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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

基本信息

批准号：
8123209
负责人：
Chun-An Chen
金额：
$ 11.28万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-14 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8123209
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 public health relevance research and development

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The objective of this proposed research is to understand the mechanism of reactive oxygen species contributing to coronary heart diseases. Coronary heart disease (CHD) remains the primary killer in the United States, and even though the mortality rate has declined, with the aging population and increased risk factors, the incidence of CHD will likely increase for the next decade. The ultimate goal of this proposed research is to develop new therapeutic strategies against these deadly diseases.

描述（由申请人提供）：该职业发展奖的目的是继续发展陈春安博士的学术生涯，他首先担任俄亥俄州立大学心肺研究所的博士后研究员，并接受额外的博士后培训，并过渡为心血管研究领域的独立研究员，专门研究 NOS 功能和氧化还原信号传导。氧自由基生成增加，可降低一氧化氮的生物利用度，被认为是缺血/再灌注损伤的主要发病机制。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的重要酶。越来越多的证据表明，氧化应激的增加会通过氧化翻译后修饰（例如 S-谷胱甘肽化、硝化或亚硝基化）改变多种酶的功能，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独立阶段之间架起一座桥梁。在独立阶段，陈博士的研究将集中在离体小鼠模型上，研究eNOS S-谷胱甘肽化对血管功能的影响，以及Grx1对缺血/再灌注损伤的作用。几个机制问题将得到解决，目标如下：目的3是研究eNOS Cys突变体对血管功能障碍期间血管功能和氧化修饰抵抗力的影响。目的4是在小鼠离体心脏模型中确定 Grx1 在缺血/再灌注损伤中的作用，特别是在蛋白质去谷胱甘肽化和 eNOS 功能的调节中。通过了解氧化还原调节酶 (Grx) 与 NO 产生之间的关系，这将为了解缺血/再灌注和氧化应激期间心血管功能改变所涉及的机制迈出关键一步。成功获得K99/R00奖将促进陈春安博士的职业研究发展，并使陈春安博士成为心血管研究领域的独立研究者。公共健康相关性：这项研究的目的是了解活性氧导致冠心病的机制。冠心病（CHD）仍然是美国的主要杀手，尽管死亡率有所下降，但随着人口老龄化和危险因素的增加，冠心病的发病率在未来十年可能会增加。这项研究的最终目标是开发针对这些致命疾病的新治疗策略。