The present application is for renewal of 20 prior years of support so that novel concepts and unique experimental designs can be ap[plied to the understanding of fundamental mechanisms of bioenergetics of the normal and diseased myocardium. The theme of this Program Project continues to be the identification of factors that govern the efficiency of ATP synthesis and utilization in the myocardium. The rationale is to provide fundamental cellular or molecular concepts which are at the core of understanding the development and prevention of myocardial insufficiency or failure. Myocardial failure is the major cause of death in the U.S. and is usually the end result of one or several of the following condition: insufficient chemical energy supply (ischemic heart), imbalance between ATP production and utilization (hypertrophic heart) or derangement of ion gradients (arrhythmia). The focus of this application is to understand, at a molecular level, the links between ATP production, ATP utilization and ATPases and ionic gradients in the myocardium. While the interconversion between chemical and ion gradient """"""""energy"""""""" is common to all cells, in myocardial cells it is far more tightly coupled, thus imbalances between energy supply and demand are unforgiving. With major reorganization and the addition of two new Projects, this application is now far more focused than before and consists of components. The components, titles and subtitles are: Control of cardiac ATP synthase: Understanding the efficiency of ATP formation. Cellular Mg++ homeostasis in myocardium: A new look at modulation of ATPases, kinases and metabolism. Thyroid hormone control of cardiac Na-K ATPase expression: A modulation of ATP utilization. Membrane domains of a novel Mg++ ATPase: Genetic approaches to understanding P-class ATPases. Ca++ ATPase studies at a submolecular level: Structural understanding of ion motive ATPases and ion transport. Some of the broad questions addressed by this application are: what controls respiration?; what modulates ATP consumption and ATPases or kinases?; how can genetic and structural approaches unveil selective ATPase domains involved in ion binding, transport and ATP hydrolysis? Through the interaction of several investigators, in all the components there is a healthy mix of molecular and structural approaches with the use of cell, perfused or ectopic hearts and intact animals. Hence, although this application is more focused than before in molecular and structural studies, it continues to maintain a strong clinical relevance. The major strength of this application is the convergence of established and productive researchers having a broad variety of expertise, novel approaches, a long history of working together, a focused theme and a continued major commitment to this Program Project.
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