CapZ, PKC Signaling and Control of Sarcomere Function

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DESCRIPTION (provided by applicant): Ample evidence indicates that the integrity of the Z-disc is critical to normal cardiac function and homeostasis. Linkage of cardiac dysfunction with mutations in the Z-disc proteins demonstrates this clearly. We reported recently that transgenic mice engineered to display a reduction in the Z-disc actin capping protein, CapZ, affect the myofilament response to Ca2+ and also induce alterations in PKC Z-disc localization. This evidence forms the bedrock of our overall objective to test the hypothesis that disturbances in the Z-disc protein network modulate myofilament activation via a "remote control" mechanism. In order to elucidate the role and the mechanism by which events at the Z-disc, through CapZ, influence the sarcomeric function and PKC signaling, we propose to address the following questions: Aim 1. What are the specific contributions of actin capping protein, CapZ, to myofilament function and PKC signaling? Aim 2. What are the components of CapZ - PKC signaling complexes? Aim 3. What is the role of actin capping protein, CapZ, in facilitating localization of PKC to the Z-disk? These studies will provide important information relevant to our understanding of events leading to severe cardiac dysfunction.