Mechanisms of myocardial ischemia and reperfusion

描述(由申请人提供)： 最常见的心脏病形式是心肌缺血，其特征是由于冠状动脉阻塞，心脏的血液、基质和氧气供应不足。如果不治疗，就会以心肌梗死(心脏病发作)的形式造成不可逆转的损害。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，项目和核心之间的主要互动。所有项目都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核心，这是将项目捆绑在一起的粘合剂，并提供计划项目的协同特性。该计划项目的一个独特方面是使用大型哺乳动物模型，这是项目1和2的核心。项目1“心脏去神经对缺血保护的影响”涉及到在慢性器械清醒猪的第二个缺血保护窗口中心脏保护机制的研究。该项目在一定程度上是基于一项新的观察，即局部心脏去神经或肾上腺素能受体阻断取消了第二个保护窗口。项目2，“慢性晕厥心肌的分子机制”，与项目1的相似之处在于，它也使用了有意识的、慢性器质性的猪模型，但重点是该项目在上一个资助期开发的慢性、重复的晕厥模型。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，也显示了心肌保护，可能是通过第三个保护窗口。项目3“MST-1的细胞死亡促进机制”也涉及对细胞存活和细胞死亡的研究，特别强调MST-1分子，即哺乳动物不育激酶。该项目是基于当前资助期间的发现，即MST-1属于最近被发现的由心肌缺血激活的进化保守的蛋白激酶级联，具有意想不到的和多样化的功能，不仅限于促凋亡，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，重点研究了H11激酶激活的心脏保护机制。这个项目是基于在最初的资助期内完成的工作，在那里发现的涉及心肌顿抑和冬眠的新的分子机制之一是H11激酶，这是一种以前在心脏中没有研究过的分子，被发现对心肌缺血具有强大的保护作用。项目和核心之间的互动是项目项目方法的例证，它加强了每个单独的项目，旨在提高我们的理解，并为冠状动脉疾病患者描绘新的治疗方法。

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.