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Title page for ETD etd-05032018-145237


Type of Document Dissertation
Author Parikh, Shan S.
URN etd-05032018-145237
Title Maturation and implementation of human induced pluripotent stem cell derived cardiomyocytes for modeling cardiac disease
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Dan Roden Committee Chair
Charles Hong Committee Member
David Weaver Committee Member
Eric Delpire Committee Member
Keywords
  • ipsc
  • calcium
  • lamin
  • dilated cardiomyopathy
  • t-tubules
  • calcium hanlding
  • crispr
  • hipsc-cm
  • excitation-contraction coupling
  • electrophysiology
Date of Defense 2018-04-27
Availability restricted
Abstract
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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