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

肌膜 KATP 通道对 ROS/RNS 生成和钙处理的影响

• 批准号: 7739650
• 负责人: Richard J Gumina
• 金额: $ 11.87万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-04 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739650
• 关键词: ATP sensitive potassium channel complex; Advisory Committees; Affect; Animals; Award; Biochemical; Biology; Calcium; Cardiac; Cardiac Myocytes; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Clinical; Diastolic blood pressure; Doctor of Philosophy; Etiology; Female; Generations; Genes; Heart; Homeostasis; Human; Hyperbaric Oxygenation; Image; Imaging Techniques; Imaging technology; Injury; Investigational Therapies; Ischemia; Knock-out; Knowledge; Laboratories; Lung; Magnetic Resonance Imaging; Mediating; Mediator of activation protein; Medicine; Mentors; Metabolic; Methods; Modification; Molecular; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardial Ischemia; Myocardial dysfunction; Myocardial tissue; Myocardium; National Heart, Lung, and Blood Institute; Nitrogen; Ohio; Outcome; Oxidation-Reduction; Oxygen; Pathway interactions; Physiological; Post-Translational Protein Processing; Potassium; Predisposition; Principal Investigator; Proteins; Rattus; Reactive Nitrogen Species; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Reporting; Research; Research Institute; Research Personnel; Resources; Role; Rotation; Sex Characteristics; Signal Transduction; Spectrum Analysis; Techniques; Tissues; Training; Translations; United States; Universities; Work; abstracting; base; career; design; effective therapy; in vivo; insight; knowledge base; mortality; planetary Atmosphere; preconditioning; programs; response; response to injury; sex; sexual dimorphism; skills; success; tissue oxygenation; working group

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)

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，VVE必须了解导致缺血性心脏病的机制，以便可以设计更有效的疗法。该奖项将扩大主要研究者（PI）的技能，并通过结合一项职业计划，以将自己的知识库与实验室轮换与该领域的专家相结合，从而发展他在心血管缺血再灌注医学方面的学术生涯。 PI是Ph.D/M.D。通过心血管医学和介入心脏病学的高级研究和临床培训。 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戴维斯心脏和肺部研究所（DHLRI）以及俄亥俄州立大学的生物医学光谱和成像中心。 NHLBI工作组的报告强调了理解负责缺血性心脏病的机制的重要性。 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州立大学EPR成像中心。具体目的是检查以下方面使用KATP通道敲除观察到的性二态性：（1）SARC-KATP通道活性对在体内形成反应性氧和氮种（ROS，RNS）和组织氧气的体内形成的影响，并在心脏 - 心脏不良症状造成的症状效果和（2）效应的效应效应的效应效应和（2）效应的效应。 S-亚硝基化响应于体内和离体的缺血再灌注损伤。在OSU，导师和咨询委员会的杰出专业知识以及PI的资格上，基于世界一流的EPR成像技术的可用性为所描述的计划中的成功提供了极好的氛围。这项研究将提供对SARC-KATP通道影响心肌缺血 - 再灌注损伤的易感性的机制的批判性理解。 （抽象的结尾）