INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION

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Experiments proposed in this interactive and synergistic program arise from the following questions: What are the signals by which heart cells sense a change in load and how are signals processed to alter myofilament activity? By what mechanisms do the signals effectively adapt myofilament function to a change in hemodynamic load and why does the adaptation process fail? The hypothesis is that changes in cell strain associated with cell length changes, acting independently or in conjunction with changes in cellular Ca2+ or altered cascades of phosphoryl group transfer reactions involving protein kinase C (PKC), constitute the signaling mechanism. Project 1 (John Solaro/Anne Martin) is "Molecular Signaling in Cardiac Myofilaments." This project investigates the molecular mechanisms by which cardiac myofilaments are turned on and off and how their activity is modified by protein isoform switching, sarcomere length and protein phosphorylation. Project 2 (Brenda Russell) is "Mechanical Activity and Regional Protein Synthesis." This project investigates the essential thematic element of the linkages among mechanical work and strain, intracellular signals, and protein synthesis. Project 3 (Peter Buttrick) is "Effect of Protein Kinase C on Cardiac Hypertrophy." Using transgenic approaches, this project focuses on the primary signaling pathway that sets into motion the adaptive and maladaptive processes. Project 4 (Pieter deTombe) is "Mechanisms of Transition from Hypertrophy to Failure," and addresses the question of the cellular mechanisms of transition from compensatory responses in the early phase to end-stage heart failure induced by myocardial infarction. These four projects are supported by Administrative, Animal and Physiology, and Myocyte and Morphology Cores. The programmatic effort proposed here will provide important understanding of how mechanical and biochemical signals that arise from a hemodynamic stressor such as hypertension or myocardial infarction are integrated to give rise to physiological compensation and why decompensation occurs in heart failure.