ANESTHETIC-INDUCED CARDIAC PRECONDITIONING

本项目的研究建议将描述挥发性麻醉药在体内对缺血和再灌注损伤的心脏保护作用的机制，并将直接阐明体外调节的特定信号转导途径的机制。我们相信，对于心肌缺血及其对麻醉药反应这一复杂的临床相关问题，最有效的方法是在多个层面上整合我们的研究。我们提出了一个由三个相互关联的研究项目组成的计划项目，该项目由一个专注于基本机制的核心设施提供支持 负责挥发性麻醉诱导的预处理（APC）的心脏保护作用。这种综合方法不仅将汇集一个多方面的研究人员，包括心脏电生理学家和分子生物学家，但也将利用心血管研究中心，生物物理研究所和药理学，生理学，生物化学和麻醉学在威斯康星州医学院的部门之间的互动的独特优势。 项目一麻醉诱导的体内预处理。该项目将描述负责挥发性麻醉剂对缺血和再灌注损伤的新的心脏保护作用的机制，并将提供初步证据，参与特定的信号转导途径调节APC。项目总监：大卫C. Warltier，医学博士，博士 项目二.麻醉诱导预适应中的心脏K、T通道这 本课题将研究APC对心室肌细胞中天然肌膜和线粒体KATp通道、表达的重组KATp通道和脂质双层中的通道对核苷酸和钾通道开放剂和阻断剂的反应的影响。项目负责人：Zeljko J. Bosnjak博士 项目三.麻醉诱导预处理的心脏电生理学。 这个项目将描述心律失常和离子机制的基础挥发性 麻醉剂对心脏电生理学的作用，包括主要的电压门控离子通道类型（快Na通道、L型Ca通道和瞬时外向K通道），其最终可能直接或间接参与APC。项目总监：郭伟明博士 生物化学和分子生物学核心。生化与分子生物学核心 本计划的项目将提供一个高度专业化的专业人员团队，能够在设备齐全的设施中组织各种测定，以支持项目I，II和III中开发的假设的调查。导演：Meetha Medhora博士还有大卫·哈德博士

Research proposals developed in this Program Prqject will characterize the mechanisms responsible for the cardioprotective effects of volatile anesthetics against ischemia and reperfusion iniury in vivo, and will directly elucidate mechanisms regarding the specific signal transduction pathways modulated in vitro. It is our belief that the most effective approach to the complex and clinically relevant issue of myocardial ischemia and its response to anesthetics is to integrate our studies at multiple levels. We propose a Program Project consisting of three interrelated research projects supported by a Core facility focused on fundamental mechanisms responsible for the cardioprotective effects of volatile anesthetic-induced preconditioning (APC). This integrative approach will not only bring together a multi-talented group of investigators including cardiac electrophysiologists and molecular biologists, but also will capitalize on the unique advantage of interactions amongst the Cardiovascular Research Center, Biophysics Research Institute and the Departments of Pharmacology, Physiology, Biochemistry and Anesthesiology at the Medical College of Wisconsin. Project I. ANESTHETIC-INDUCED PRECONDITIONING IN VIVO. This project will delineate mechanisms responsible for the novel cardioprotective effects of volatile anesthetics against ischemia and reperfusion injury in vivo and will provide initial evidence for the involvement of specific signal transduction pathways modulating APC. Project Director: David C. Warltier, M.D., Ph.D. Project II. CARDIAC K,T, CHANNELS IN ANESTHETIC-INDUCED PRECONDITIONING. This prqject will investigate the effects of APC on the response of native sarcolemmal and mitochondfial KATp channels in cardiac ventricular myocytes, expressed recombinant KATp channels and channels in a lipid bilayer to nucleotides and potassium channel openers and blockers. Project Director: Zeljko J. Bosnjak, Ph.D. Project III. CARDIAC ELECTROPHYSIOLOGY IN ANESTHETIC-INDUCED PRECONDITIONING. This project will characterize arrhythmias and the ionic mechanisms underlying volatile anesthetic action on cardiac electrophysiology including major voltage-gated ion channel types (fast Na channel, L-type Ca channel, and transient outward K channel) that may ultimately be directly or indirectly involved in APC. Project Director: Wai-Meng Kwok, Ph.D. BIOCHEMICAL AND MOLECULAR BIOLOGY CORE. The Biochemical and Molecular Biology Core of this Program Prqiect will provide a highly specialized team of professional staff, capable of organizing a variety of assays in a well equipped facility to support investigation of hypotheses developed in Projects I, II and III. Core Directors: Meetha Medhora. Ph.D. and David Harder. Ph.D.