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肌细胞和生物体生死存亡的最重要因素，但有关新陈代谢控制的许多问题仍未得到解答。此外，缺血在底物供应和呼吸链水平上引起氧化代谢控制点的重构，并显著改变细胞内离子的稳态。所有这些因素都将显著影响心脏生物能量学，但每种因素在决定缺血后心脏恢复方面的相对重要性尚不清楚。线粒体也在对抗与缺血和再灌流相关的损伤中发挥核心作用，这一事实最近随着人们认识到预适应现象依赖于线粒体离子通道的激活而受到关注。需要一种综合的方法来了解许多由缺血引起的代谢缺陷如何有助于整个心脏的生物能量反应和急性缺血发作后的生存。该计划项目汇集了约翰·霍普金斯大学一个多学科研究团队的集体资产和经验，以详细了解线粒体在缺血性心脏病中的核心作用。以下主要问题将被解决：i)什么机制和细胞内因素控制线粒体氧化磷酸化对工作负荷变化的反应？Ii)线粒体的结构(在蛋白质组水平)和功能是如何因缺血和再灌流或预适应而改变的？Iii)线粒体能量失效的主要机制是什么？以及iv)什么是预适应的关键线粒体蛋白效应因子？该计划围绕一个暴露在全球缺血-再灌流中的常见兔子模型、Q预适应和一个强大的计算模型开发核心进行组织，该核心将允许在中央集成模拟环境中解释数据。目标包括确定阳离子(钙、钠和钾)从细胞质转移到线粒体的动力学如何影响生物能量学和力量产生(项目1)，检查线粒体内膜K+通道介导的心脏保护的分子效应(项目2)，确定缺血再灌注期间线粒体蛋白质组如何重塑(项目3)以及这种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合成酶及其调节蛋白伙伴的影响(项目3)。

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).