Mechanisms of Myocardial Ischemia and Reperfusion

本计划项目申请的总体目标是确定对缺血性心脏病的进展及其进展为心力衰竭至关重要的生理、生化和分子机制。这一目标将通过综合科学家和基础科学家相结合的方法来实现。有四个项目和四个核心，项目和核心之间的主要互动。项目范围从细胞和分子研究(项目1-4)到整体动物生理学(项目1-4)。该计划项目的申请在很大程度上依赖于综合方法。即使是细胞/分子项目也与体内模型有很强的联系。项目1使用NOEL联合方法来确定顿抑心肌中基因和蛋白质的变化。虽然这一领域的大多数其他研究都使用啮齿动物模型，但该项目的一个独特之处是使用了大型哺乳动物模型。与细胞存活有关的基因组学，钙离子调节，肌瘤蛋白，以及以前未描述的基因将被检查。项目2代表了S.Vatner博士的实验室工作的继续，该实验室使用四种不同的冬眠心肌模型来了解大多数冬眠心肌生理模型中的血流和功能调节，以了解短期、慢性和真正冬眠的最生理模型中的血流和功能调节。第一组为短期冬眠模型，冠状动脉狭窄90分钟，再灌流4天。第二种是冬眠心肌模型，该模型将通过90分钟冠状动脉和12小时再灌流的重复顿抑来获得。第三种是另一种冬眠心肌模型，这种冬眠心肌是在猪的冠状动脉慢性无色素性收缩中诱导出来的。第四个模型是冬眠的土拨鼠的真正冬眠之一。与项目2相关，将使用核磁共振波谱研究心肌代谢的两个新方面，重点是一氧化氮在心肌缺血和再灌流过程中介导对代谢的潜在有益影响的作用。项目3旨在研究细胞和分子信号机制对细胞凋亡的影响。在项目3中，主要的动物模型是小鼠，尽管也将在猪身上进行研究。项目4是另一个项目，它也使用大型动物模型，类似于项目2，即猪，但专注于电生理功能异常和心律失常的细胞机制。这个项目还有几个新奇的特点。这些研究代表了第一个心肌顿抑模型，在分离的心肌细胞中进行了机械和电生理功能的平行实验。

The overall aim of this Program Project application is to identify physiological, biochemical and molecular mechanisms which are fundamental to the progression of ischemic heart disease and its progression to heart failure. This aim will be accomplished by utilizing a combined approach of integrative and basic scientists. There are four projects and four cores, with major interactions among projects and cores. The projects range from cellular and molecular studies (Projects 1-4) to integrative whole animal physiology (Projects 1-4). This Program Project application relies heavily on the integrative approach. Even the cellular/molecular projects have a strong link to in vivo models. Project 1 utilizes a combined noel approach to determining the alteration in genes and proteins in stunned myocardium. Whereas most other studies in this field employ rodent models, one unique feature of this project is the use of the large mammalian model. Genomics elated to cell survival, Ca2+ regulation, sarcomeric proteins, and previously undescribed genes will be examined. Project 2 represents a continuation of the work in Dr. S. Vatner's laboratory using four different models of hibernating myocardium to understand the regulation of blood flow and function in the most physiological models of hibernating myocardium to understand the regulation of blood flow and function in the most physiological models of short-term, chronic and true hibernation. The first is a model of short-term hibernation, 90-minute coronary stenosis with 4 days reperfusion. The second is a model of hibernating myocardium that will be derived from repetitive bouts of stunning using the model of 90- minute coronary and 12 hour reperfusion. The third involves another model of hibernating myocardium, which is induced in pigs with chronic ameroid constriction on a coronary artery. The fourth model is one of true hibernation in hibernating woodchucks. As related to Project 2, two novel aspects of myocardial metabolism will be investigated using NMR spectroscopy focusing on the role of nitric oxide in mediating a potential beneficial effect on metabolism during the effect of myocardial ischemia, and reperfusion. Project 3 is directed at examining cellular and molecular signaling mechanisms mediating apoptosis. In Project 3, the predominant animal models are murine, although studies in pigs will be carried out as well. Project 4 is another project that also uses large animal models, similar to Project 2, i.e., the pig, but concentrates on the cellular mechanisms of abnormalities in electrophysiological function and arrhythmias. There are several novel features of this projects as well. These studies represent the first model of myocardial stunning with parallel experiments of mechanical and electrophysiological function in isolated myocytes.