Genetic Studies of Sarcomere-based Cardiac Diseases

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DESCRIPTION (provided by applicant): The ability of cardiomyocytes to sense and respond to mechanical stimuli is fundamental in both cardiogenesis and cardiomyopathies. However, our understanding of how mechanical stimuli modulate cardiomyocyte size still remains incomplete. This proposal focuses on a novel inhibitory mechanotransduction response that has been suggested by our studies of zebrafish 1-actinin2 (actn2), a predominant sarcomeric Z-disc protein, and tcap, a component of the Z-disc-based stretch sensor complex. Depletion of actn2 during cardiogenesis results in severely reduced ventricle chamber size, which can be rescued by arrested heart beat. At the molecular level, we found tcapb, a zebrafish cardiac tcap homologue, is activated in actn2 knockdown embryos. Depletion of tcapb rescues the reduced chamber size in actn2 knockdown embryos, suggesting that transcriptional activation of tcap confers an inhibitory mechanotransduction response. In addition to heart development, activated tcap expression was detected in an adult zebrafish model of cardiomyopathy, and overexpression of tcap attenuates the enlarged heart and increases the survival rate in adult fish models of cardiomyopathy. Together, our preliminary observations support the central hypothesis of this proposal predicting that transcriptional activation of Tcap confers inhibitory mechanotransduction response incurred by mechanical stimuli that reduces ventricular chamber size. We will test this hypothesis by the following three specific aims. In Specific Aim 1, we propose to validate the hypothesis that the reduced ventricular chamber size in actn2 knockdown is ascribed to mechanical stimuli that inhibit ventricular chamber enlargement. In Specific Aim 2, we propose to validate the hypothesis that transcriptional activation of Tcap confers the inhibitory mechanotransduction signaling to control ventricular chamber size. In Specific Aim 3, we propose to test the hypothesis that transcriptional activation of Tcap occurs in various adult cardiomyopathies and can be enhanced for cardioprotective benefits. The information gained from here will provide novel insights into the pathophysiology of Tcap-based cardiomyopathy and muscular dystrophy type 2G. Moreover, because the mechano-signaling in cardiomyocytes plays a pivotal role in the pathogenesis of both acquired and inheritable cardiomyopathies, our proposed research will have broad impacts on cardiomyopathies of different etiologies.