CORE--COMPUTATIONAL/BIOINFORMATIC

这项研究旨在研究线粒体能量学和综合心脏功能是如何 从分子水平到蛋白质组，再到对完整肌肉兴奋-收缩(EC)偶联和耗氧量的整体影响，缺血和再灌流对其进行了全面的重塑。然而，由于氧化磷酸化机制中以及线粒体、肌膜和细胞质之间复杂的控制相互作用，很难形成一个特定的实验发现如何影响心肌细胞整体功能的完整的心理图景。为了帮助应对这一挑战， 计算/生物信息学将开发包含线粒体生物物理详细描述的心肌细胞的综合计算模型 能量学，它将被用来解释这个项目中正在进行的一系列实验的结果。我们的团队率先开发了电生理学和钙处理特性、离子传输过程和线粒体能量学的详细模型，现在我们正在将其集成到全面的虚拟心肌细胞模型中。重点是使用这些模型作为解释实验结果的工具，并建议新的实验，以揭示在正常或病理生理条件下控制心肌细胞功能的基本性质。我们将把领导人现有的合作重点放在线粒体问题上 用普通实验动物模型和普通动物模型研究缺血后心脏功能障碍 定量数学/计算模型。它还将促进不同学科的专家之间的新的协作互动。除了开发和利用计算模型外，我们还将在代谢控制分析的定量方法方面提供专业知识和支持，以确定缺血后心脏氧化磷酸化的关键控制因素。

This is designed to investigate how mitochondrial energetics and integrated cardiac function are remodeled by ischemia and reperfusion in a comprehensive manner, spanning from the molecular level, to the proteome, to global effects on excitation-contraction (EC) coupling and oxygen consumption in intact muscle. However, as a result of complex control interactions within the machinery of oxidative phosphorylation and between mitochondria, the sarcolemma and the cytoplasm, it is difficult to form a complete mental picture of how a particular experimental finding impacts myocyte function as a whole. To help address this challenge, the COMPUTATIONAL/BIOINFORMATICS will develop integrative computational models of the cardiac ventricular myocyte incorporating biophysically detailed descriptions of mitochondrial energetics, which will be used to interpret results from the range of experiments being pursued in this project. Our team has pioneered the development of detailed models of the electrophysiology and Ca2+ handling properties, ion transport processes and mitochondrial energetics, which we are now integrating into comprehensive virtual cardiac ventricular myocyte models. The emphasis has been on using these models as tools for the interpretation of experimental results and for suggesting new experiments that can reveal the fundamental nature of the control of myocyte function under normal or pathophysiological conditions. We will focus the existing collaboration of the leaders on the problem of mitochondrial dysfunction in the post-ischemic heart using a common experimental animal model and a common quantitative mathematical/computational model. It will also foster new collaborative interactions between experts in diverse disciplines. In addition to developing and exploiting the computational model, we will provide expertise and support in the quantitative methodology of metabolic control analysis, for identifying the key controlling factors in oxidative phosphorylation in the post-ischemic heart.