干细胞的因果变体RS9349379的重要性，2）PhActr1在动脉粥样硬化 - 相关的内皮细胞功能中的作用，以及3）PHACTR1在动脉粥样硬化血管疾病中的作用。朝向这些目标，古普塔博士将利用创新方法，例如在诱导的多能干细胞中进行基因组编辑以及原发性血管细胞系，内皮细胞迁移的共聚焦和活细胞显微镜以及对PHACTR1敲除小鼠的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，并建立作为独立的学术物理科学家的职业。