GPCR drug discovery using the Zebrafish model.

This project is an exciting opportunity to combine zebrafish genetics with chemical biology to understand the function of a G protein-coupled receptor (GPCR). The GPCR superfamily includes targets of many known drugs, but also retains enormous potential for future drug discovery. The focus of this project is on Adgrg6 (Gpr126), an adhesion class GPCR with known roles in development of the inner ear and myelination of the peripheral nervous system. Mutations in Adgrg6 are known to result in human disease. The project will use the zebrafish embryo as a screening tool to identify small molecules that can modulate the Adgrg6 signalling pathway. Compounds will be tested further using a range of secondary assays in the developing embryo and in vitro. The aim is to uncover compounds that are both potent and specific for the Adgrg6 pathway; these will be useful new tools for the developmental biologist, and may have potential as lead compounds for the design of new therapeutic drugs. In parallel, there will be the opportunity to create new genetic variants of adgrg6 in the zebrafish using CRISPR technology, and to examine their effects on the developing ear or on myelination. The student will primarily be based in the Whitfield lab and Sheffield Zebrafish Screening Unit at the University of Sheffield, where they will join our vibrant postgraduate community. The project will include a 3-month placement at Heptares Therapeutics, Welwyn Garden City.