Vinculin and Talin in Cardiocyte Integrity and Adhesion

心肌细胞的机械和电偶联是允许心肌细胞的机械和电偶联的基本性质。 心肌作为合胞体发挥功能。最近对人类和动物模型的研究表明， 在蛋白质中，协调这些特性可能导致心肌病或心律失常的起源。 位于肌细胞钝的双极末端的闰盘提供了结构和功能。 心肌的电完整性。在椎间盘内发现了三种独特的连接类型： 桥粒、间隙连接和粘附连接。闰盘中的粘附连接起着 加强收缩细胞的联系，桥接收缩器和肌动蛋白基 相邻细胞的细胞骨架。缝隙连接允许动作电位在细胞之间快速传导， 肌细胞肌细胞的稳定性也是通过细胞-基质的相互作用来维持的。 细胞表面。 目前建议的重点是确定两个肌动蛋白连接蛋白，黏着斑蛋白和 相互结合的talin将肌节连接到细胞骨架，在细胞-细胞连接中起作用， 也在细胞-细胞外基质粘附中。这些蛋白质各自具有高度表达的变体形式， 在心脏中，分别为metavinculin和talin-2。我们的总体假设是黏着斑蛋白，talin和它们的 各自的变体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 其广泛使用独特的小鼠模型。他们是： 1)评估心肌细胞特异性黏着斑蛋白表达减少如何导致心脏功能异常， 易患心律失常并在闰盘和细胞-基质粘附的不稳定中起作用， 2)研究与黏着斑蛋白不同的肌肉特异性剪接变体后黏着斑蛋白的功能， 3)评价talin-1和talin-2在心肌细胞中的作用。 Metavinculin与人类心肌病有关。 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。 它还将为未来开发定向心力衰竭治疗提供见解。

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.