Integrated Mechanisms of Cardiac Maladaptation

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Experiments proposed here continue highly interactive and synergistic interactions among four projects supported by three cores. The projects and cores are linked by a central theme of experiments, which test the hypothesis that sarcomeric remodeling is a critical determinant of the transition from compensated hypertrophy to decompensation and symptomatic heart failure. We broadly define sarcomeric remodeling as post-translational modifications, shifts in isoform population, and shuttling of sarcomeric associated proteins to other signaling pathways. Project 1 (R. John Solaro) is "Molecular Signaling in Cardiac Sarcomeres"; Project 2 (Brenda Russell) is" Mechanical Activity and Myocyte Remodeling ", which tests the hypothesis that the remodeling responses are regulated by the strength of mechanical stimuli and the intervals between them. Project 3 (Peter Buttrick) is " Sarcomeric Modifications and Progressive Cardiac Maladaptation", and Project 4 (Pieter de Tombe) is "Molecular Mechanisms of Myofilament Dysfunction in Heart Failure", which tests the hypothesis that up-regulation of protein kinase C and specific phosphorylation of sarcomeric targets leads to decompensation. These 4 projects are supported by Administrative, Animal, and Analytical Biochemistry Cores. Approaches include structural, mechanical and proteomic approaches in studies of normal and failing preparations at the level of proteins, single myofibrils, cells, muscles, and hearts. Data from these experiments provide novel insights into the mechanisms of heart failure and potential therapies.