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.
Showing the most recent 10 out of 76 publications
