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Title: Investigating the role of ciliary localisation of the TRPP Channel, Polycystin2 (PKD2), on development and progression of polycystic kidney disease
Author: Walker, Rebecca
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common inherited disease, affecting 1:400-1000 people worldwide and leads to end-stage renal failure in most patients before their 6th decade. ADPKD is characterised by abnormal persistent cellular proliferation combined with luminal fluid secretion in the kidneys leading to bilateral development of cysts. There are two causative genes associated with the development of ADPKD; PKD1 and PKD2. PKD2 is an essential Ca2+ permeable cation channel which localises to the primary cilium in renal tubules as well as other locations within the cell. Here we investigate the effects of aberrant cellular localisation of PKD2, specifically the loss of ciliary localisation. We used a non-ciliary localising mutant allele (Pkd2lrm4) which retains channel function, for in vitro and in vivo mouse studies to show that there is an absolute requirement for the protein within the cilium. Embryonically, Pkd2lrm4/lrm4 kidneys exhibit gross cystic development, beginning at E15.5. Heterozygotes develop a mild cystic phenotype in combination with polycystic liver disease. When expressed in combination with an inducible null allele in the proximal tubule of the adult kidney, a progressive development of cysts is observed. In vitro studies using Pkd2lrm4/lrm4 MEFs show specific accumulation of the protein at the mother centriole. In addition to protein glycosylation studies, this indicates that PKD2 is able to traffic normally to the ciliary base, but cannot enter the cilium. This work indicates an essential role for PKD2 in the cilium and that non-ciliary function alone is not sufficient to prevent cyst formation. In addition, this work provides a viable genetic model for the study of progression in Polycystic Kidney Disease.
Supervisor: Christian, Helen ; Norris, Dominic Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available