Adhesion Molecules of the Intercalated Disc in Cardiomyopathy

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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.