This SCOR Program will include 5 Projects/4 Cores focused on the molecular physiology of heart failure using an integrated approach, based upon multiple model systems that can allow the incorporation of genetic- based approaches followed by the assessment of physiological function in the intact heart and in single cardiac muscle cells. These insights from experimental systems will be integrated into a systematic analysis of a large, phenotypically well-characterized DNA bank that has been established from patients with idiopathic dilated cardiomyopathy and that has already borne significant fruit regarding the isolation of one of the first genes that is associated with inherited idiopathic dilated cardiomyopathy in a subset of patients. Accordingly, the objectives of the Program are as follows: 1) To explore the role of biomechanical stress- inducible pathways in the initiation and progression of cardiac hypertrophy and heart failure; 2) To explore the role of cytoskeletal gene defects in the initiation, onset, and progression of dilated cardiomyopathy and heart failure; 3) To explore the role of downstream signaling pathways mediated by p38 alpha and beta MAP kinases in the onset of cardiac hypertrophy and heart failure; 4) To explore the role of Ca++/calmodulin dependent pathways and SR function in the initiation and progression of hypertrophy and heart failure; 5) To directly contrast different lesions within the cytoskeleton with respect to initiation, maturation, and progression of heart failure in a variety of experimental model systems, with a particular emphasis on lesions in the dystroglycan complex that have already been documented to be associated with human forms of dilated cardiomyopathy; 6) To explore the role of these molecular pathways that have already been strongly implicated in the initiation and progression of experimental heart failure with genetically- based forms of human dilated cardiomyopathy; 7) To explore the role of adenylate cyclase activity and the control of beta-adrenergic pathways in the initiation and progression of dilated cardiomyopathy and heart failure. These studies should lead to a critical evaluation of model systems and direct exploration of their relevance in the setting of genetically-based forms of human dilated cardiomyopathy. These insights may ultimately yield new therapeutic targets/strategies for the failing heart.
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