Redox Regulation of Endothelial Nitric Oxide Synthase and Cardiovascular Diseases

项目总结： 这个职业发展奖的目的是为了继续发展春安博士的学术生涯 陈，最初是俄亥俄州立大学心肺研究所的博士后研究员， 额外的博士后培训和向心血管领域的独立研究员过渡 专门研究一氧化氮合酶功能和氧化还原信号。增加氧自由基的产生，这 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，内皮型一氧化氮合酶(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， 氧化应激通过氧化翻译后修饰改变几种酶的功能，如 如S-谷胱甘肽化、硝化或亚硝化，所有这些都与信号转导有关。 在指导阶段，Aim1和AIM2将解决几个问题：Aim1将确定 内皮型一氧化氮合酶的详细机制S-谷胱甘肽和硫醇氧化，因为它与心血管疾病有关。 AIM2的目的是确定Grx1在谷胱甘肽化过程、氧化还原调节和NOS功能中的作用。 指导阶段培训的结果将在指导阶段和指导阶段之间架起一座桥梁 独立阶段。在独立阶段，陈博士的研究将集中在体外小鼠模型上 关于eNOS S谷胱甘肽基化对血管功能的影响及Grx1对血管功能的影响 缺血/再灌注损伤。将解决几个机械问题，目标如下：AIM3是 内皮型一氧化氮合酶半胱氨酸突变体对大鼠血管功能及抗氧化能力的影响 血管功能障碍。目的探讨Grx1在脑缺血再灌注损伤中的作用，特别是在心肌缺血再灌注损伤中的作用。 小鼠体外心脏模型中蛋白质去谷胱甘肽和eNOS功能的调节。通过理解 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 对心血管功能改变机制的认识 缺血/再灌流和氧化应激。 成功获得K99/R00奖将促进陈俊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员。

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.