£6,000 FindAPhD Scholarship | APPLICATIONS CLOSING SOON! £6,000 FindAPhD Scholarship | APPLICATIONS CLOSING SOON!

Intestinal G protein-coupled receptors (GPCRs): characterising gut GPCR-signalling with potential to treat colitis.


   Wolfson Centre for Age Related Disease

This project is no longer listed on FindAPhD.com and may not be available.

Click here to search FindAPhD.com for PhD studentship opportunities
  Prof H Cox, Dr Alastair Brown , Dr Rie Suzuki  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

AIMS: i) to establish the efficacy of first-in-class compounds for gastrointestinal (GI) G protein-coupled receptors (GPCRs) and,

ii) to characterise signaling pathways that protect and/or reverse colitis in a mouse model.

Free fatty acid receptors (FFARs) are GPCRs known to be expressed in enteroendocrine cells and are therefore likely to be involved in nutrient- and microbial metabolite signaling in the mammalian GI tract. FFA1 and FFA4 are co-activated by long-chain fatty acids (LCFAs) while FFA2 and FFA3 are preferentially co-stimulated by microbial-derived short chain fatty acids (SCFAs). The nonselectivity between these pairs of receptors is complicated further by other GPCRs with affinity for fatty acids. For example, SCFAs activate GPR109A (also known as HCA2; Husted et al 2017) as well as olfactory receptors Olf78 and Olf558 (Bellono et al 2017) making specific FFAR functions difficult to characterise, due to lack of selective ligands. Thus, the roles of this GPCR group remain obscure in terms of GI health and disease. 

Using commercially available tools, Cox et al have however partially characterized FFA1-4 signaling in healthy GI mucosae and established their effects on GI transit in mice (Forbes et al 2015; Moodaley et al 2017; Tough et al 2018). This has been achieved using a combination of proven electrophysiological in vitro methods (measuring epithelial ion transport and barrier function in parallel in mucosae) and measuring changes in upper and lower GI transit (Tough et al 2011). Our in-depth understanding of neuro-epithelial signaling within the GI tract, has been critical too. Notably, we see similar pharmacology and cellular mechanisms for FFA2 & FFA3 activities in normal mouse and human colon (Tough et al 2018) indicating translation of this approach. Selective, potent FFAR ligands are now critical for continued progress. With Sosei-Heptares, our combined understanding of GI signalling is allowing us to characterise mucosal functions in health and dysfunctions induced by acute GI inflammation. To this end we will include a mild colitis, dextran sulphate sodium (DSS) model which our PhD student, C.Evans (in Cox lab) is showing currently, recapitulates aspects of colitis pathology observed in man, allowing us to test the protective potential of novel ligands in mice.  

Heptares have via their proprietary GPCR-targeted STaR® technology (https://soseiheptares.com/about-sosei-heptares) produced structurally diverse, first-in-class FFA4 and GPR109A ligands as well as selective FFA1, FFA2 and FFA3 synthetic agonists, with therapeutic potential as modulators of GI immune responses (van Daal et al 2021). However, the relative drug potencies in defined GI regions are unknown. This project will utilise chosen ligands for the target GPCR, to establish their efficacies in mouse GI tract allowing clear signalling pathways and functional significance of the specific receptor to be identified. 

Heptares also collaborate with a CRO (Selvita, in Zagreb, Croatia) who provide us with pathological validation of different rodent models of colitis. We benefit significantly from this established relationship and Evans (LiDO student in year 3, also funded by Heptares) is currently optimising a low dose, repeated dextran sodium sulphate (DSS) exposure that induces mild colitis in mice (Evans et al unpublished). We plan to include this optimised model in future assessments of novel drug anti-inflammatory GI activities.

Our proposal will establish therapeutic utility and ligand bioavailability underpining GI efficacy in vivo, thus contributing understanding of a novel potential therapy for colitis treatment.

Knowledge exchange

Throughout this project the student will join our bimonthly on-line meetings with Sosei-Heptares, plus monthly Cox lab meetings with Selvita and Sosei-Heptares. At both gatherings we update colleagues on recent data and agree next steps. This efficient, frequent dialogue has been running for 5 years and will continue into 2026. We aim to publish our data in journals with high impact and, in years 2-3 the student will present their work to members of WCARD (KCL) and at national meetings (e.g. British Pharmacological or Physiological Society) and international meetings (year 4; Keystone or AGA meetings, USA).  

Funding Notes:

This project is fully funded for four years, with the student receiving the following support:

-         Stipend: Students will receive a tax-free stipend for each year of study, starting on £20,562 in year 1 and increasing each year with inflation.

-         Tuition fees: Students tuition fees for each year of study are fully covered. The amount of £4,596 in 2022/23, rates for subsequent years will be announced by UKRI.

-         Bench fees: a generous allowance of £6,400 each year provided towards research consumable and project costs.

-         Travel and conference allowance: £300 each year provided to support students in attending UK and international conferences.

Funding source: this project is co-funded by the Medical Research Council and the Industry Partner, Sosei-Heptares Therapeutics Ltd, Cambridge, UK.

Eligibility:

To be classed as a home student, candidates must meet the following criteria:

•Be a UK National (meeting residency requirements), or

•Have settled status, or

•Have pre-settled status (meeting residency requirements), or

•Have indefinite leave to remain or enter

Enquiries email name and address:

Prof Helen Cox ( [Email Address Removed] )

Application Web Page:

Full details on how to apply here: https://kcl-mrcdtp.com/studentships/icase-studentships/icase-application-process/


References

Al-Horani R et al (2022) Nat Revs Drug Disc. 21, 15-16. Bellono NW et al (2017) Cell, 170, 185-198. Forbes S & Cox HM (2014) Neurogastroenterol. Motil. 26, 1605-1614. Forbes S et al (2012) Br J Pharmacol. 166, 2307-2316. Forbes S et al (2015) Diabetes, 64, 3763-3771. Husted AM et al (2017) Cell Metab. 25, 777-796. Moodaley R et al (2017) Br J Pharmacol. 174, 4508-4522. Tough IR et al (2011) Br J Pharmacol. 164, 66-79. Tough IR et al (2018) Neurogastroenterol. Motil. 30(12), e13454. van Daal MT et al (2021) Pharmacol Rev. 73, 198-232. Wirtz S et al (2017) Nature Protocols 12, 1295-1309.
Search Suggestions
Search suggestions

Based on your current searches we recommend the following search filters.

PhD saved successfully
View saved PhDs