The overall goal of this proposed theoretical study is to develop cardiac tissue computer modeling tools to be used for the following applications: (1) analysis of steady-state data on myoglobin saturation and oxygen distribution in isolated perfused hearts; (2) analysis of transient data on energetics metabolism and oxygen transport in cardiac tissue; and (3) design and analysis of experiments for probing signaling and control mechanisms linking metabolic and transport processes. The proposed project takes a step toward a (more) complete multi-scale description of molecular, cellular, and tissue function by focusing on the coupling between substrate transport and cellular energetics in cardiac muscle tissue. The tools that we develop will integrate state-of-the-art knowledge of the relevant pathways of metabolism and energy transduction in working cardiomyocytes, oxygen transport in cardiac muscle tissue, and microvascular blood flow in coronary capillary networks. Spectrographic measurements of myoglobin saturation in isolated perfused guinea pig hearts have prompted us to develop a transport model for oxygen in cardiac tissue to be used to analyze and interpret the experimental findings. With this model, we are beginning to make quantitative sense of the data from the isolated hearts. Next, we aim to extend this model to link to a model of distributed energy transduction. This integrated model will allow us to investigate more complex phenomena, including transient data on oxygen uptake and 31P-NMR data on cardiac energetics. Further applications of the proposed integrated model include profiling physiological responses to several challenges, such as (1) exercise; (2) ischemia; and (3) myoglobin and adenylate kinase gene deletions.
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