The University of Sheffield

Faculty of Medicine, Dentistry & Health

Department of Infection and Immunity

ADPKD as a disease of hyperphosphorylation: investigating a new paradigm of disease pathogenesis (KRUK funded studentship)

Supervisors: 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. 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).

Starting with PC2 dephosphorylation as a paradigm, we will test this hypothesis using a series of different experimental approaches.Identification of specific kinases or phosphatases that regulate key rate-limiting steps could lead directly to new treatments to prevent or retard cyst formation in ADPKD.

This prestigious studentship, funded by Kidney Research UK, will be an exciting opportunity to join a highly successful group working on a common human genetic disease. The project will build on active collaborations with the MRC Protein Phosphorylation Unit, Dundee and other leading scientific groups in the USA and Europe.

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. 249-50.

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. 2407-18.

Entry Requirements:

Candidates must have a first or upper second class honors degree or significant research experience. Evidence of interest and experience in genetics, cell biology or protein biochemistry and its translation to human disease would be an advantage.

Enquiries:

Interested candidates should in the first instance contact Prof Albert Ong ().

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.

Website: http://www.sheffield.ac.uk/faculty/medicine-dentistry-health/graduateschool/prospectivepg/vacancies/ii

Closing date: Monday 30th June 2014