Although the incidence, prevalence and mortality of congestive heart failure appear to be increasing, little is known regarding the basic mechanism(s) responsible for this clinically important syndrome. The overall hypothesis which underlies this SCOR Program is that clinical congestive heart failure (CHF) results from distinctive identifiable alterations in the cellular and subcellular components of the cardiomyocyte. Project 1 will examine potential differential alterations in carefully selected pressure overload hypertrophy triggers, transducers and target proteins which occur in the transition to CHF using an animal model which clearly manifests these two phenotypes. Project 2 will examine the potential role of genetic variants of P-adrenergic receptors in the pathophysiology of early and late human congestive heart failure. Project 3 will study the gene regulation and expression of the cardiac SR Ca2+ ATPase in normal arid cardiomyopathic hearts using conventional molecular biologic techniques, transgenic mice which overexpress wild type or mutated SR ATPase pumps and patients with early and late CHF. Project 4 will rigorously examine the function of the calcium cycling regulatory protein phospholamban using a similar analytic approach involving creation of transgenic animals with over- or underexpression of normal and mutant phospholamban. Parallel studies of altered phospholamban levels will be conducted in patients with early and late CHF. Project 5 will test the hypothesis that the regulatory or phosphorylatable myosin light chain plays a critical role in normal and pathologic cardiac function using a parallel approach to Project 3 and 4 involving transgenic models and patients with early and late CHF. The entire ensemble of projects will be assisted in their technical and analytical thrusts by two critical core facilities. The Molecular Physiology Core will provide analyses of cardiomyocyte function, calcium kinetics and quantitative PCR for Projects 1-5. The Clinical Physiology Core will provide invasive and noninvasive assessment of ventricular function and endomyocardial biopsies from patients with early and late CHF for Projects 2-5. We believe that the proposed multilevel attack on the problem which involves molecular biology, cell biology and integrative physiology approaches will contribute significantly to our understanding of the pathogenesis and treatment of human congestive heart failure.
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