This Program Project has as its focus the understanding of the regulation of contraction in cardiac muscle. Since contractile regulation in the heart is of such great significance to both normal and pathologic function, it is important to understand this mechanism. Although the regulatory architecture is common between cardiac and skeletal muscle, there are quantitative differences which give rise to differences in important physiological properties. These studies are designed to discover the protein isoforms and interactions which are responsible for these differences. In four projects, with three cores for support, we will answer a number of the crucial questions of contractile regulation in cardiac muscle. What are the interactions within and along the thin filament that occur during regulation? What role does strong cross- bridge attachment play in activating the thin filament along with Ca binding? What is the mode of regulation? Are the number of interacting sites regulated or the cross-bridge kinetics and how are cross-bridge kinetics regulated? How does sarcomere length have such a profound effect on cardiac contractile regulation? Is it through effects on Ca binding, strong cross-bridge attachment, or cross-bridge kinetics? With extensive collaboration and using preparations from isolated proteins in the in vitro motility assay, to skinned preparations, to intact preparations, we will use newly devised techniques to answer these questions. The results should have great significance to understanding contractile regulation in both the normal and pathologic heart. A more complete understanding will aid both in developing new drugs by providing an experimental model for the evaluation of the mechanism of action and in developing other approaches to therapy.
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