Despite recent advances in the treatment of human heart failure, the overall impact on morbidity and mortality has been limited, and heart failure remains the pre-eminent cardiovascular health problem in the country. Limitations in our understanding can be attributed, in part, to the inability to examine basic mechanisms in appropriate animal models in which the progressive pathogenesis of hypertrophy and heart failure can be studied. Thus, the overall aim of this Program Project is to identify physiological, biochemical and molecular mechanisms which are fundamental to the progression from imposition of the abnormal load to development of compensated hypertrophy to heart failure. A secondary goal is to understand the mechanism of potential therapeutic agents within the context of the pathogenesis of hypertrophy and heart failure, focusing on beta-adreriergic blockade therapy. The latter is central to one of the major themes of this Program Project, i.e., alterations in beta-adrenergic and G-protein signaling in hypertrophy and heart failure. To achieve these goals, we will focus primarily on the study of transgenic mice and a novel canine model of heart failure superimposed on chronic, severe cardiac hypertrophy. The organization of the Program Project includes 4 projects and 3 cores. The first Project will examine genomic and proteomic mechanisms of hypertrophy and heart failure utilizing the novel canine model of severe, chronic cardiac hypertrophy with heart failure superimposed. The next Project will emphasizes altered beta-adrenergic receptor signaling and signaling mechanisms involving stress-activated protein kinases in hypertrophy and heart failure. The overall goals of this projectare to elucidate cellular and molecular mechanisms, which may explain the adverse action of enhanced beta-adrenergic receptor signaling in heart failure and conversely, the salutary action of beta-adrenergic receptor blockade therapy. The next Project is designed to provide novel information on molecular mechanisms of adenylyl Cyclase regulation, also, using transgenic models. The final Project will focuses on molecular mechanisms involving Gprotein coupled receptor signaling, e.g., beta-adrenergic and angiotensin receptors in the development of hypertrophy and heart failure. This Program Project will provide significant new information on molecular mechanisms involved in mediating hypertrophy and heart failure, which will also have relevance for understanding corresponding mechanisms in myocardial ischemic disease as well.
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