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Phd - Functional consequences of biased signalling at neuronal G protein-coupled receptors

Employer
Global Academy Jobs
Location
United Kingdom
Closing date
Dec 5, 2016

Job Details

Supervisors: Prof Kelly, University of Bristol, Dr Bailey, University of Bath. The discovery of biased agonism at G protein-coupled receptors (GPCRs) has revolutionised GPCR research and presented opportunities for the development of novel drugs to treat a range of disease states. This proposal will address a key unanswered question in the field: what are the long-term consequences of biased signalling at GPCRs? Activated GPCRs signal through intracellular G-proteins, but can then be phosphorylated by G-protein coupled receptor kinases (GRKs). Arrestin binds to the phosphorylated receptor, leading to desensitization of the receptor and drug tolerance. Although ~40% of current drug treatments act through GPCRs, very few are GPCR agonists, largely because of drug tolerance. Recently, however, agonist-specific GPCR signalling (‘biased agonism’) has been shown.

A major form of biased agonism is in terms of an agonist’s ability to signal via G-proteins vs phosphorylation and desensitization via GRK/arrestin. This could lead to the design of novel compounds that can induce conventional G-protein-mediated signalling, but evade desensitization and tolerance. This project will use a powerful combination of molecular techniques, whole animal behaviour and brain slice electrophysiology to study the long-term functional consequences of biased signalling at GPCRs. The mu-opioid receptor (MOPr) has been at the forefront of biased signalling studies, including from the supervisory team (e.g. Mol Pharm 2015 88:347; Br J Pharm 2015 172:593; Nature 2015 524:315). Mice will be treated with unbiased MOPr agonist, or novel G protein- or arrestin-biased MOPr agonists (synthesized by Prof. Husbands, Bath) both acutely and chronically. Brain samples from treated animals will be taken and used to investigate the phosphorylation state of the MOPrs, using Western blotting with phospho-specific antibodies and Mass spectrometry/phosphoproteomics with subsequent bioinformatics analysis (Prof Kelly, Bristol).

In parallel MOPr function will be assessed both in the whole animal (analgesia, respiration, reward testing; Prof Henderson, Bristol and Dr Bailey, Bath) and in ex vivo brain slices using patch-clamp electrophysiology (Dr Bailey, Bath).This transdisciplinary project will for the first time uncover the long term consequences of biased agonism at MOPrs in neurones, findings which will be relevant to many other neuronally-expressed GPCRs. Added Value: The student will gain experience in techniques and approaches across discipline boundaries: medicinal chemistry, molecular pharmacology and phosphoproteomics, slice electrophysiology and in vivo behaviour. State-of-the-art technologies include phosphoproteomics and bioinformatics. Knowledge Transfer: Results will be disseminated to key stakeholders by presenting findings at international conferences, by publishing in high impact factor journals and by direct interactions with industry: the project supervisors have partnerships with the pharmaceutical industry (eg. GSK, Pharmnovo).

Funding Notes

This is a 4 year studentship funded by the South West Biosciences Doctoral Training Partnership (SWBio DTP) and covers: a stipend (at the standard Research Councils UK rate; currently £14,296 per annum for 2016-2017), research and training costs, tuition fees and additional funds to support fieldwork, conferences and a 3-month internship

For full details on eligibility and how to apply please go to the following links: View Website and View Website PLEASE ENSURE that you select the Faculty of Biomedical Sciences and the programme choice South West Biosciences Doctoral Training Partnership (PhD)

Supervisor: Dr Kelly

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