This is an application for the continuation of highly interactive research by several established and productive investigators on physiological mechanisms and pathological deviations of cardiac bioenergetics. The theme of this Program Project is the identification of factors that govern tissue oxygen delivery and efficiency of ATP synthesis and utilization in the myocardium. This new application consists of seven interactive projects and one administrative core and is highly focused on molecular and structural studies of oxygen carriers and ATPases, while maintaining a strong clinical relevance. Overall, the investigation stresses a broad approach to the study of cardiac function from various levels of cell organization (isolated enzymes, enzyme hybrids, isolated membranes, intracellular organelles, isolated cells, perfused hearts, hearts in situ in both animal models and humans) and emphasizes the application of new technologies, experimental approaches, and technical developments. The factors that govern oxygen delivery in myocardia will be carried out at all three levels of cellular organization. Structure-function correlations will be investigated at the molecular and atomic level in both myoglobin and myoglobin mutants as myoglobin is a major oxygen carrier and diffusion facilitator in heart. Factors affecting oxygen distribution in normal and ischemic hearts will be studied with the hypothesis that signals derived from ATP depletion cause metabolic heterogeneity in the myocardium. Regulation of metabolic pathways in the myocardium will also be investigated in normal and ischemic hearts with the working hypothesis that intramitochondrial Ca2+ controls substrate choice of the myocyte. The efficiency of ATP utilization will also be studied at multiple levels. ATP utilization by the Ca2+ ATPase, a newly discovered Mg2+ ATPase and a novel ATP receptor will be studied by structural, molecular and kinetic approaches. Mg2+ transport and its hormonal regulation in heart will be studied with the long view of understanding its effects on the overall cardiac bioenergetics. Finally, NMR studies are proposed to give valuable biochemical information on hypoxic and hypertrophic hearts using large animal models and human patients. These studies are essential as cell and animal models do not always perfectly correlate with the diversity and genetic variability of human disease. It is anticipated that the important fundamental questions, the favorable confluence of techniques, the studies at the atomic, molecular, cellular and organ levels, and the established interactions among the various investigators will continue to produce rapid progress toward the overall understanding of cardiac bioenergetics during the next interval of support.
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