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Title: A study of ADPKD pathogenesis and treatment in zebrafish models
Author: Metzner, Aylin
ISNI:       0000 0004 5993 270X
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2016
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Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most common monogenic diseases with a worldwide incidence of 1/1000. It is caused by mutations in PKD1 or PKD2. Around 10% of all end-stage renal disease results from ADPKD, translating into an annual cost of €1.5 billion across Europe. Although tolvaptan has recently been licensed for use in patients with evidence of rapid disease progression, it is only moderately effective and associated with significant side effects, resulting in the urgent need to identify new treatments. In this project, a pkd2 zebrafish mutant (pkd2hu2173) was used for compound library screens with commercial drug libraries. The dorsal tail curvature phenotype, the most penetrant ADPKD-related trait in this mutant, was chosen as the assay read-out. After thorough testing, the most promising compounds were studied in three-dimensional mammalian cyst assays using both canine (MDCK) and human (Ox161c1; PKD1-/- ) cell lines. Experiments in cyst assays largely confirmed the hit compounds as relevant to cyst formation and expansion. Several hits linked to pathways previously implicated in other ADPKD models including androgens, prostaglandins and TGFß but the precise role of others remains to be identified. Using a novel kidney calcium-reporter zebrafish line enpep:Gal4;UAS:GCaMP7a, in vivo Ca2+ levels were found to be reduced in pkd2 mutant fish compared to sibling controls. Genetic interactions between pkd2 and elipsa, a ciliary protein, were observed for tail curvature and glomerular dilatation, providing the first evidence of a non-redundant function for pkd2 in the zebrafish pronephros. In conclusion, this study has identified several new compounds and pathways relevant to cystogenesis using a zebrafish pkd2 model and provided the first evidence of a nonredundant function for pkd2 in the zebrafish kidney. The zebrafish pkd2 mutant will continue to be a useful model to study ADPKD pathogenesis and potential treatments.
Supervisor: Ong, Albert ; van Eeden, Freek Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available