GPCR drug discovery using the Zebrafish model.

这个项目是一个令人兴奋的机会，联合收割机斑马鱼遗传学与化学生物学相结合，以了解G蛋白偶联受体（GPCR）的功能。GPCR超家族包括许多已知药物的靶标，但也保留了未来药物发现的巨大潜力。该项目的重点是Adgrg 6（Gpr 126），这是一种粘附类GPCR，在内耳发育和周围神经系统髓鞘形成中具有已知作用。已知Adgrg 6中的突变会导致人类疾病。该项目将使用斑马鱼胚胎作为筛选工具，以识别可以调节Adgrg 6信号通路的小分子。将在发育中的胚胎和体外使用一系列次级测定进一步测试化合物。其目的是发现对Adgrg 6通路既有效又特异的化合物;这些化合物将成为发育生物学家有用的新工具，并可能成为设计新治疗药物的先导化合物。与此同时，将有机会使用CRISPR技术在斑马鱼中创建adgrg 6的新遗传变体，并检查它们对发育中的耳朵或髓鞘形成的影响。学生将主要在惠特菲尔德实验室和谢菲尔德斑马鱼筛选单位在谢菲尔德大学，在那里他们将加入我们充满活力的研究生社区。该项目将包括在韦林加登城的Heptares Therapeutics实习3个月。

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.