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Defining the interplay between polycystin 1/2 signalling and cAMP signalling in different subcellular domains

BBSRC Interdisciplinary Bioscience DTP

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Prof M Zaccolo No more applications being accepted Funded PhD Project (European/UK Students Only)

About the Project

Primary cilia are ubiquitous organelles fundamental for vision, hearing, smell perception, breathing, excretion, reproduction and development and their disruption or loss leads to several diseases (ciliopathies). Primary cilia act as cellular antenna that receive, integrate, and transmit extracellular signals to intracellular compartments via modulation of signalling cascades, including Ca2+ and cAMP pathways. Polycystin-1 (PC1) and polycystin-2 (PC2) are required for induction of calcium transients in response to ciliary bending, however the precise function of the PC complexes on the cilium is a hotly debated and unresolved issue and there are fundamental questions outstanding as to whether changes in Ca2+ and cAMP in the cilia compartment can have the observed global cytoplasmic effects associated with PC1/PC2 mutations. Mutations in PC1 and PC2 cause autosomic dominant polycystic kidney disease (ADPKD), a condition where a complex involving PC1/2: PKA: Akap150: PDE4C has been suggested to drive cyst formation.

The student will use genetically encoded FRET reporters for cAMP that are targeted to specific subcellular sites (including cilia, basolateral membrane and endoplasmic reticulum) and mutagenesis or knock down (siRNA) of PC1/2, in combination with selective pharmacological manipulation of cAMP levels in order to establish how different PC domains modulate compartmentalised cAMP signalling and how this affects cellular function. The impact on compartmentalised cAMP signalling of manipulation of PDE4 activity will be investigated.

The research will be conducted predominantly in the Department of Physiology, Anatomy and Genetics at the University of Oxford and partly in the Mironid laboratories at Strathclyde University, central Glasgow.

The student will be trained in the development of novel targeted cAMP sensors, in their validation and calibration using ‘in cell’ approaches (for quantitative analysis of cAMP dynamics), as well as in real-time FRET imaging. In addition, the students will gain skills in isolation of primary cells, tissue culture, cell proliferation essays , fluid excretion (MDCK cysts formation essay, gene expression and knock down (siRNA) and general molecular biology and biochemistry techniques (quantitative PCR, immunoprecipitations and western blotting, immunocytochemistry). During the placement with Mironid Ltd. the training will include an understanding of the principles of drug discovery (structure activity relationships, translational relevance of bench science and pharmacokinetic properties required for drug development).

Attributes of suitable applicants: We are looking for a strongly motivated and committed individual with an enthusiastic approach to science and with excellent organisational and verbal skills. The candidate must hold a degree in a relevant area such as biomedical sciences, physiology or biochemistry and an interest in cellular signalling.

How to apply:
If you are interested in applying for a BBSRC iCASE studentship please contact the named supervisor, Manuela Zaccolo ([Email Address Removed]) for further information and to determine whether they would encourage you to apply. Applicants who wish to apply for a BBSRC iCASE studentship should make an enquiry to the Interdisciplinary Bioscience DTP via [Email Address Removed] for advice on making a full and formal application to the University.

Funding Notes

Funding notes: This project is funded for four years by the Biotechnology and Biological Sciences Research Council BBSRC. BBSRC eligibility criteria apply ( Annexe 1). EU nationals who do not meet BBSRC residence criteria are encouraged to contact the programme administrator to check their eligibility for BBSRC funding before submitting a formal application. Successful students will receive a stipend of no less than the standard RCUK stipend rate, currently set at £14,777 per year, which will usually be supplemented by the industrial partner.
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