CapZ, PKC Signaling and Control of Sarcomere Function

描述(由申请人提供)：充足的证据表明，Z型椎间盘的完整性对正常的心脏功能和内稳态至关重要。心脏功能障碍与Z-Disc蛋白突变的联系清楚地表明了这一点。我们最近报道，转基因小鼠表现出Z-Disc肌动蛋白帽蛋白CAPZ的减少，影响了肌丝对钙离子的反应，并诱导了PKC Z-Disc定位的改变。这些证据构成了我们总体目标的基石，以检验Z-Disc蛋白网络中的干扰通过“远程控制”机制调节肌丝激活的假说。为了阐明Z-Disc上的事件通过CAPZ影响肌节功能和PKC信号的作用和机制，我们提出了以下问题：目的1.肌动蛋白封顶蛋白CAPZ对肌丝功能和PKC信号的具体贡献是什么？目的2.CAPZ-PKC信号复合体的组成成分是什么？目的3.肌动蛋白封端蛋白CAPZ在促进PKC定位到Z盘中的作用是什么？这些研究将为我们了解导致严重心脏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.