Molecular Pharmacology of the Lipid/pH-sensing GPCRs as modulators of immune cell function

The Lipid/pH-sensing receptor family are a cluster of four G protein coupled receptors (GPCRs) with roles in immune cell function and cancer cell proliferation1. They respond to changes in levels of lipid mediators and/or pH caused by microenvironmental changes in different physiological contexts. Members of this family are present in cells such as monocytes and macrophages but only limited information is available concerning how they modulate the inflammatory response.

This project aims to increase our fundamental understanding of these GPCRs by defining how they engage different intracellular signalling pathways to control cellular responses, using recently developed intracellular biosensors. Initially, these GPCRs will be studied using model cell systems but observations will be extended to physiologically-relevant contexts including surrogate monocyte-like cell lines and primary cultures of monocytes/macrophages.

A major challenge in the development of new therapies is to define the molecular mechanisms of drugs that drive their physiological effect. In historical drug discovery, this gap is often unresolved when candidate compounds enter clinical testing, increasing the likelihood of failure. A new approach is to generate matrices of data across many different parameters, and to harness modelling and/or AI/ML data analytic approaches to identify predictors of efficacy. The student will utilise available experimental approaches along with in house analytical support to build a data matrix for a chosen GPCR from the lipid/pH-sensing family.