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Title page for ETD etd-05032018-145237
|Type of Document
||Parikh, Shan S.
||Maturation and implementation of human induced pluripotent stem cell derived cardiomyocytes for modeling cardiac disease
- dilated cardiomyopathy
- calcium hanlding
- excitation-contraction coupling
|Date of Defense
Mutations in lamin A/C (LMNA) are the second most common contributor to genetic cases of dilated cardiomyopathy (DCM). Despite the autosomal-dominant inheritance of LMNA DCM, gene-targeted mouse models of LMNA DCM show minimal human-like disease progression unless generated in a homozygous fashion. The combination of poor LMNA cross-species sequence conservation and limited disease manifestation in mice necessitates a more human-like cellular model. Thus, developing a human cellular model with phenotypes specific to LMNA DCM is a critical step for advancing mechanistic understanding of this disease. While human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) have successfully modeled other genetic forms of DCM, they have provided limited mechanistic insight into LMNA DCM, possibly due to their structural and functional immaturity. My findings combine hiPSC-CM and gene editing technology to study a disease-causing LMNA mutation (c.1526dupC) and establish a framework for establishing pathogenicity of LMNA mutations. In addition, I identify an additive effect of T3 + Dexamethasone in combination with Matrigel mattress for induction of early t-tubule development and SR maturation. Overall, my findings provide a framework for assessing the pathogenicity of disease-causing LMNA mutations using hiPSC-CM and provide a method for generating hiPSC-CM with more adult-like excitation-contraction coupling.
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