Cardiomyopathies represent a heterogeneous group of diseases of the heart muscle that often lead to progressive heart failure with high morbidity and mortality. In a significant and increasing percentage of the patient population, cardiomyopathies have been associated with hereditary mutations in genes encoding critical cellular components that make up the cytoarchitecture of cardiac muscle cells, or cardiomyocytes. While specific mutations have been linked to different classes of cardiomyopathies, it is however not well understood how these mutations cause cytostructural abnormalities that ultimately lead to dysfunction of cardiomyocytes. To gain insights into the pathogenesis of inherited cardiomyopathies, we focus in this thesis on a particular set of mutations in the cardiac cytoskeleton and desmosomes that are associated with dilated and arrhythmogenic cardiomyopathies, and probe their pathogenic mechanisms using cardiomyocytes derived from human induced pluripotent stem cells and bioengineered culture platforms. In part one, we describe the mechanical and molecular basis for the assembly of sarcomeres, the fundamental contractile units within cardiomyocytes, and reveal how mutations in titin (TTN) abolish this process by disrupting cell-matrix interaction and impairing diastolic force generation, a hallmark of dilated cardiomyopathy. In the second part of this thesis, we reveal that plakophilin-2 (PKP2) mutations that are associated with arrhythmogenic cardiomyopathy lead to impaired systolic function by destabilizing cell-cell junctions and in turn disrupting sarcomere stability and organization. Together, our studies establish a deeper understanding of how cell-matrix and cell-cell interactions contribute to the organization and function of cardiomyocytes and how disruption of these interactions by pathogenic mutations lead to cardiac dysfunction. / 2022-05-18T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/41029 |
| Date | 19 May 2020 |
| Creators | Zhang, Kehan |
| Contributors | Chen, Christopher S. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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