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dc.contributor.advisorChen, Christopher S.en_US
dc.contributor.authorZhang, Kehanen_US
dc.date.accessioned2020-05-19T19:21:53Z
dc.date.issued2020
dc.identifier.urihttps://hdl.handle.net/2144/41029
dc.description.abstractCardiomyopathies 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.en_US
dc.language.isoen_US
dc.subjectBiomedical engineeringen_US
dc.subjectAdherens junctionen_US
dc.subjectARVDen_US
dc.subjectCardiac myosinen_US
dc.subjectContractilityen_US
dc.subjectDesmosomeen_US
dc.subjectSarcomerogenesisen_US
dc.titleMechanotransduction through cytoskeleton and junctions in cardiomyopathiesen_US
dc.typeThesis/Dissertationen_US
dc.date.updated2020-05-19T04:03:00Z
dc.description.embargo2022-05-18T00:00:00Z
etd.degree.nameDoctor of Philosophyen_US
etd.degree.leveldoctoralen_US
etd.degree.disciplineBiomedical Engineeringen_US
etd.degree.grantorBoston Universityen_US
dc.identifier.orcid0000-0002-7979-3001


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