Vinculin and Talin in Cardiocyte Integrity and Adhesion

纽蛋白和 Talin 在心肌细胞完整性和粘附中的作用

• 批准号: 7905100
• 负责人: Robert Scott Ross
• 金额: $ 31.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7905100
• 关键词: Actins; Action Potentials; Address; Adherens Junction; Adhesions; Adhesives; Adult; Affect; Age; Animal Model; Animals; Arrhythmia; Binding; Biochemical; Biological Process; Breeding; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Adhesion; Cell surface; Cell-Matrix Junction; Cells; Cellular Structures; Complex; Coupling; Cytoskeleton; Defect; Desmosomes; Development; Dilated Cardiomyopathy; Excision; Exons; Extracellular Matrix; Family member; Functional disorder; Future; Gap Junctions; Generations; Genes; Giant Cells; Heart; Heart Diseases; Heart failure; Human; Hypertrophy; Integrins; Intercalated disc; Intercellular Junctions; Investigation; Knock-out; Knockout Mice; Laboratories; Lateral; Lead; Link; Mechanics; Molecular; Mus; Muscle; Muscle Cells; Muscle function; Mutation; Myocardium; Partner in relationship; Pathway interactions; Phenotype; Physiological; Play; Predisposition; Property; Proteins; RNA Splicing; Role; Sarcomeres; Series; Structure; Sudden Death; Surface; Talin; Technology; Testing; Tissues; VCL gene; Variant; Ventricular; Vinculin; Work; base; heart function; insight; link protein; man; metavinculin; mortality; mouse model; mutant; myosin light chain 2; programs; protein expression; stoichiometry

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.

心肌细胞的机械和电耦合是必不可少的特性 心肌充当合胞体。对人和动物模型的最新研究表明缺陷 在编排这些特性的蛋白质中，可以导致心肌病或心律不齐的起源。 位于钝的椎间盘的插入式椎间盘，肌细胞的双极末端可提供结构和 心肌的电气完整性。在光盘中找到了三种独特类型的共同点： 脱骨，间隙连接和粘附连接。插入式磁盘中的粘附连接可用于 加强收缩细胞的连锁，桥接收缩设备和基于肌动蛋白的设备 相邻细胞的细胞骨架。差距连接允许在之间快速导电电位 心肌细胞。肌细胞的稳定性也通过侧面的COSTAMERES中的细胞 - 矩阵相互作用维持 细胞的表面。 当前建议的重点是定义两种肌动蛋白链接蛋白的功能作用 彼此结合的塔林（Talin 也在细胞 - 细胞基质粘附中。这些蛋白质每个具有高度表达的变体形式 在心中，分别是metavinculin和talin-2。我们的全球假设是Vinculin，Talin及其 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 广泛使用独特的鼠标模型。他们： 1）评估心肌细胞的特异性降低杂质蛋白表达如何导致心脏功能异常， 心律不齐和功能在插入式磁盘和细胞矩阵粘附的稳定中的功能， 2）研究肌肉特异性剪接变化的元符素的功能，与vinculin不同，和 3）评估Talin-1和Talin-2在心肌细胞中的作用。 荟萃维环蛋白与人的心肌病有关。更好地理解这一相关的相关 蛋白质将提高我们对正常和异常心脏功能分子基础的理解。 它还将提供洞察力，以允许未来开发定向心力衰竭疗法。