GPCR drug discovery using the Zebrafish model.
Lead Research Organisation:
University of Sheffield
Department Name: Biomedical Science
Abstract
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.
People |
ORCID iD |
Tanya Whitfield (Primary Supervisor) |
Publications
Diamantopoulou E
(2019)
Identification of compounds that rescue otic and myelination defects in the zebrafish adgrg6 (gpr126) mutant.
in eLife
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
BB/M011151/1 | 01/10/2015 | 30/09/2023 | |||
1961673 | Studentship | BB/M011151/1 | 01/10/2017 | 30/09/2021 | |
BB/R50581X/1 | 01/10/2017 | 30/09/2021 | |||
1961673 | Studentship | BB/R50581X/1 | 01/10/2017 | 30/09/2021 |
Description | We have uncovered novel compounds that can alleviate inner ear and myelination defects associated with zebrafish adgrg6 mutant larvae. Moreover, we have analysed the structures of such compounds to identify key properties shared between them which in turn have helped us identify additional compounds that induce similar rescuing effects. Finally, we have been able to build evidence surrounding the cellular targets of each compound based on their effects on multiple adgrg6 allelic mutants. Research article in eLIFE: Diamantopoulou et al., 2019 Identification of compounds that rescue otic and myelination defects in the zebrafish adgrg6 (gpr126) mutant |
Exploitation Route | Compounds from our work will provide useful new tools for the developmental biologist, and may have potential as lead compounds for the design of new therapeutic drugs to target myelination defects. |
Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
URL | https://elifesciences.org/articles/44889#fig1s1 |
Description | Sosei Heptares industry collaboration on PhD project |
Organisation | Heptares Therapeutics Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | I have completed a three month placement at Sosei Heptares during which I continued my PhD project research in the industry setting. The findings throughout my project are shared with Sosei Heptares. |
Collaborator Contribution | Sosei Heptares have provided funding towards my PhD project and have shared lab equipment and consumables for experimental work. |
Impact | None as of yet but a Thesis and manuscript will be in the pipeline later this year. |
Start Year | 2017 |