The human heart beats upwards of 100,000 times a day, and contractile forces place unique physical and regulatory demands on the protein complexes that join cardiomyocytes together to form a functional heart muscle. Mechanical coupling and chemical communication between cardiomyocytes is accomplished through a specialized adhesive structure called the intercalated disc (ICD). The ICD comprises adherens junctions and desmosomes that connect the actin and intermediate filament cytoskeletons, respectively, to the plasma membrane. ICD formation requires multiple adhesion and cytoskeletal proteins, and mutations in these proteins can cause cardiomyopathies. However, little is known about how these adhesive complexes are assembled or regulated to withstand the forces of cardiomyocyte contraction and maintain tissue integrity. Determining how protein complexes function at the ICD to maintain adhesive homeostasis is critical for understanding heart function and disease. The core of the adherens junction is the cadherin-catenin complex, which is connected to the actin cytoskeleton through ?-catenin. ?-Catenin is multifunctional actin-binding protein that localizes to the ICD in cardiomyocytes, and loss of ?-catenin function in mice causes cardiomyopathy. However, ?-catenin functions in cell-cell adhesion in cardiomyocytes are poorly understood. We hypothesize that ?-catenin regulates cardiomyocyte cell-cell adhesion by coupling actin and intermediate filaments to ICD junctional complexes. In this proposal, we seek to 1) define how actomyosin tension regulates adherens junction assembly and organization in cardiomyocytes; 2) identify how the molecular properties of ?T-catenin, a largely uncharacterized ?-catenin expressed in the heart, regulate adherens junction organization and linkage to the actomyosin network; and 3) determine how ?T-catenin links to actin and intermediate filament cytoskeletons to regulate cardiomyocyte adhesion. Our work will develop new tools and acquire new knowledge about the molecular mechanisms of cell-cell adhesion in cardiomyocytes, which in turn will provide the foundation for assessing the impact of mutations in ICD proteins on cardiac pathophysiology and inform the development of new strategies for the treatment of cardiomyopathies.
Heart muscle cells must be physically connected for proper heart development and function. Protein complexes control the formation and maintenance of these connections, and mutations affecting these proteins cause heart disease. Understanding how these protein complexes are formed and how they establish cell connections is critical to human health and the focus of this research.
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