ANESTHETIC-INDUCED CARDIAC PRECONDITIONING

本计划中提出的研究建议将在体内表征挥发性麻醉药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控的特定信号转导途径的机制。我们认为，对于复杂且临床相关的心肌缺血及其对麻醉药的反应，最有效的方法是整合我们在多个水平上的研究。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 负责挥发性麻醉剂诱导的预适应(APC)的心脏保护作用。这一综合方法不仅将汇集包括心脏电生理学家和分子生物学家在内的多方面的研究人员，还将利用心血管研究中心、生物物理研究所和威斯康星医学院药理学、生理学、生物化学和麻醉学系之间互动的独特优势。 项目I.麻醉剂诱导的体内预适应。本项目将阐明挥发性麻醉剂在体内对缺血再灌注损伤具有新的心脏保护作用的机制，并将为参与调节APC的特定信号转导通路提供初步证据。项目主管：David C.Warltier，医学博士 项目II：麻醉诱导预适应中的心脏K，T通道。这 本课题将研究APC对心肌细胞天然肌膜和线粒体KATP通道、表达的重组KATP通道和脂质双层通道对核苷酸和钾通道开放剂和阻断剂的反应的影响。项目主管：Zeljko J.Bosnjak博士 项目III：麻醉诱导预适应中的心脏电生理学。 这个项目将描述心律失常和挥发性心律失常的离子机制。 麻醉对心脏电生理的作用包括可能直接或间接参与APC的主要电压门控离子通道类型(快钠通道、L型钙通道和瞬时外向钾通道)。项目总监：郭伟明博士。 生物化学和分子生物学核心。生物化学和分子生物学的核心 在这项计划中，Prcheect将提供一支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分析，以支持对项目I、II和III中开发的假设的调查。核心主任：Meetha Medhora。博士和大卫·哈德。博士学位。

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.