Browsing by Author "Machiraju, Pranav"

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    Development and Optimization of a Cellular Model for the Dilated Cardiomyopathy with Ataxia Syndrome
    (2019-01-22) Machiraju, Pranav; Greenway, Steven C.; Khan, Aneal; Shutt, Timothy E.
    The 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.