SIGNAL TRANSDUCTION IN MYOCARDIAL ISCHEMIC INJURY

描述：（申请人摘要的逐字逐句）本提案的目标 是为了阐明心肌细胞内的亚细胞信号通路 能迅速适应缺血性应激这种适应（称为缺血性 预处理（IP）发生在对短暂的非致死性事件的反应中， 心肌缺血，表现为梗死面积显著减小 由随后的致死性局部缺血发作引起。因此， 这种适应的基本机制将加强对 不可逆的肌细胞损伤，并可能导致新的和创新的临床 急性心肌梗死的治疗策略。最近的研究 提示蛋白激酶活化在缺血性适应中起重要作用 应力然而，到目前为止，对这些亚细胞信号的进一步分析 由于完整的动物模型的复杂性，该途径受到限制。在 为了简化对这些信号通路的分析，研究者 建立了成年犬离体心室肌缺血模型 肌细胞这项提议将检验心肌缺血 启动一个信号级联，通过激活一个序列， 蛋白激酶，结果在心脏保护通过稳定的 肌细胞骨架心肌细胞的信号传导通路 缺血到稳定的细胞骨架将被分成一系列 一系列事件。此外，特定的细胞骨架靶点稳定 蛋白激酶的活性将被评估。实验设计将 包括对分离病毒进行形态学、生物化学和药理学评价 心肌细胞遭受心肌缺血。

DESCRIPTION: (Verbatim from the Applicant's Abstract) The goal of this proposal is to elucidate the subcellular signaling pathways through which myocardium acutely adapts to ischemic stress. Such adaptation (termed ischemic preconditioning; IP) occurs in response to short, non-lethal episodes of myocardial ischemia and is manifest by a marked reduction in infarct size resulting from a subsequent lethal episode of ischemia. Thus, characterization of the underlying mechanisms of this adaptation will enhance understanding of irreversible myocyte injury and may lead to new and innovative clinical strategies in the therapy of acute myocardial infarction. Recent studies have implicated activation of protein kinases as important in adaptation to ischemic stress. However, to date, further analysis of these subcellular signaling pathways has been limited due to the complexity of intact animal models. In order to simplify analysis of these signaling pathways, the investigator has developed a model of in vitro ischemia in adult canine isolated ventricular myocytes. This proposal will test the hypothesis that myocardial ischemia initiates a signaling cascade which, working through activation of a sequence of protein kinases, results in cardioprotection through stabilization of the myocyte cytoskeleton. The proposed signaling pathways leading from myocardial ischemia to stabilization of the cytoskeleton will be dissected into a series of sequential events. In addition, the specific cytoskeletal targets stabilized by protein kinase activation will be evaluated. Experimental design will include morphologic, biochemical, and pharmacologic assessment of isolated myocytes subjected to myocardial ischemia.