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: 7907668
• 负责人: Richard J Gumina
• 金额: $ 12.02万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7907668
• 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，我们必须了解导致缺血性心脏病的机制，以便设计更有效的疗法。该奖项将通过将补充其知识库的职业计划与与该领域专家的实验室轮换相结合，扩大首席研究员（PI）的技能并发展他在心血管缺血再灌注医学领域的学术生涯。 PI 是博士/医学博士。拥有心血管医学和介入心脏病学方面的先进研究和临床培训。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 博士以及世界领导者 Elizabeth Murphy 博士指导在心肌缺血再灌注生物学和性别差异方面，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中心提供的独特资源进行研究光谱和成像中心。 NHLBI 保护心脏疗法转化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“知识方面仍然存在根本性差距，限制了心脏保护疗法从实验到有效转化”临床环境。”该研究计划将研究肌膜 ATP 敏感钾通道 (sarc-KATp) 在缺血再灌注 (L/R) 损伤易感性中的作用，特别检查对钙处理以及活性氧和活性氮生成的影响使用 Zweier 实验室和俄亥俄州立大学 EPR 成像中心独有的生理、生化、分子和 EPR 技术来识别物种。具体目的是检查 KATP 通道敲除所观察到的性别二态性：(1) 心肌缺血期间，sarc-KATP 通道活性对体内活性氧和氮物质（ROS、RNS）形成以及组织氧合的影响-再灌注损伤，以及(2)在体内和离体缺血再灌注损伤中，sarc-KATP通道表达对钙处理蛋白水平、活性和S-亚硝基化的影响。 OSU 提供世界一流的基于 EPR 的成像技术、导师和咨询委员会的杰出专业知识以及 PI 的资格为所述计划的成功提供了良好的氛围。这项研究将为对 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理解。 （摘要完）