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. To achieve these goals, we will focus primarily on the study of transgenic mice and pigs. The organization of the Program Project includes 4 projects and 4 cores. The physiological studies contained in Project 1 examine mechanisms of altered myocardial function in ventricular hypertrophy and failure. An additional component of Project 1 is to understand the mechanisms of cardiac dysfunction in terms of energy metabolism. Accordingly, NMR technology will complement the work on integrative physiology. Project 2 emphasizes altered beta-adrenergic receptor signalling and signalling mechanisms involving stress-activated protein kinases in hypertrophy and heart failure. Both of these projects will study transgenic animal models, including that of cardiac Gsalpha overexpression, which develops cardiomyopathy later in life. Project 3 is designed to provide novel information on molecular mechanisms of adenylyl cyclase regulation, also using transgenic models. Project 4 focuses on novel sarcomeric protein mutation-induced cardiomyopathies. Thus, this Program Project represents a multi-disciplinary approach to the problems of myocardial hypertrophy and heart failure combining expertise in integrative physiology and cellular and molecular biology.
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