Nazmutdinova, Jekaterina;
(2018)
Ciliopathies: genetic testing, disease modelling and therapeutic interventions.
Doctoral thesis (Ph.D), UCL (University College London).
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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.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Ciliopathies: genetic testing, disease modelling and therapeutic interventions |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2018. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10064717 |
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