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Title: "Mechanotransduction through Cytoskeleton and Junctions in Cardiomyopathies: Committee: Christopher Chen, BME (Advisor, Chair) Michael Smith, BME John Ngo, BME Jonathan Seidman, Harvard Medical School - Department of Genetics Abstract: Cardiomyopathies, diseases of the heart muscle, represent a heterogeneous group of diseases that often lead to progressive heart failure with significant morbidity and mortality. A significant and increasing percentage of patients with cardiomyopathies have been discovered to have inheritable mutations in genes encoding critical components of the cardiomyocyte cytoarchitecture, and these myopathic states are often accompanied by morphological changes in the cytoarchitecture. The building and organization of cytoarchitecture is critical for cardiomyocyte structural adaptation during both development and disease. However, it remains unclear how pathogenic mutations affect this process, in part due to lack of good cellular models for studying human cardiac cell biology and pathogenesis. With recent advances in human induced pluripotent stem cell (hiPSC) differentiation into cardiomyocytes and CRISPR/Cas9 mediated genome editing technology allowing the creation of isogenic control and mutant human cardiomyocytes, this proposal aims to investigate the molecular and mechanical basis of human cardiomyocyte cytoarchitecture assembly with the attempt to uncover novel disease mechanisms of genetic cardiomyopathies.