Mechanisms of Myocardial Ischemia and Reperfusion

本项目申请的总体目标是确定缺血性心脏病进展及其进展为心力衰竭的基本生理、生化和分子机制。这一目标将通过综合和基础科学家的联合方法来实现。有四个项目和四个核心，项目和核心之间有很大的互动。项目范围从细胞和分子研究（项目1-4）到综合整体动物生理学（项目1-4）。这个项目的应用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利用一种结合的新方法来确定休克心肌中基因和蛋白质的改变。尽管该领域的大多数其他研究都采用啮齿动物模型，但本项目的一个独特之处在于使用了大型哺乳动物模型。基因组学相关的细胞存活，Ca2+调节，肉瘤蛋白，和以前未描述的基因将被检查。项目2代表了S. Vatner博士实验室工作的延续，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调节和功能，以了解短期、慢性和真正冬眠的大多数生理模型中的血流调节和功能。第一种是短期冬眠模型，90分钟冠脉狭窄，4天再灌注。第二种是利用90分钟冠状动脉再灌注12小时模型，通过反复电击获得冬眠心肌模型。第三种涉及另一种冬眠心肌模型，该模型是在冠状动脉慢性ameroid收缩的猪中诱导的。第四种模式是冬眠土拨鼠的真正冬眠模式。与项目2相关，我们将利用核磁共振波谱研究心肌代谢的两个新方面，重点研究一氧化氮在心肌缺血和再灌注过程中介导代谢的潜在有益作用。项目3旨在研究介导细胞凋亡的细胞和分子信号机制。在项目3中，主要的动物模型是小鼠，尽管猪的研究也将进行。项目4是另一个同样使用大型动物模型的项目，与项目2类似，即猪，但侧重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颖的特点。这些研究代表了心肌休克的第一个模型，并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.