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Title: The role of primary cilia in the pathogenesis of ADPKD
Author: Prosseda, Philipp Paolo
ISNI:       0000 0004 6062 5109
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 the most common inherited kidney disease. Mutations in PKD1 (85%) or PKD2 (15%) account for almost all cases of ADPKD. The ADPKD proteins, termed polycystin-1 (PC1) and polycystin-2 (PC2) form a receptor-ion channel complex and in part, co-localise to the primary cilia. Since primary cilia are reported to be structurally normal in ADPKD unlike other ciliopathies, this project sought to test the hypothesis that changes in ciliary dynamics in relation to extracellular or intracellular stimuli might be an unrecognised feature of ADPKD. Primary cilia assembly and disassembly was assessed in several established cellular models and shown to be synchronised to the cell cycle. In both control and ADPKD cell models, changes in intracellular Ca2+ and cAMP were found to similarly regulate ciliary length. Unexpectedly, primary cilia in ADPKD cell models were consistently shorter compared to normal controls; this was confirmed in diseased kidney tissue. Disease cells showed evidence of increased actin and microtubule polymerisation and disorganisation compared to controls. Of significance, the defect in cilia length could be fully restored by cytochalasin D, an inhibitor of actin polymerisation. This effect was independent of cAMP/PKA signalling. Inhibition of Rho GTPases showed differential effects on cilia length between control and disease cells with the most specific difference observed with a Rho inhibitor. Disease cells were less able to reorient cilia towards the migratory axis in wounding assays. Finally, several cystoproteins were shown to bind to either polycystin-1 or polycystin-2 and regulated cilia length (INPP5E) or polycystin-2 localisation to cilia (INVS). These results indicate that a primary defect in actin organisation may result from polycystin-1 deficiency. Restoring actin dynamics in ADPKD may restore the structure and function of the primary cilium and could offer an alternative treatment strategy for ADPKD.
Supervisor: Ong, Albert ; Streets, Andrew Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available