Local Signals and Macromolecular Architecture in Heart

描述（由申请人提供）： 正常的心脏细胞功能依赖于Ca 2+信号传导与心肌细胞凋亡之间的密切联系。 T-小管中的元素和缝隙连接处的传导大分子复合物。这些 关键的分子是局部组织和控制的信号级联，相互作用， 连续动态的细胞骨架这个复杂网络的功能重要性 最近强调了它与获得性和遗传性人类扩张性疾病的联系， 心肌病尽管人们逐渐认识到心脏的关键作用， 细胞骨架网络，这些结构，以及控制它们的信号级联， 组织，几乎不被理解。通过项目负责人的协调努力， PPG试图了解Ca 2+信号传导如何依赖于动态细胞骨架组织 以及它们是如何被心脏中的局部靶向信号级联调节的。项目1将 研究磷酸酶在控制t-小管细胞骨架结构中的作用（链接到 项目2）和L型钙通道功能（链接到项目4）。的重要性 磷酸酶靶向将通过靶向基序的异位表达进一步检查 并在心肌病的动物模型中进行了测试（链接到项目3）。项目2将审查 心肌细胞的细胞骨架，特别是血影蛋白和肌营养不良蛋白网络， 组织和稳定肌膜和T管膜。这些网络在 组织缝隙连接（链接到项目3）和维持适当的t-小管/SR 通信（链接到项目4）将得到解决，将磷酸化的影响， 这些功能（链接到项目1）。项目3将研究压力激活信号在 细胞骨架结构的破坏（链接到项目2）和间隙连接处连接蛋白-43的丢失 通过使用转基因小鼠心力衰竭模型。我们的目标是确定 压力激活信号对磷酸酶重定向的机制（链接到项目1）， EC耦合受损（链接至项目4）。项目4将研究Ca 2+信号如何 依赖于t-小管细胞结构的丝蛋白（链接到项目1和2）和 信号蛋白的磷酸化状态（链接到项目1和3）。转基因研究 动物将探索细胞骨架的重组如何有助于改变Ca 2 + 在心肌病中观察到的信号传导（链接到项目2和3）。因此， 项目负责人将提供有关基本分子主题的新信息， 机械应力局部细胞信号和？细胞分裂症这些都是人类 心脏病

DESCRIPTION (provided by applicant): Proper heart cell function depends on the intimate association between Ca2+ signaling elements in t-tubules and the conduction macromolecular complexes at gap junctions. These crucial molecules are locally organized and controlled by signaling cascades that interact with the continuous, dynamic cytoskeleton. The functional importance of this intricate network has been recently emphasized by its links to acquired and inherited forms of human dilated cardiomyopathies. Despite the emerging appreciation for the crucial role of cardiac cytoskeletal networks, these structures, and the signaling cascades that control their organization, are barely understood. Through the coordinated efforts of the project leaders, this PPG seeks to understand how Ca2+ signaling depends upon dynamic cytoskeletal organization and how they are both regulated by local, targeted signaling cascades in heart. Project 1 will examine the role of phosphatases in control of cytoskeletal architecture at t-tubules (link to Project 2) and L-type Ca2+ channel function (link to Project 4). The importance of phosphatases targeting will be further examined through ectopic expression of targeting motifs and tested in animal models of cardiomyopathies (link to Project 3). Project 2 will examine the cytoskeleton of cardiac myocytes, particularly the spectrin and dystrophin networks that organize and stabilize the sarcolemma and t-tubular membranes. The role of these networks in organizing gap junctions (link to Project 3) and in maintaining proper t-tubule/SR communication (link to Project 4) will be addressed, as will the effects of phosphorylation on these functions (link to Project 1). Project 3 will examine the role of stress-activated signaling in disruption of cytoskeletal structures (link to Project 2) and loss of connexin-43 at gap junctions through the use of transgenic mouse heart failure models. A goal will be to identify molecular mechanisms of stress-activated signaling on phosphatase retargeting (link to Project 1) and compromised EC coupling (link to Project 4). Project 4 will examine how Ca2+ signaling depends on filament proteins of t-tubule cytoarchitecture (link to Projects 1 and 2) and on the phosphorylation state of signaling proteins (link to Projects 1 and 3). Studies in transgenic animals will explore how the reorganization of the cytoskeleton contributes to altered Ca2+ signaling seen in cardiomyopathies (link to Projects 2 and 3). Thus, the well-integrated plans of the Project Leaders will provide new information on the fundamental molecular themes that link mechanical stress to local cellular signaling and ?cytoskeletonopathies? that underlie human heart disease.