Effect of sarcolemmal KATP channels on ROS/RNS generation and calcium handling

空间 但前提是。 心血管疾病是美国发病率和死亡率的主要原因。如上所述 VVE必须了解导致缺血性心脏病的机制，以便更多地 可以设计出有效的治疗方法。该奖项将扩大首席调查员(PI)的技能和 结合职业生涯规划发展他在心血管缺血再灌注医学领域的学术生涯 通过与该领域的专家进行实验室轮换来补充他的知识库。PI是一个博士/医学博士学位。 在心血管医学和介入心脏病学方面拥有先进的研究和临床培训。 由Jay Zweier博士指导，他是公认的缺血再灌注损伤的世界领先者，磁共振 和Muthu Periasamy博士，心肌细胞生物学和氧化生物学的世界领先者 和伊丽莎白·墨菲博士，心肌缺血-再灌注生物学和 性别差异，PI将使用Davis心脏和肺脏可用的独特资源进行研究 俄亥俄州立大学生物医学光谱和成像中心。 强调了了解导致缺血性心脏病的机制的重要性。 由NHLBI保护心脏疗法翻译工作组的报告 认识到“知识上的根本差距仍然限制了心脏保护的有效翻译” 从实验到临床环境的治疗。这项研究计划将调查 心肌细胞膜ATP敏感性钾通道与缺血再灌注敏感性(L/R) 损伤，具体检查对钙处理和活性氧物种产生的影响 和活性氮物种使用生理、生化、分子和EPR技术 在Zweier实验室和俄亥俄州立大学EPR成像中心独一无二地提供。具体的 目的是研究在KATP通道基因敲除中观察到的性别二型性：(1) SARC-KATP通道活性对体内活性氧和氮物种(ROS、RNS)形成的影响 以及(2)SARC-KATP对心肌缺血再灌注损伤的影响 钙处理蛋白水平、活性和S亚硝化在缺血反应中的通道表达 体内、外再灌流损伤。 俄亥俄州立大学基于EPR的世界级成像技术的可用性，以及 导师和咨询委员会，以及国际和平协会的资格为 在所描述的项目中取得成功。这项研究将通过以下方式提供对机制的批判性理解 哪些SARC-KATP通道影响心肌缺血再灌注损伤的易感性。

SPACE PROVIDED. Cardiovascular Disease is the leading cause of morbidity and mortality in the United States. As stated above it is imperative that vve understand the mechanisms responsible for ischemic heart disease so that more effective therapies can be designed. This award will expand the Principal investigator's (PI) skills and develop his academic career in Cardiovascular Ischemia-Reperfusion Medicine by combining a career plan to supplement his knowledge base with laboratory rotations with experts in the field. The PI is a Ph.D/M.D. with advanced research and clinical training in Cardiovascular Medicine and Interventional Cardiology. Mentored by Dr. Jay Zweier, a recognized world leader in ischemia-reperfusion injury, magnetic resonance imaging techniques and oxidative biology, and Dr. Muthu Periasamy, a world leader in myocyte biology and calcium handling, and Dr. Elizabeth Murphy, a world leader in myocardial ischemia-reperfusion biology and sex-differences, the PI will perform studies using the unique resources available within Davis Heart and Lung Research Institute (DHLRI) and The Ohio State University Biomedical Spectroscopy and Imaging Center. The importance of understanding the mechanisms responsible for ischemic heart disease was highlighted by the report of the NHLBI Working Group on the Translation of Therapies for Protecting the Heart which recognized that "fundamental gaps in knowledge remain that limit the effective translation of cardioprotective therapies from experimental to clinical settings." This research program will investigate the role of the sarcolemmal ATP-sensitive potassium channel (sarc-KATp) in susceptibility to ischemia-reperfusion (l/R) injury, examining specifically the effect on calcium handling and the generation of reactive oxygen species and reactive nitrogen species using physiological, biochemical, molecular and EPR techniques that are uniquely available within the Zweier lab and The Ohio State University EPR imaging center. The specific aims are to examine the sexual dimorphisms observed with KATP channel knockout with respect to : (1) The effect of sarc-KATP channel activity on in vivo formation of reactive oxygen and nitrogen species (ROS, RNS) and tissue oxygenation during myocardial ischemia-reperfusion injury, and (2) The effect of sarc-KATP channel expression on calcium handling protein levels, activity, and S-nitrosylation in response to ischemia- reperfusion injury in vivo and ex vivo. The availability of world-class EPR-based imaging technologies at The OSU, the outstanding expertise of the Mentor and Advisory Committee, and the qualifications ofthe PI provide an excellent atmosphere for success in the program described. This research will provide critical understanding ofthe mechanisms by which sarc-KATP channels influence the susceptibility to myocardial ischemia-reperfusion injury.