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

空间 提供了 心血管疾病是美国发病率和死亡率的主要原因。如上所述 必须了解缺血性心脏病的机制， 可以设计有效的治疗方法。该奖项将扩大首席研究员（PI）的技能， 通过结合职业规划，发展他在心血管缺血再灌注医学方面的学术生涯。 通过与该领域专家的实验室轮换来补充他的知识基础。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。 在缺血再灌注损伤领域公认的世界领导者Jay Zweier博士的指导下， 成像技术和氧化生物学，以及Muthu Periasamy博士，他是肌细胞生物学和 钙处理，伊丽莎白墨菲博士，心肌缺血再灌注生物学的世界领导者， 性别差异，PI将使用Davis Heart and Lung内可用的独特资源进行研究 研究所（DHLRI）和俄亥俄州州立大学生物医学光谱和成像中心。 强调了了解缺血性心脏病机制的重要性 NHLBI保护心脏疗法翻译工作组的报告， 认识到“知识的根本差距仍然限制了心脏保护的有效转化， 从实验到临床。“这项研究计划将调查的作用， 肌膜ATP敏感性钾通道（sarc-KATp）与缺血再灌注（I/R）易感性 损伤，特别是检查对钙处理和活性氧产生的影响 和活性氮物种的生理，生物化学，分子和EPR技术， 在Zweier实验室和俄亥俄州州立大学EPR成像中心内是唯一可用的。具体 目的是检查在KATP通道敲除的情况下观察到的性二态性：（1） sarc-KATP通道活性对体内活性氧和氮类（ROS，RNS）形成影响 （2）sarc-KATP在心肌缺血再灌注损伤中的作用 通道表达对钙处理蛋白水平、活性和S-亚硝基化的影响， 体内和离体再灌注损伤。 OSU拥有世界一流的基于EPR的成像技术， 导师和咨询委员会，以及PI的资格提供了一个良好的氛围， 在节目中所描述的成功。这项研究将提供关键的理解机制， 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.