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

描述（由申请人提供）：心血管疾病是美国发病率和死亡率的主要原因。如上所述，我们必须了解缺血性心脏病的机制，以便设计出更有效的治疗方法。该奖项将扩大主要研究者（PI）的技能，并通过结合职业计划来发展他在心血管缺血再灌注医学方面的学术生涯，以补充他的知识基础，并与该领域的专家进行实验室轮换。PI为Ph.D/M.D.。在心血管医学和介入心脏病学方面具有先进的研究和临床培训。由缺血再灌注损伤、磁共振成像技术和氧化生物学领域公认的世界领导者Jay Zweier博士、肌细胞生物学和钙处理领域的世界领导者Muthu Periasamy博士和心肌缺血再灌注生物学和性别差异领域的世界领导者Elizabeth Murphy博士指导，PI将使用戴维斯心肺研究所（DHLRI）和俄亥俄州州立大学生物医学光谱和成像中心的独特资源进行研究。NHLBI保护心脏疗法转化工作组的报告强调了了解缺血性心脏病机制的重要性，该报告认识到“知识的根本差距仍然限制了心脏保护疗法从实验到临床的有效转化。“这项研究计划将研究肌膜ATP敏感性钾通道（sarc-KATp）对缺血-再灌注（I/R）损伤的易感性，使用生理，生化，Zweier实验室和俄亥俄州州立大学EPR成像中心独有的分子和EPR技术。具体目的是检查KATP通道敲除在以下方面观察到的性二态性：（1）sarc-KATP通道活性对体内活性氧和氮物质形成的影响（2）sarc-KATP通道表达对心肌缺血-再灌注损伤中钙处理蛋白水平，活性，和S-亚硝基化在体内和离体响应缺血-再灌注损伤中的作用。在OSU世界一流的EPR成像技术的可用性，导师和咨询委员会的杰出专业知识，以及PI的资格，为所描述的计划的成功提供了良好的氛围。本研究为深入了解sarc-KATP通道影响心肌缺血再灌注损伤易感性的机制提供了重要的理论依据。 (End摘要）

DESCRIPTION (provided by applicant): 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 of the 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. (End of Abstract)