Vinculin and Talin in Cardiocyte Integrity and Adhesion

心肌细胞的机械和电气耦合是允许 心肌起到合胞体的作用。最近在人类和动物模型中的研究表明，缺陷 在协调这些特性的蛋白质中，可能会导致心肌病或心律失常的起源。 位于心肌细胞两极末端钝化的间盘提供了结构和 心肌的电完整性。在圆盘内发现了三种独特类型的接头： 桥粒、缝隙连接和粘连连接。插入盘中的粘连连接用于 加强收缩细胞的联系，连接收缩装置和以肌动蛋白为主的 相邻细胞的细胞骨架。缝隙连接允许动作电位的快速传导 肌细胞。肌细胞的稳定性也是通过外侧的胞间相互作用来维持的。 细胞的表面。 目前的提案的重点是确定两种肌动蛋白连接蛋白的功能作用，vinculin和 Talin相互结合，在肌节和细胞骨架之间架起桥梁，在细胞-细胞连接和 也存在于细胞与细胞外基质的黏附。这些蛋白质都有高度表达的不同形式。 在内心，分别为Metavinculin和talin-2。我们的全球假说是纽蛋白、塔林和它们的 各种不同的形式在心脏中都有独特的作用。为了评估这一假设，我们提出了三个目标 它广泛使用了独特的鼠标模型。它们是： 1)评估心肌细胞特异性的纽蛋白表达减少如何导致心功能异常， 易发生心律失常，并在间盘和细胞-基质粘连的不稳定中起作用， 2)研究肌肉特异性剪接变异型Metavinculin与纽蛋白的不同功能，以及 3)评价talin-1和talin-2在心肌细胞中的作用。 Metavinculin被认为与人类的心肌病有关。更好地了解这一组相关的 蛋白质将促进我们对正常和异常心脏功能的分子基础的理解。 它还将提供洞察力，使定向心力衰竭疗法的未来发展成为可能。

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.