The INSL5/ relaxin (RXFP4) receptor axis: How the large intestine is controlled
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Project Leader/Supervisor
Professor John Furness
Project Details
Our team has been investigating structurally-related analogues and the physiological roles of the gut hormone, insulin-like peptide 5 (INSL5), an endogenous ligand for the G protein-coupled receptor RXFP4. Our recent discoveries indicate that INSL5 is a physiological regulator of colonic emptying and that RXFP4 agonists and antagonists have the otential for treating constipation and diarrhea, respectively, unmet medical needs that are associated with significantly reduced health-related quality of life.
In this project, we are optimising lead compounds, including enhancing half-lives and oral bioavailability and carrying out a structure-based drug design program that will lead to the production of long-acting analogues with improved oral bioavailability. We are validating the effectiveness and specificity of the novel RXFP4 agonists and antagonists in transfected cells, isolated organs, and in vivo.
Researchers
- Project supervisors: Professor John Furness, Professor Akhter Hossain
- Project members: Professor Akhter Hossain, Professor Ross Bathgate, Professor John Furness; Dr Tom Handley, Mr Hongkang Wu, Ms Enie Lei
Collaborators
Professor Frank Reimann (University of Cambridge)
Dr Ada Koo (Peter MacCallum Institute)
Research Publications
Diwakarla S, Bathgate RAB, Zhang X, Hossain MA and Furness JB: Colokinetic effect of an insulin-like peptide 5 related agonist of the RXFP4 receptor. Neurogastro Motil 32, e13796 (2020)
Pustovit RV, Zhang X-Z, Liew J, Praveen P, Liu M, Koo A, Oparija-Rogenmozere L, Ou Q, Kocan M, Nie S, Bathgate RAB, FurnessJBand Hossain MA. A novel antagonist peptide reveals a physiological role of insulin-like peptide 5 in control of colorectal function. ACS Pharmacol Translational Sci. 4, 1666-1674 (2021) doi.org/10.1021/acsptsci.1c00171.
Koo A, Pustovit RV, Woodward ORM, Lewis JE, Gribble FM, Hossain MA, Reimann F, Furness, JB: Expression of the relaxin family peptide 4 receptor by enterochromaffin cells of the mouse large intestine. Cell Tissue Res 389,1-9 (2022) doi.org/10.1007/s00441-022-03635-8