Cell-Cell and Cell-ECM Adhesion in Cardiac Function and Disease

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Cell adhesion molecules (CAMs) can mediate both cell-cell and cell-extracellular matrix (ECM) adhesions, as welt as govern the most fundamental properties within multicellular organisms, including cell morphology, migration, proliferation, differentiation, tissue morphogenesis, and embryonic development. Recent studies have now also revealed that mutations in genes encoding CAMs are found and associated with various diseases, including cancers, autoimmune diseases as well as cardiomyopathies This proposal is to test the central hypothesis that cardiac components of cell-cell (ie. plakoglobin), and/or cell-ECM (ie.PINCH) adhesion complexes play important roles in the etiology of arrhythmogenic right ventricular dysplasia/ cardiomyopathy (ARVD/C) and cardiac function and/or repair. Accordingly, the specific aims are: Specific Aim 1: To understand the molecular mechanism by which the human plakoglobin mutation results in Naxos disease, a recessive form of ARVD/C. Specific Aim 2: To determine whether the ARVD/C phenotype results from a cell autonomous requirement for plakoglobin in cardiomyocytes and to understand the role of ICD and cytoplasmic/nuclear plakoglobin in this disease. Specific Aim 3: To study the functional role of PINCH in cardiac development, injury, and repair.