Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.771853
Title: Ciliopathies : genetic testing, disease modelling and therapeutic interventions
Author: Nazmutdinova, Jekaterina
ISNI:       0000 0004 7660 0993
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Abstract:
Nephronophthisis (NPHP) is a frequent ciliopathy leading to renal failure before the onset of adulthood with no effective preventative treatment available to date. My first aim was to model NPHP on zebrafish by morpholino knockdown of several NPHP genes. I chose ift172/nphp17 morphant in two drug-repurposing screens. First, in the screen of 640 FDA drugs I identified 19 compounds that exacerbated cystic phenotype, but none which could rescue it. Second, a screen of fifteen Polycystic Kidney Disorder drugs identified three that do rescue cystic phenotype of both ift172 morphant and ift144 mutant zebrafish. In the second study I used alternative approach for disease modeling and characterised renal epithelial cells derived from BBS patients' urine with or without renal involvement with an aim to identify phenotypic read-outs for potential therapeutic intervention. Urine-derived Renal Epithelial Cells (URECs) were cultured as 3D organoids and data on 13 Bardet-Biedl Syndrome patients showed striking differences in proliferative index, 3D growth profiles and cilia length of BBS URECs, potentially offer ex vivo strategy to personalise medicine for patients with ciliopathies. In the third study I sequenced 117 BBS multi-ethnic cohort of patients without molecular diagnosis by using Fluidigm targeted sequencing approach. Most of the patients originated from Turkey (71/117), representing the largest BBS Turkish cohort studied to date. Definite molecular diagnosis was established for just under 50% of cases, with a different genotype distribution to Caucasian BBS patients. Forty-eight pathogenic variants are reported for the first time, confirming heterogeneity of the molecular genetics of BBS.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.771853  DOI: Not available
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