Novel cell models for the study of spinocerebellar ataxia type 7 pathogenesis and therapy in a South African patient cohort

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dc.contributor.advisorGreenberg, Jacquieen_ZA
dc.contributor.advisorWood, Matthewen_ZA
dc.contributor.authorWatson, Laurenen_ZA
dc.date.accessioned2014-07-28T14:53:20Z
dc.date.available2014-07-28T14:53:20Z
dc.date.issued2012en_ZA
dc.descriptionIncludes abstract.
dc.descriptionIncludes bibliographical references.
dc.description.abstractSpinocerebellar ataxia type 7 (SCA7) is a dominantly-inherited neurodegenerative disease, resulting from a CAG trinucleotide repeat expansion in the ataxin-7 gene. The Ataxin-7 protein is known to play a role in transcriptional regulation through association with cellular histone acetylation complexes, and several studies have highlighted the role of transcriptional dysregulation, caused by the presence of mutant Ataxin-7, in the neuronal dysfunction that precedes the onset of disease symptoms.This study aimed to establish patient-derived cell models of SCA7, for use in the investigation of pathogenesis (with particular reference to transcriptional alterations), and in the evaluation of previously-developed therapies for the disease.The high prevalence of SCA7 in the South African population, as a result of a founder effect, makes this disease particularly amenable to allele-specific RNA interference (RNAi)-based therapy. Thus, this study also evaluated the feasibility of these cell models as a vehicle to test previously-developed RNAi therapeutics, using the alteration of expression of key transcripts as a phenotypic marker. SCA7 patient and control dermal fibroblasts were reprogrammed to pluripotency by retroviral transduction. The resultant induced pluripotent stem cell (iPSC) lines were characterised with respect to endogenous markers of pluripotency, differentiation capacity and transgene silencing. These cells were then subjected to neuronal differentiation, the success of which was confirmed by the expression of early neuronal markers.en_ZA
dc.identifier.apacitationWatson, L. (2012). <i>Novel cell models for the study of spinocerebellar ataxia type 7 pathogenesis and therapy in a South African patient cohort</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics. Retrieved from http://hdl.handle.net/11427/3108en_ZA
dc.identifier.chicagocitationWatson, Lauren. <i>"Novel cell models for the study of spinocerebellar ataxia type 7 pathogenesis and therapy in a South African patient cohort."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics, 2012. http://hdl.handle.net/11427/3108en_ZA
dc.identifier.citationWatson, L. 2012. Novel cell models for the study of spinocerebellar ataxia type 7 pathogenesis and therapy in a South African patient cohort. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Watson, Lauren AB - Spinocerebellar ataxia type 7 (SCA7) is a dominantly-inherited neurodegenerative disease, resulting from a CAG trinucleotide repeat expansion in the ataxin-7 gene. The Ataxin-7 protein is known to play a role in transcriptional regulation through association with cellular histone acetylation complexes, and several studies have highlighted the role of transcriptional dysregulation, caused by the presence of mutant Ataxin-7, in the neuronal dysfunction that precedes the onset of disease symptoms.This study aimed to establish patient-derived cell models of SCA7, for use in the investigation of pathogenesis (with particular reference to transcriptional alterations), and in the evaluation of previously-developed therapies for the disease.The high prevalence of SCA7 in the South African population, as a result of a founder effect, makes this disease particularly amenable to allele-specific RNA interference (RNAi)-based therapy. Thus, this study also evaluated the feasibility of these cell models as a vehicle to test previously-developed RNAi therapeutics, using the alteration of expression of key transcripts as a phenotypic marker. SCA7 patient and control dermal fibroblasts were reprogrammed to pluripotency by retroviral transduction. The resultant induced pluripotent stem cell (iPSC) lines were characterised with respect to endogenous markers of pluripotency, differentiation capacity and transgene silencing. These cells were then subjected to neuronal differentiation, the success of which was confirmed by the expression of early neuronal markers. DA - 2012 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2012 T1 - Novel cell models for the study of spinocerebellar ataxia type 7 pathogenesis and therapy in a South African patient cohort TI - Novel cell models for the study of spinocerebellar ataxia type 7 pathogenesis and therapy in a South African patient cohort UR - http://hdl.handle.net/11427/3108 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/3108
dc.identifier.vancouvercitationWatson L. Novel cell models for the study of spinocerebellar ataxia type 7 pathogenesis and therapy in a South African patient cohort. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics, 2012 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/3108en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDivision of Human Geneticsen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherHuman Geneticsen_ZA
dc.titleNovel cell models for the study of spinocerebellar ataxia type 7 pathogenesis and therapy in a South African patient cohorten_ZA
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhDen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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