dc.creator | Parikh, Shan S. | |
dc.date.accessioned | 2020-08-22T00:39:41Z | |
dc.date.available | 2020-05-21 | |
dc.date.issued | 2018-05-21 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-05032018-145237 | |
dc.identifier.uri | http://hdl.handle.net/1803/12262 | |
dc.description.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. | |
dc.format.mimetype | application/pdf | |
dc.subject | ipsc | |
dc.subject | calcium | |
dc.subject | lamin | |
dc.subject | dilated cardiomyopathy | |
dc.subject | t-tubules | |
dc.subject | calcium hanlding | |
dc.subject | crispr | |
dc.subject | hipsc-cm | |
dc.subject | excitation-contraction coupling | |
dc.subject | electrophysiology | |
dc.title | Maturation and implementation of human induced pluripotent stem cell derived cardiomyocytes for modeling cardiac disease | |
dc.type | dissertation | |
dc.contributor.committeeMember | David Weaver | |
dc.contributor.committeeMember | Charles Hong | |
dc.contributor.committeeMember | Eric Delpire | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Pharmacology | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2020-05-21 | |
local.embargo.lift | 2020-05-21 | |
dc.contributor.committeeChair | Dan Roden | |