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

描述(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，VVE必须了解导致缺血性心脏病的机制，以便设计更有效的治疗方法。这一奖项将扩展首席研究员(PI)的技能，并通过结合职业计划来补充他的知识库，与该领域的专家进行实验室轮换，从而发展他在心血管缺血-再灌注医学方面的学术生涯。该中心拥有心血管医学和介入心脏病学方面的高级研究和临床培训的博士/医学博士学位。在缺血再灌注损伤、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、心肌细胞生物学和钙处理领域的世界领先者Muthu Periasamy博士以及心肌缺血再灌注生物学和性别差异方面的世界领先者伊丽莎白·墨菲博士的指导下，PI将利用戴维斯心肺研究所(DHLRI)和俄亥俄州立大学生物医学光谱和成像中心提供的独特资源进行研究。NHLBI心脏保护疗法翻译工作组的报告强调了了解导致缺血性心脏病的机制的重要性，该报告认识到“知识中的根本空白仍然限制了心脏保护疗法从实验环境到临床环境的有效转换。”本研究项目将探讨肌膜三磷酸腺苷敏感钾通道在L缺血再灌注损伤易感性中的作用，特别是利用兹韦尔实验室和俄亥俄州立大学电子顺磁共振成像中心独有的生理、生化、分子和电子顺磁共振技术，具体检测对钙处理以及活性氧物种和活性氮物种生成的影响。本实验的具体目的是观察KATP通道敲除后所观察到的性二态现象：(1)SARC-KATP通道活性对心肌缺血再灌注损伤时体内ROS、RNS形成和组织氧合的影响；(2)SARC-KATP通道表达对体内外心肌缺血再灌注损伤后钙调节蛋白水平、活性和S硝化反应的影响。俄亥俄州立大学基于EPR的世界级成像技术的可获得性、导师和咨询委员会的杰出专业知识以及PI的资质为所述项目的成功提供了良好的氛围。本研究将对SARC-KATP通道影响心肌缺血再灌注损伤易感性的机制提供重要的认识。(摘要结束)

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)