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
‘Medicine’ as the department.
Website: http://www.sheffield.ac.uk/faculty/medicine-dentistryhealth/graduateschool/prospectivepg/vacancies/ii
Closing date: To be agreed