Anti-apoptotic mechanisms of estrogen in cardiomyocytes

雌激素抗心肌细胞凋亡机制

基本信息

批准号：
7293704
负责人：
Jin Kyung Kim
金额：
$ 12.18万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-25 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7293704
关键词：
Advisory Committees Affect Agonist American Antioxidants Apoptosis Apoptotic California Cardiac Cardiac Myocytes Cardiology Cardiovascular system Cell Culture System Cells Cessation of life Complex Coronary artery Data Development Plans Doctor of Philosophy Echocardiography Electron Transport Estradiol Estrogen Receptors Estrogens Event Exposure to Faculty Fellowship Funding Gene Activation Gene Targeting Generations Goals Heart failure Hypoxia Immunoblotting Immunohistochemistry In Situ In Vitro Injury Internal Medicine Ischemia Knockout Mice Left Ventricular Function Ligands Ligation MAPK14 gene Mediating Mediator of activation protein Medical Medicine Mentors Mitochondria Mus Myocardial Ischemia Oxidative Stress Pathway interactions Phosphotransferases Physicians Physiological reperfusion Placebos Prevention Preventive Process Protein Isoforms Protein p53 Proteins Puma Rattus Reactive Oxygen Species Regulation Reperfusion Therapy Research Research Personnel Research Project Grants Research Proposals Role Scientist Signal Transduction Simulate Stress System TP53 gene Testing Therapeutic Training Transactivation Transgenic Mice Translating Universities Work abstracting career cytochrome c in vitro Model in vivo in vivo Model member prevent programs research and development research study simulation

项目摘要

DESCRIPTION (provided by applicant): This application outlines research and career development plans for Jin Kyung Kim, whose long-term objective is to become an independent physician-scientist in cardiovascular research. She is a graduate of an NIH-funded M.D.-Ph.D. Program and has received rigorous training in internal medicine and cardiology. She is currently conducting research as part of her subspecialty fellowship under the auspice of the American Board of Internal Medicine Research Pathway. Her immediate goal includes successful completion of the ongoing research project and preparing for a career in academic cardiology and research. Her mentor, Dr. Ellis R. Levin, is Vice Chair of Medicine at the University of California, Irvine, and an established medical scientist in the field of cardiovascular research. An advisory committee of senior faculty members will provide additional guidance on the applicant's career and scientific progress. Dr. Kim has full institutional support for her proposed career development and research plan. The overall goal of the research proposal is to study the protective role of estrogen in cardiomyocytes. Initial work by the applicant revealed that estrogen-mediated survival of cardiomyocytes exposed to simulated ischemia-reperfusion.(l/R) depends on regulation of p38 alpha and p38 beta. The two kinase isoforms possess opposing functions in the cell fate (p38 alpha being pro-apoptotic and p38 beta pro-survival), but little is known about how the two modulate the apoptotic signaling. An attractive downstream target of the kinase is p53, a well-known mediator of apoptosis. The proposed experiments will test the hypothesis that the cytoprotective actions of estrogen involve regulation of p53 via p38. The specific aims are: (1) to study the effect of ligand-activated estrogen receptors on p53 in cardiomyocyte apoptosis, (2) to characterize the relationship between p38 alpha, p38 beta, and p53, (3) to examine how estrogen signaling to p53 via p38 impact the intrinsic mitochondrial death pathway. In addition to cultured rat cardiomyocytes for the in-vitro analysis of apoptosis and the relevant proteins, coronary artery ligation/release in ovariectomized mice with or without estrogen supplement will serve as an in-vivo model of I/R to correlate the in-vitro data. Findings from this research will further our understanding of how estrogen protects stressed heart muscle cells, and promote potential preventive and therapeutic options in ischemic heart disease. (End of Abstract)

描述（由申请人提供）：本申请概述了 Jin Kyung Kim 的研究和职业发展计划，其长期目标是成为心血管研究领域的独立医师科学家。她是 NIH 资助的医学博士毕业生。计划并接受过严格的内科和心脏病学培训。她目前正在美国内科研究途径委员会的支持下进行研究，作为其亚专业奖学金的一部分。她的近期目标包括成功完成正在进行的研究项目，并为学术心脏病学和研究领域的职业生涯做好准备。她的导师 Ellis R. Levin 博士是加州大学欧文分校医学系副主席，也是心血管研究领域的知名医学科学家。由高级教职人员组成的咨询委员会将为申请人的职业和科学进步提供额外的指导。金博士提出的职业发展和研究计划得到了机构的全力支持。该研究提案的总体目标是研究雌激素对心肌细胞的保护作用。申请人的初步工作揭示了雌激素介导的暴露于模拟缺血再灌注的心肌细胞的存活。(l/R)取决于p38α和p38β的调节。这两种激酶亚型在细胞命运中具有相反的功能（p38 α 促凋亡，p38 β 促存活），但人们对两者如何调节凋亡信号传导知之甚少。该激酶的一个有吸引力的下游靶标是 p53，它是一种众所周知的细胞凋亡介质。拟议的实验将检验雌激素的细胞保护作用涉及通过 p38 调节 p53 的假设。具体目标是：(1) 研究配体激活的雌激素受体对心肌细胞凋亡中 p53 的影响，(2) 表征 p38 α、p38 β 和 p53 之间的关系，(3) 检查雌激素信号传导如何影响心肌细胞凋亡。 p53 通过 p38 影响内在的线粒体死亡途径。除了用于体外分析细胞凋亡和相关蛋白的培养大鼠心肌细胞外，补充或不补充雌激素的卵巢切除小鼠的冠状动脉结扎/释放将作为 I/R 的体内模型，以将体外模型与体外模型相关联。数据。这项研究的结果将进一步了解雌激素如何保护应激的心肌细胞，并促进缺血性心脏病的潜在预防和治疗选择。（摘要完）