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G protein-coupled receptor (GPCR) signalling in the mouse and human gastrointestinal (GI) tract.

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  • Full or part time
    Prof H Cox
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (UK Students Only)
    Funded PhD Project (UK Students Only)

Project Description

Aim

To establish the mechanisms of GPR35 signalling in the mouse and human GI tract.

Background

GPR35 is an orphan receptor that lacks an endogenous ligand but is highly expressed in mammalian GI tract, particularly in the colon and is implicated in the onset of inflammatory bowel disease (IBD). Without selective agonists GPR35's mechanisms of action remain obscure. Some studies suggest that aromatic acids derived from microbial metabolism can activate GPR35, implicating a microbial sensor role for the GPCR. At high doses the clinically validated drug, sodium chromoglycate also activates GPR35 and appears to protect GI mucosa from inflammation. GPR35 is therefore a target with therapeutic potential and is of interest to our project partners at Heptares Therapeutics Ltd (Granta Park, Cambridge). Heptares have synthesised a range of potent, selective GPR35 agonists and we will evaluate their efficacies alongside chromoglycate and the aromatic acid, kynurenic acid (KA) a microbial metabolite of tryptophan. Elucidation of specific GPR35 signalling in healthy GI tissues will inform subsequent investigations of inflamed GI mucosa and the receptor’s protective potential in models of IBD. To this end we will include a mouse model of mild colitis with alternate models that most closely recapitulate human IBD, collectively tackling an unmet need for improved translational biology.

Potential Plan

Year 1
Cellular GPR35 signaling in epithelia, enteric nerves, enteroendocrine or mast cells will be investigated using proven pharmacological strategies in mouse and human colon. The student will compare the efficacies of novel GPR35 agonists, with chromoglycate and KA in normal colonic mucosae using established methods (Cox lab). Determining whether mucosal responses are luminally or basally-directed will be important for predicting future formulation, delivery and exposure effects to support work in years 2-4. In vivo transit assays will establish if i.p. or oral drug alters GI transit in normal mice.

Year 2
A proportion of this year will be spent at Heptares where the student will utilise mutated GPR35 (generated at Heptares) to establish a high confidence homology model to elucidate the molecular mechanisms of ligand binding and signalling. Autoradiographic analysis of ex vivo GI tissue will identify the cells targeted by oral or i.p. [3H]-GPR35 ligand, complementing year 1 functional studies. Inflamed GI tissues from appropriate colitis models will be assessed both functionally (at KCL) and for GPR35 expression together with other key genes implicated in mucosal changes that most closely recapitulate those in human IBD.

Years 3-4
Using chosen IBD models the student (in KCL) will treat mice with a chosen GPR35 ligand, monitoring the onset of GI inflammation by measuring epithelial integrity functionally and histologically (scoring the degree of inflammation and stool consistency) and comparing murine mucosal erosion and dysplasia with that in human IBD colon. Optimised GPR35 ligand dosing (oral or i.p.) will test whether administered drug protects against a given inflammatory challenge and maintains mucosal health and normal rates of GI and colonic transit. Finally, the student will integrate their results into a predictive model of GPR35 signaling, i) common to healthy mouse and human tissue, ii) in inflamed colon and in-so-doing determine whether, and hopefully where, GPR35 is a therapeutic target for treating IBD.

Impact

This research will improve our understanding of GPR35 signalling in healthy gut and uncover how this biology changes in models of IBD. By comparing signalling in IBD models that emulate aspects of human IBD we aim to better translate GPCR biology from mouse in to man. Failure to treat IBD is currently a significant health-burden and often patients require parenteral feeding or GI surgery.

Funding Notes

Fully funded place including home (UK) tuition fees and a tax-free stipend in the region of £16,777, plus a stipend enhancement of £2,000 per annum. Students from the EU are welcome to submit an application for funding, any offers will be subject to BBSRC approval and criteria.

References

Example citations from Cox and key collaborators:

Tough IR, Forbes S, Herzog H, Jones RM, Schwartz TW & Cox HM (2018) Bidirectional GPR119 agonism requires peptide YY and glucose for activity in mouse and human colon mucosa. Endocrinol. 159, 1704-1717.
Alamshah A, McGavigan AK, Spreckley E, Kinsey-Jones JS, Amin A, Tough IR, O'Hara HC, Moolla A, Banks K, France R, Hyberg G, Norton M, Cheong W, Lehmann A, Bloom SR, Cox HM, Murphy KG. (2016) L-arginine promotes gut hormone release and reduces food intake in rodents. Diabetes Obes Metab. 18(5), 508-18.
and Heptares Therapeutics Ltd:
Jazayeri A, Rappas M, Brown AJH, Kean J, Errey JC, Robertson NJ, Fiez-Vandal C, Andrews SP, Congreve M, Bortolato A, Mason JS, Baig AH, Teobald I, Doré AS, Weir M, Cooke RM, Marshall FH. (2017) Crystal structure of the GLP-1 receptor bound to a peptide agonist. Nature, 546 (7657): 254-258.
Jazayeri A, Doré AS, Lamb D, Krishnamurthy H, Southall SM, Baig AH, Bortolato A, Koglin M, Robertson NJ, Errey JC, Andrews SP, Teobald I, Brown AJ, Cooke RM, Weir M, Marshall FH. (2016) Extra-helical binding site of a glucagon receptor antagonist. Nature, 533 (7602): 274-277.



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