The University of Sheffield Faculty of Medicine, Dentistry & Health Department of Infection and Immunity Regulation of compartmentalised cellular signalling in Autosomal Dominant Polycystic Kidney Disease Supervisor: Prof Albert Ong and Dr Andrew Streets, Kidney Genetics Group, Academic Nephrology Unit Project: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney disease known. It has an incidence of 1 in 500 and affects 12 million people world-wide. ADPKD is caused by mutations in two genes, PKD1 (85%) and PKD2 (15%). PKD1 encodes a Type 1 integral membrane protein, polycystin-1 (PC1) with a predicted modular structure. The PKD2 protein, polycystin-2 (PC2 or TRPP2) is a high conductance non-selective Ca2+ permeable channel. The PC1/PC2 protein complex has been immunolocalised to several cellular compartments including primary cilia/centrosomes and cell-cell junctions where it can function as a mechanosensitive or ligand-activated receptor. Mutations in PKD1 or PKD2 result in alterations in Ca2+ and cAMP-dependent signaling. Agents that alter cAMP signalling have been shown to slow disease progression in man. We have recently proposed a new disease paradigm for how the complex might function and be altered in disease. PC2 is hyperphosphorylated at a critical protein kinase A (PKA) regulated site in the absence of PC1: the function of PC1 is to recruit protein-phosphatase-1 (PP1) to dephosphorylate PC2 possibly at basolateral junctions. Another group has reported that PC2 binds to a PKA regulated complex in primary cilia via a distinct PKA adaptor protein (AKAP). This project will test the hypothesis that PC1 and PC2 function in distinct signalling microdomains and that this is mediated by different protein scaffolds exemplified by PKA/AKAP/PP1 protein complexes. Knowledge of these critical steps will facilitate the rational design of new therapies to treat ADPKD. The successful applicant will have the exciting opportunity to join a highly successful research group working on a common human genetic disease and will gain experience in cutting-edge techniques in protein chemistry, molecular biology and cell biology. References 1. Streets, A.J., et al., Hyperphosphorylation of polycystin-2 at a critical residue in disease reveals an essential role for polycystin-1-regulated dephosphorylation. Human molecular genetics, 2013. 22(10): p. 1924-39. 2. Watnick, T.J. and G.G. Germino, Polycystic kidney disease: Polycystin-1 and polycystin-2-it's complicated. Nature reviews. Nephrology, 2013. 9(5): p. 24950. 3. Chang, M.Y. and A.C. Ong, New treatments for autosomal dominant polycystic kidney disease. British journal of clinical pharmacology, 2013. 76(4): p. 524-35. 4. Choi, Y.H., et al., Polycystin-2 and phosphodiesterase 4C are components of a ciliary A-kinase anchoring protein complex that is disrupted in cystic kidney diseases. Proceedings of the National Academy of Sciences of the United States of America, 2011. 108(26): p. 10679-84. 5. Torres, V.E., et al., Tolvaptan in patients with autosomal dominant polycystic kidney disease. The New England journal of medicine, 2012. 367(25): p. 240718. Entry Requirements: Candidates must have a first or upper second class honors degree or significant research experience. Enquiries: Interested candidates should in the first instance contact Prof Albert Ong (a.ong@sheffield.ac.uk). How to apply: Please complete a University Postgraduate Research Application form and attach at least two references to your application. To complete the application form please visit: www.shef.ac.uk/postgraduate/research/apply. Please clearly state the prospective main supervisor in the respective box and select ‘Infection & Immunity’ as the department. 'The Medical School has received a Silver Athena SWAN award for promoting gender equality’ Website: http://www.sheffield.ac.uk/faculty/medicine-dentistryhealth/graduateschool/prospectivepg/vacancies/ii Closing date: 3rd February 2014