Redox Regulation of Endothelial Nitric Oxide Synthase and Cardiovascular Diseases

内皮一氧化氮合酶的氧化还原调节与心血管疾病

• 批准号: 8464354
• 负责人: Chun-An Chen
• 金额: $ 24.9万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-14 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464354
• 关键词: Address; Affect; Award; Biological Availability; Blood Vessels; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cells; Coronary heart disease; Cysteine; Development; Disease; Endothelium; Enzymes; Fostering; Functional disorder; Generations; Goals; Heart; Human; In Vitro; Incidence; Injury; Investigation; Ischemia; K-Series Research Career Programs; Laboratories; Lung; Measurement; Mentors; Modeling; Modification; Molecular; Mus; Nitric Oxide; Ohio; Oxidants; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Phase; Play; Post-Translational Protein Processing; Process; Production; Protein S; Proteins; Reactive Oxygen Species; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Research Institute; Research Personnel; Resistance; Risk Factors; Role; Secure; Signal Transduction; Signaling Molecule; Small Interfering RNA; Sulfhydryl Compounds; System; Techniques; Training; Transfection; Transgenic Mice; United States; Universities; aging population; career; free radical oxygen; genetic regulatory protein; glutaredoxin; human NOS3 protein; in vivo; mortality; mouse model; mutant; nitration; novel therapeutics; overexpression; oxidation; post-doctoral training; prevent; research and development

Project Summary: The objective of this career development award is to continue to develop the academic career of Dr. Chun-An Chen, first as a postdoctoral researcher at The Ohio State University Heart and Lung Research Institute, with additional postdoctoral training and transition to an independent investigator in the field of cardiovascular research specializing in NOS function and redox signaling. Increased oxygen free radical generation, which can reduce the bioavailability of nitric oxide, is believed to be the primary pathogenesis of ischemia/reperfusion injuries. In the endothelium, endothelial nitric oxide synthase (eNOS) is the important enzyme that produces this critical molecule maintaining the cardiovascular function. Growing evidence suggests that increased oxidative stress alters the function of several enzymes through oxidative post-translational modifications, such as S-glutathionylation, nitration, or nitrosylation, all of which have been implicated in signal transduction. During the mentored phase, several questions will be addressed in Aim1 and Aim2: Aim1 is to determine the detailed mechanism of eNOS S-glutathionylation and thiol oxidation, as it pertains to cardiovascular diseases. Aim2 is to determine the role of Grx1 in the deglutathionylation process, redox regulation, and NOS function. The results gained from the mentored phase training will provide a bridge between mentored phase and independent phase. During the independent phase, Dr. Chen's research will focus on ex vivo mouse models regarding the effect of eNOS S-glutathionylation on vascular function, and the role of Grx1 on ischemia/reperfusion injury. Several mechanistic questions will be addressed with the following aims: Aim3 is to study the effect of eNOS Cys mutants on vascular function and resistance to oxidative modification during vascular dysfunction. Aim4 is to identify the role of Grx1 in ischemia/reperfusion injury, especially in the regulation of protein deglutathionylation and eNOS function, in mouse ex vivo heart models. By understanding the relationship between a redox regulatory enzyme (Grx) and NO production, this will provide a critical step toward understanding the mechanisms involved in the alteration of cardiovascular function during ischemia/reperfusion and oxidative stress. Successfully securing this K99/R00 award will foster Dr. Chun-An Chen's career research development and enable Dr. Chun-An Chen to become an independent investigator in the field of cardiovascular research.

项目概要： 该职业发展奖的目的是继续发展淳安博士的学术生涯 陈首先在俄亥俄州立大学心肺研究所担任博士后研究员， 额外的博士后培训并过渡为心血管领域的独立研究者 专门从事NOS功能和氧化还原信号传导的研究。氧自由基的产生增加， 可以降低一氧化氮的生物利用度，被认为是缺血/再灌注的主要发病机制 受伤。在内皮细胞中，内皮一氧化氮合酶（eNOS）是产生 这种维持心血管功能的关键分子。越来越多的证据表明，增加 氧化应激通过氧化翻译后修饰改变多种酶的功能，例如 如 S-谷胱甘肽化、硝化或亚硝基化，所有这些都与信号转导有关。 在指导阶段，目标 1 和目标 2 中将解决几个问题： 目标 1 是确定 eNOS S-谷胱甘肽化和硫醇氧化的详细机制，因为它与心血管疾病有关。 目的2 是确定 Grx1 在去谷胱甘肽过程、氧化还原调节和 NOS 功能中的作用。 从指导阶段培训中获得的结果将在指导阶段和培训阶段之间架起一座桥梁。 独立相。在独立阶段，陈博士的研究将集中在离体小鼠模型上 关于 eNOS S-谷胱甘肽化对血管功能的影响，以及 Grx1 对血管功能的作用 缺血/再灌注损伤。几个机制问题将通过以下目标得到解决： 研究 eNOS Cys 突变体对血管功能和抗氧化修饰的影响 血管功能障碍。目的4是确定Grx1在缺血/再灌注损伤中的作用，特别是在 小鼠离体心脏模型中蛋白质去谷胱甘肽化和 eNOS 功能的调节。通过了解 氧化还原调节酶 (Grx) 和 NO 产生之间的关系，这将提供关键的一步 了解心血管功能改变的机制 缺血/再灌注和氧化应激。 成功获得 K99/R00 奖项将促进陈春安博士的职业研究发展和 使陈春安博士成为心血管研究领域的独立研究者。