Vinculin and Talin in Cardiocyte Integrity and Adhesion

心肌细胞的机械和电耦合是允许心肌细胞的基本特性 心肌发挥合胞体的功能。最近对人和动物模型的研究表明，缺陷 协调这些特性的蛋白质可能导致心肌病或成为心律失常的根源。 闰盘位于肌细胞的钝双极端，提供结构和功能。 心肌的电完整性。在圆盘内发现了三种独特类型的连接点： 桥粒、间隙连接和粘附连接。闰盘中的粘附连接用于 加强收缩细胞的联系，桥接收缩装置和基于肌动蛋白的 相邻细胞的细胞骨架。间隙连接允许快速传导动作电位 肌细胞。肌细胞的稳定性也通过外侧肋节中的细胞-基质相互作用来维持 细胞表面。 当前提案的重点是定义两种肌动蛋白连接蛋白，纽蛋白和 踝蛋白相互结合，将肌节与细胞骨架桥接起来，在细胞与细胞的连接中发挥作用 也参与细胞-细胞外基质粘附。这些蛋白质各自具有高度表达的变体形式 在心脏中，分别是metavinculin 和talin-2。我们的总体假设是纽蛋白、talin 及其 各自的变异形式在心脏中具有独特的作用。为了评估这一假设，提出了三个目标 其广泛使用独特的鼠标模型。他们是： 1) 评估心肌细胞特异性纽蛋白表达减少如何导致心功能异常， 易导致心律失常，并导致闰盘和细胞基质粘附不稳定， 2) 研究与纽蛋白不同的肌肉特异性剪接变体元纽蛋白的功能，以及 3)评价talin-1和talin-2在心肌细胞中的作用。 美达霉素与人类心肌病有关。更好地了解这组相关的 蛋白质将增进我们对正常和异常心脏功能的分子基础的理解。 它还将为定向心力衰竭疗法的未来发展提供见解。

Mechanical and electrical coupling of cardiac myocytes are essential properties which allow for the myocardium to function as a syncytium. Recent studies in man and animal models have shown that defects in proteins which orchestrate these properties can lead to cardiomyopathies or be the origin of arrhythmias. The intercalated disc located at the blunted, bipolar ends of the myocytes provide for both structural and electrical integrity of cardiac muscle. Within the disc are found three unique types ofjunctions: desmosomes, gap junctions and adherens junctions. Adherens junctions in the intercalated disk serve to strengthen the linkage of the contractile cells, bridging the contractile apparatus and actin-based cytoskeleton of adjacent cells. Gap junctions allow for rapid conductance of action potentials between myocytes. Stability of the myocyte is also maintained by cell-matrix interactions in costameres at the lateral surface of the cells. The focus of the current proposal is to define the functional role of two actin-linking proteins, vinculin and talin, which bind to each other, bridge the sarcomere to the cytoskeleton, function in cell-cell junctions and also in cell-extracellular matrix adhesion. These proteins each have variant forms that are highly expressed in heart, namely metavinculin and talin-2, respectively. Our global hypothesis is that vinculin, talin and their respective variant forms have unique role in the heart. To evaluate this hypothesis, three aims are proposed which make extensive use of unique mouse models. Theyare: 1) Assess how cardiac myocyte specific reduction of vinculin expression leads to abnormal cardiac function, predisposes to arrhythmias and functions in destabilization of the intercalated disk and cell-matrix adhesions, 2) Study the function of the muscle-specific splice-variant metavinculin as distinct from vinculin, and 3) Evaluate the role of talin-1 and talin-2 in cardiac myocytes. Metavinculin has been linked to cardiomyopathy in man. A better understanding of this group of related proteins will advance our understanding about the molecular basis of normal and abnormal cardiac function. It will also give insight to allow future development of directed heart failure therapies.