Mechanisms of myocardial ischemia and reperfusion

描述（由申请人提供）： 心脏病最常见的形式是心肌缺血，其特征在于由于冠状动脉阻塞导致心脏的血液、底物和氧气供应不足。如果不治疗，不可逆转的损害会以心肌梗死（心脏病发作）的形式出现。该计划项目申请的总体目标是确定对了解缺血性心脏病至关重要的机制，这将通过综合和基础科学家的综合方法来实现。有4个项目和5个核心，项目和核心之间存在重大互动。所有项目包括细胞和分子研究以及整体动物生理学。所有项目都使用所有的核心，核心是将项目结合在一起的粘合剂，并提供了计划项目的协同特性。该计划项目的一个独特之处是使用大型哺乳动物模型，这是项目1和2的核心。项目1，“心脏去神经支配对缺血保护的影响”，涉及在慢性仪器清醒猪的缺血保护的第二窗口中的心脏保护机制的研究。该项目部分基于新的观察结果，即区域心脏去神经支配或肾上腺素能受体阻滞剂废除了第二个保护窗口。项目2，“慢性击昏心肌细胞的分子机制”，与项目1相似，因为它也使用有意识的，慢性仪器化的猪模型，但重点是在上一个资助期在该项目中开发的慢性，重复性击昏模型。该模型概括了慢性冠状动脉疾病患者冬眠心肌的许多特征，并且还可能通过第三个保护窗口表现出心肌保护作用。项目3，“Mst 1的细胞死亡促进机制”，也涉及细胞存活和细胞死亡的研究，特别强调Mst 1分子，哺乳动物不育激酶。该项目基于当前资助期间的发现，即Mst 1属于最近鉴定的由心肌缺血激活的进化保守蛋白激酶级联，具有意想不到的和多样的功能，不仅限于促细胞凋亡，而且有助于心功能障碍。项目4，“H11激酶在心肌缺血中的生存作用”，是一个新的项目，重点是H11激酶引起的心脏保护机制。该项目基于最初资助期间完成的工作，其中发现的涉及心肌顿抑和冬眠的新分子机制之一是H11激酶，这是一种以前未在心脏中研究过的分子，并发现对心肌缺血提供强大的保护。项目和核心之间的相互作用体现了计划项目方法，它加强了每个单独的项目，旨在提高我们对冠状动脉疾病患者的理解并描绘新的治疗方法。

DESCRIPTION (provided by applicant): The most common form of heart disease is myocardial ischemia, which is characterized by an insufficient supply of blood, substrates and oxygen to the heart due to coronary artery obstruction. If not treated, irreversible damage ensues in the form of myocardial infarction (heart attack). The overall aim of this Program Project application is to identify mechanisms which are fundamental to the understanding of ischemic heart disease, which will be accomplished by utilizing a combined approach by integrative and basic scientists. There are 4 projects and 5 cores, with major interactions among projects and cores. All the projects include cellular and molecular studies as well as integrative whole animal physiology. All Projects use all the Cores, which is the glue that binds the Projects and provides the synergy characteristic of a Program Project. One unique aspect of this Program Project is the use of the large mammalian model, which is central to Projects 1 and 2. Project 1, "Effects of Cardiac Denervation on Ischemic Protection", involves the study of the mechanisms of cardiac protection in the second window of ischemic protection in chronically instrumented conscious swine. The project is based, in part, on the novel observation that either regional cardiac denervation or adrenergic receptor blockade abrogates the second window of protection. Project 2, "Molecular Mechanisms in Chronically Stunned Myocardium", parallels Project 1 in that it also uses the conscious, chronically instrumented swine model, but focuses on the chronic, repetitive stunning model developed in this project in the last funding period. This model recapitulates many of the features of hibernating myocardium in patients with chronic coronary artery disease, and also exhibits myocardial protection, potentially through a third window of protection. Project 3, "Cell Death Promoting Mechanisms of Mst 1", also involves the study of cell survival and cell death with special emphasis on the molecule Mst 1, mammalian sterile kinase. This project is based on findings during the current funding period that Mst 1, belonging to a recently identified evolutionary conserved protein kinase cascade activated by myocardial ischemia, has unexpected and diverse functions not limited to pro-apoptosis but which contributes to cardiac dysfunction. Project 4, "Survival Role of H11 Kinase during Myocardial Ischemia", is a new project which focuses on cardioprotection mechanisms invoked by H11 kinase. This project is based on work completed during the initial funding period, where one of the novel molecular mechanisms involved in myocardial stunning and hibernation discovered was H11 kinase, a molecule not previously studied in the heart, and found to afford powerful protection against myocardial ischemia. The Program Project approach is exemplified by the interactions among Projects and Cores, which strengthens each individual project and is designed to improve our understanding and delineate new therapies for patients with coronary artery disease.