MITOCHONDRIAL FUNCTION IN ISCHEMIC HEART DISEASE

描述（由申请人提供）： 虽然心血管疾病的病因多种多样，但可以说，能源供需不匹配是一个普遍特征。线粒体功能的保存是决定心脏细胞和生物体存活或死亡的最重要因素，但关于代谢控制的许多问题仍然没有答案。此外，缺血导致在底物供应和呼吸链水平的氧化代谢的控制点的重塑，并显着改变细胞内离子稳态。所有这些因素都将显著影响心脏生物能量学，但每个因素在确定缺血后心脏恢复方面的相对重要性尚不清楚。线粒体在抵抗与缺血和再灌注相关的损伤中也起着核心作用，这一事实最近随着认识到预处理现象依赖于线粒体离子通道的激活而成为焦点。需要一个综合的方法来了解许多缺血诱导的代谢缺陷如何有助于全心脏的生物能量反应和急性缺血发作后的生存。这个计划项目收集了约翰霍普金斯大学多学科研究小组的集体资产和经验，以详细了解线粒体在缺血性心脏病中的核心作用。以下主要问题将得到解决：i）什么机制和细胞内因素控制线粒体氧化磷酸化的反应，以改变工作量？ii）缺血和再灌注或预处理如何重塑线粒体的结构（在蛋白质组水平）和功能？（3）线粒体能量衰竭的主要机制是什么？和iv）预处理的关键线粒体蛋白效应物是什么？该计划是围绕一个共同的兔模型暴露于全球缺血再灌注，q预处理，和一个强大的计算模型开发核心，将允许数据在一个中央集成的模拟环境中进行解释。目标包括确定阳离子动力学如何（Ca2+、Na+和K+）从细胞质转移到线粒体影响生物能量学和力的产生（项目1），研究线粒体内膜K+通道介导的心脏保护的分子效应（项目2），定义缺血再灌注期间线粒体蛋白质组如何重塑（项目3）以及这些变化如何影响线粒体氧化磷酸化的控制（项目1、3和4），以及研究缺血和再灌注对线粒体ATP合酶及其调节蛋白伴侣的影响（项目3、4）。

DESCRIPTION (provided by applicant): While there are various etiologies of cardiovascular disease, it can be argued that a mismatch of energy supply and demand is a universal feature. Preservation of mitochondrial function is the single most important factor in determining whether a cardiac cell, and the organism, lives or dies, yet many questions about the control of metabolism remain unanswered. Moreover, ischemia causes remodeling of the control points of oxidative metabolism at the level of both substrate supply and the respiratory chain, and markedly alters intracellular ion homeostasis. All of these factors will significantly affect cardiac bioenergetics, but the relative importance of each in determining the recovery of the postischemic heart is unknown. Mitochondria also play a central role in counteracting the injury associated with ischemia and reperfusion, a fact that has recently been brought into sharp focus with the recognition that the phenomenon of preconditioning depends upon the activation of mitochondrial ion channels. An integrative approach is required to understand how the many ischemia-induced defects in metabolism contribute to the bioenergetic response of the wholeheart and survival after an acute ischemic attack. This Program Project garners the collective assets and experience of a multidisciplinary team of investigators at Johns Hopkins University to gain a detailed understanding of the central role of mitochondria in ischemic heart disease. The following major questions will be addressed: i ) what mechanisms and intracellular factors control the response of mitochondrial oxidative phosphorylation to changes in workload? ii) how is the structure (at the level of the proteome) and function of the mitochondria remodeled by ischemia and reperfusion, or preconditioning? iii) what are the principal mechanisms responsible for mitochondrial energetic failure? and iv) what are the key mitochondrial protein effectors of preconditioning? The Program is organized around a common rabbit model exposed to global ischemia-reperfusion, q preconditioning, and a strong computational model development core that will allow data to be interpreted within a central integrated simulation environment. The objectives include determining how the dynamics of cation (Ca2+, Na+, and K+) transfer from the cytoplasm to the mitochondria influence bioenergetics and force production (Project 1), examining the molecular effectors of cardioprotection mediated by mitochondrial inner membrane K+ channels (Project 2), defining how the mitochondrial proteome remodels during ischemia-reperfusion (Project 3) and how such changes influence the control of mitochondrial oxidative phosphorylation (Projects 1,3, and 4), and an investigation of the effects of ischemia and reperfusion on the mitochondrial ATP synthase and its regulatory protein partners (Projects 3,4).