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钙信号之间的密切联系 T形小管中的元素和缝隙连接处的导电大分子复合体。这些 关键分子由相互作用的信号级联在局部组织和控制 连续的、动态的细胞骨架。这个复杂网络在功能上的重要性 最近强调了它与后天和遗传形式的人类扩张症的联系 心肌病。尽管人们开始认识到心脏的关键作用 细胞骨架网络，这些结构，以及控制其 组织，几乎不被理解。通过项目负责人的协调努力，这 PPG试图了解钙信号如何依赖于动态的细胞骨架组织 以及它们都是如何受到心脏中局部的、有针对性的信号级联的调控。项目1将 研究磷酸酶在控制T管细胞骨架结构中的作用(链接 项目2)和L型钙通道功能(链接到项目4)。重要的是 将通过靶向基序的异位表达来进一步研究磷酸酶靶向 并在心肌病的动物模型上进行了测试(链接到项目3)。项目2将研究 心肌细胞的细胞骨架，特别是 组织和稳定肌膜和T管膜。这些网络在以下方面的作用 组织缝隙连接(链接到项目3)并维护适当的T管/SR 将讨论沟通(链接到项目4)，以及磷酸化对 这些功能(链接到项目1)。项目3将研究应激激活信号在 细胞骨架结构的破坏(链接到项目2)和缝隙连接处连接蛋白43的丢失 通过使用转基因小鼠心力衰竭模型。一个目标将是识别分子 应激激活信号转导磷酸酶重定向的机制(链接至项目1)和 EC耦合受损(链接到项目4)。项目4将研究钙信号如何 取决于T小管细胞结构的细丝蛋白(链接到项目1和2)以及 信号蛋白的磷酸化状态(链接到项目1和3)。转基因技术研究进展 动物们将探索细胞骨架的重组如何促进钙离子的改变 在心肌病中看到的信号(链接到项目2和3)。因此，美国政府的综合计划 项目负责人将提供有关基本分子主题的新信息 机械应激对局部细胞信号和细胞骨架疾病的影响？这是人类的基础 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.