Development and Optimization of a Cellular Model for the Dilated Cardiomyopathy with Ataxia Syndrome

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dc.contributor.advisorGreenway, Steven C.
dc.contributor.authorMachiraju, Pranav
dc.contributor.committeememberKhan, Aneal
dc.contributor.committeememberShutt, Timothy E.
dc.date2019-06
dc.date.accessioned2019-01-23T16:25:37Z
dc.date.available2019-01-23T16:25:37Z
dc.date.issued2019-01-22
dc.description.abstractThe dilated cardiomyopathy with ataxia syndrome (DCMA) is an autosomal recessive disorder caused by mutations in the poorly-characterized but essential gene DNAJC19. Tissue studies have shown that the loss of functional DNAJC19 protein has major consequences for mitochondrial structure and function, but the mechanism of disease remains unknown. Given that affected individuals frequently die in early childhood due to intractable heart failure, the development of therapeutics is imperative. Cellular modelling in vitro represents an important first step in characterizing the disease phenotype and testing the effect of potential drug therapies. This thesis aimed to characterize mitochondrial structural abnormalities in DCMA using patient dermal fibroblasts and cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs). We hypothesized that patient cells would identify abnormalities in mitochondrial structure and function and that treatment with the mitochondrially-targeted peptide SS-31 would be effective in correcting these deficiencies. We report increased mitochondrial fragmentation and increased production of reactive oxygen species (ROS) in fibroblasts, both of which improved following treatment with SS-31. A similar phenotype was found in iPSC-CMs. Additional work to improve our iPSC-CM model used the pan-retinoic acid receptor inverse agonist BMS493 to direct the specification and maturation of iPSCs into ventricular cardiomyocytes. Cells treated with BMS493 demonstrated a slower beating rate and increased contractility compared to untreated cells. This thesis provides a previously-lacking characterization of DCMA mitochondria in fibroblasts and iPSC-CMs, identifies SS-31 as a potentially effective therapeutic for DCMA and developed and improved a patient-, tissue-, and disease-specific in vitro model for DCMA using iPSC-CMs that will be useful for further characterization and modelling of DCMA and other cardiomyopathies.en_US
dc.identifier.citationMachiraju, P. (2019). Development and Optimization of a Cellular Model for the Dilated Cardiomyopathy with Ataxia Syndrome (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/35755
dc.identifier.urihttp://hdl.handle.net/1880/109496
dc.language.isoenen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectDilated cardiomyopathy with ataxiaen_US
dc.subjectDCMAen_US
dc.subjectpediatricen_US
dc.subjectcardiomyopathyen_US
dc.subjectdisease modellingen_US
dc.subjectprecision medicineen_US
dc.subjectregenerative medicineen_US
dc.subjectstem cellsen_US
dc.subjectfibroblastsen_US
dc.subject.classificationEducation--Sciencesen_US
dc.subject.classificationBiology--Cellen_US
dc.subject.classificationMedicine and Surgeryen_US
dc.subject.classificationBiochemistryen_US
dc.subject.classificationEngineering--Biomedicalen_US
dc.titleDevelopment and Optimization of a Cellular Model for the Dilated Cardiomyopathy with Ataxia Syndromeen_US
dc.typemaster thesisen_US
thesis.degree.disciplineMedicine – Cardiovascular/Respiratory Scienceen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameMaster of Science (MSc)en_US
ucalgary.item.requestcopytrue
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