Polycystic kidney disease is the most common hereditary cause of kidney failure in man. It comprises a spectrum of diseases of which Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common form in adults and Nephronophthisis (NPHP) the most common form in children. Apart from tolvaptan, a vasopressin receptor-2 antagonist in adult patients with ADPKD, there are no other therapies currently available. Since cystoproteins form distinct protein complexes, it has been proposed that common (PC1, PC2) and rare (NPHP) cystoproteins function in a common cystic pathway1. The cytoproteins have been linked to structural or functional abnormalities in primary cilia (the cilia hypothesis) leading to these diseases being classified as ‘ciliopathies’. However, there is a large body of evidence linking their functions beyond the cilia compartment.
Several homologues of cystoproteins have been linked to actin organization and endocytic trafficking in the nematode C.elegans2. In addition, loss of the Drosophila cystogene homologue, BicC, leads to cyst-like structures in Malpighian tubules – the fly analogue of renal tubules3. Therefore, these invertebrate model organisms offer a unique opportunity to study an evolutionarily conserved mechanism which could underlie human PKD.
In this project, the student will test the hypothesis that defects in endocytosis and actin organization are primarily responsible for cyst formation in PKD. Using the adult fly kidney, the student will aim to identify the cellular basis for cyst formation using immunohistochemistry and live imaging with high-resolution microscopy, combined with quantitative analysis. Secondly, the student will aim to identify novel cystic genes using RNA interference in the C.elegans model. Finally, these novel genes will be validated genetically in the fly kidney for their effects on cyst formation and biochemically in human patient cells.
A clearer understanding of how BICC alters cellular organization and function, identification of how it interacts with other cystoproteins in flies as well as identification of novel genetic modifiers, will clarify the molecular and cellular pathogenesis of PKD and reveal new targets for developing novel treatments.
For information about the research groups visit: https://bulgakova.group.shef.ac.uk/
Twitter: @bulgakova_lab https://www.ncl.ac.uk/camb/staff/profile/josanarodriguez.html https://www.sheffield.ac.uk/iicd/profiles/ong
We encourage any student who might be interested in the project to contact Dr Natalia Bulgakova ([email protected]
) to discuss the project details.
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website: http://www.dimen.org.uk/
1 Ong, A. C. & Harris, P. C. A polycystin-centric view of cyst formation and disease: the polycystins revisited. Kidney Int 88, 699-710, doi:10.1038/ki.2015.207 (2015).
2 Lazetic, V., Joseph, B. B., Bernazzani, S. M. & Fay, D. S. Actin organization and endocytic trafficking are controlled by a network linking NIMA-related kinases to the CDC-42-SID-3/ACK1 pathway. PLoS Genet 14, e1007313, doi:10.1371/journal.pgen.1007313 (2018).
3 Gamberi, C., Hipfner, D. R., Trudel, M. & Lubell, W. D. Bicaudal C mutation causes myc and TOR pathway up-regulation and polycystic kidney disease-like phenotypes in Drosophila. PLoS Genet 13, e1006694, doi:10.1371/journal.pgen.1006694 (2017).