The complex nature of the cardiac phenotype in heart failure suggests that diverse pathways will be responsible for disease initiation and progression. Recently, the identification of genes that are responsible for Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) and abnormalities in molecules related to the integrin signaling cascade has drawn our attention to the role that the cell-cell and cell-extracellular matrix complexes have in the development of cardiomyopathy and the response to stresses such as pressure overload. The next stage of this work involves the rigorous evaluation of these molecular complexes and their role in disease progression, linking them to specific cardiac contractile, electrophysiological, and mechanical properties in both the intact heart, the isolated heart and the isolated myocyte. This will also allow us to explore potential connections between these pathways and other known or novel pathways that are uncovered in either human or other experimental systems. Accordingly, the central objective of this program is to identify how molecular complexes in the key adhesive junctions of the cardiac myocyte trigger or contribute to the pathogenesis of cardiac hypertrophy, cardiomyopathy, and the transition to heart failure. The overall hypothesis of the proposal is that defects in the cardiac cell-cell and cell-extracellular matrix molecular complexes can lead to distinct forms of hypertrophy, cardiomyopathy and arrhythmia by disrupting electromechanical function, structural integrity or signal transduction. In the current program project grant application we will focus primarily on a subset of proteins in the intercalated disc that are involved in formation of the desmosomes (plakoglobin);and those which are part of the fascia adherens junction (coxsackievirus and adenovirus receptor (CAR), zonula occludins-1 (ZO-1), plakoglobin and vinculin/ metavinculin). In addition, we will interactively address costameric molecules on the cytoplasmic side of the sarcolemma in the integrin complex (vinculin, metavinculin, talin and PINCH).
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