CapZ, PKC Signaling and Control of Sarcomere Function

描述（由申请人提供）：充分的证据表明，Z盘的完整性对正常心脏功能和体内平衡至关重要。心脏功能障碍与Z盘蛋白突变的联系清楚地证明了这一点。我们最近报道，转基因小鼠工程显示减少的Z-盘肌动蛋白帽蛋白，CapZ，影响肌丝对Ca 2+的反应，也诱导PKC Z-盘定位的改变。这一证据构成了我们的总体目标的基石，以测试的假设，在Z-盘蛋白网络的干扰调制肌丝激活通过“远程控制”机制。为了阐明的作用和机制的事件在Z-光盘，通过CapZ，影响肌节功能和PKC信号，我们建议解决以下问题：目的1。肌动蛋白加帽蛋白CapZ对肌丝功能和PKC信号传导有什么具体贡献？目标2. CapZ-PKC信号复合物的组成成分是什么？目标3。肌动蛋白帽蛋白CapZ在促进PKC定位于Z盘中的作用是什么？这些研究将为我们了解导致严重心功能不全的事件提供重要信息。

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.