verbatim): Cardiomyopathy is characterized by structural remodeling of the heart that ultimately results in maladaptive functional consequences. Since cardiac function and structure are interdependent, optimal treatment strategies must approach the long term goal of limiting structural degeneration in progressive heart disease. Cardiac remodeling depends upon molecular signaling that regulates both cellular shape and adhesion by altering the membrane-associated cytoskeleton. The cytoskeleton transduces chemical signals into physical organization and adhesion, so control of cytoskeletal integrity is essential for normal growth and function. Cytoskeletal abnormalities are common in cardiomyopathic cells, but the relationship between cytoskeleton integrity and associated regulatory signaling pathways is poorly understood. The hypothesis of this proposal is that cytoskeletal reorganization is an integral part of the remodeling process during compensation, but that altered regulation of remodeling contributes to loss of adhesion and cardiac failure.
The specific aims are: 1) Determine the molecular pathways regulating focal adhesions that are altered in murine (TOT and racET) and human cardiac failure; 2) Activate focal adhesion signal transduction pathways in vitro and correlate with cardiomyocyte cytoskeletal reorganization; 3) Modulate focal adhesion signal transduction pathways with selective pharmacologic inhibitors and correlate with altered pathogenesis in vivo as well as cardiomyocyte cytoskeletal reorganization in vitro. Biochemical, molecular, and confocal microscopic approaches will combine to identify participants in adhesion regulation, effects upon cardiomyocyte architecture, and impact of inhibitory treatments. The significance is integration of new knowledge regarding cytoskeletal regulation in cardiac remodeling and failure into our understanding of myocardial signal transduction. Results of this study will identify molecular regulators of dilation and open new potential therapeutic targets for pharmaceutical intervention.
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