Please use this identifier to cite or link to this item: http://theses.ncl.ac.uk/jspui/handle/10443/4474
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dc.contributor.authorLee, David Charles-
dc.date.accessioned2019-09-06T13:04:46Z-
dc.date.available2019-09-06T13:04:46Z-
dc.date.issued2019-
dc.identifier.urihttp://theses.ncl.ac.uk/jspui/handle/10443/4474-
dc.descriptionPhD Thesisen_US
dc.description.abstractArrhythmogenic right ventricular cardiomyopathy / dysplasia (ARVC/D) is a cause of ventricular arrhythmia and heart failure in adults. Fifty percent of subjects with ARVC/D carry pathogenic variants in the genes encoding desmosomal proteins. ARVC/D is associated with changes in cardiac desmosomal ultrastructure and the cellular distribution of desmosomal proteins in cardiomyocytes. These changes may be part of a common pathway of pathogenesis for the disease. Induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) carrying ARVC/D associated variants have been reported to recapitulate features of the disease. Five iPSC-CM models of ARVC/D have been reported, all of which carry mutations in the gene encoding the desmosomal protein plakophilin 2. In this study iPSC-CMs were generated from the peripheral blood mononuclear cells of a control subject and three subjects with ARVC/D. The ARVC/D iPSC-CMs carried pathogenic variants three different desmosomal genes: plakophilin 2 (PKP2), desmoglein 2 (DSG2), and desmoplakin (DSP) that have not been studied previously using cellular or animal models. No differences were found in either the cellular distribution of desmosomal proteins or the ultrastructure of desmosomes when ARVC/D and control iPSC-CMs were compared. It was concluded that iPSC-CMs are not as robust a platform for modelling ARVC/D as had been previously reported. The expression of desmosomal genes in iPSCs were at levels similar to those seen in iPSC-CMs. The differentiation of iPSCs to iPSC-CMs was associated with a decrease in the expression of genes encoding desmosomal cadherins and an increase in those encoding arm-repeat proteins. There was also evidence of desmosomal protein expression and the presence of desmosomes in iPSC cultures. It is suggested that intercellular adhesion junctions containing desmosomal proteins have a role in the maintenance of pluripotency in iPSCs in vitro and changes in desmosomal gene and protein expression are important in defining the cardiac differentiation of iPSCs.en_US
dc.description.sponsorshipNewcastle upon Tyne Hospitals NHS Charityen_US
dc.language.isoenen_US
dc.publisherNewcastle Universityen_US
dc.titleStudying arrythmogenic right ventricular cardiomyopathy : dysplasia using induced pluripotent stem cellsen_US
dc.typeThesisen_US
Appears in Collections:Institute of Genetic Medicine

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