Adhesion Molecules of the Intercalated Disc in Cardiomyopathy

间盘(intercalated Diss，ICD)是主要的心肌细胞-细胞黏附结构，将肌细胞连接到 彼此之间。它们由一系列蛋白质组成，这些蛋白质被分为三个主要的连接 复合体、筋膜粘着连接、桥粒和缝隙连接，对维持 相邻肌细胞/间盘异常之间的机械和电耦合 与遗传性扩张型心肌病有关，如致心律失常的右室 语言障碍/心肌病(ARVD/C)。此外，还报告了间盘的异常 心肌病的背景。柯萨奇病毒腺病毒受体(CAR)主要定位于 成人心脏的间盘。虽然我们和其他人已经证明，汽车表情是 心血管正常发育，对CAR及其受体的功能意义知之甚少 成人心脏中的相关分子和正常间盘的形成。潜在的 该项目的假设是CAR和ZO-1的表达是心脏正常功能所必需的。 成人心脏和压力超负荷，这些分子的缺乏将导致心脏异常 与间盘结构和功能异常相关的功能。 具体目标： 目的1：确定心脏特异的、可诱导的CAR基因敲除对心脏功能的影响。 成人心脏处于正常生长和压力超负荷状态。 目的2：确定CAR干扰影响心脏功能的分子和细胞机制 重点是邻近的跨膜蛋白和肌膜蛋白位于 间盘内细胞膜的细胞质一侧。 具体目标3：确定心肌细胞是否需要ZO-1的表达才能形成 正常胚胎心脏及其在成人正常心功能和间盘形成中的作用 心。

ntercalated discs (ICD) are the major cardiac cell-cell adhesion structures, which connect muscle cells to one another. They consist of an array of proteins, which are categorized into three major junctional complexes, fascia adherens junctions, desmosomes, and gap junctions, and are essential for maintaining mechanical and electrical coupling between neighboring muscle cells/Abnormalities in the intercalated disc have been linked to hereditary forms of dilated cardiomyopathy such as arrhythmogenic right ventricular dysphasia/ cardiomyopathy (ARVD/C). Also abnormalities in the intercalated disc has been reported in the setting of cardiomyopathy. The coxsackievirus adenovirus receptor (CAR) is localized primarily at the ntercalated disc in the adult heart. While we and others have shown that CAR expression is required for normal cardiovascular development, relatively little is known of the functional significance of CAR and its associated molecules in the adult heart and in formation of the normal intercalated disc. The underlying hypothesis for this project is that CAR and ZO-1 expression are required for normal cardiac function in the adult heart and with pressure overload and that the absence of these molecules will lead to abnormal cardiac function that will be associated with abnormalities in intercalated .disc structure and function. Specific Aims: Aim 1: Determine the effect of cardiac specific and inducible CAR knockout on ventricular function in the adult heart during normal growth and with pressure overload. Aim 2: Determine the molecular and cellular mechanisms by which CAR disruption affects cardiac function with an emphasis on adjacent transmembrane proteins and sarcolemmal proteins that are located on the cytoplasmic side of the membrane within the intercalated disc. Specific Aim 3: Determine whether cardiac myocyte expression of ZO-1 is required for formation of the normal embryonic heart and its role in normal cardiac function and intercalated disc formation in the adult heart.