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.
A long-term objective of work in the Kwiatkowski lab is to gain a deep mechanistic understanding of cardiomyocyte adhesion and cytoskeletal organization at the ICD. Our approach is to define mechanisms of cell-cell adhesion, and downstream regulation of actin and intermediate filament organization, by the cadherin-catenin adhesion complex, the core of the adherens junction. Our rationale is that understanding the molecular mechanisms of adherens junction adhesion in cardiomyocytes may provide fundamental insight into cardiomyocyte cell-cell adhesion and adherens junction biology. Understanding the molecular mechanisms of cell-cell adhesion in cardiomyocytes will provide the foundation for determining how mutations in ICD proteins cause heart disease and inform the development of new strategies for the treatment of cardiomyopathies.