SSA Uncovering the pharmacology of a novel receptor target

G protein-coupled receptors are a family of cell-surface receptors, which respond to various extracellular mediators and regulate an array of physiological processes. However, the endogenous ligands of a large number of GPCRs remain unidentified, leaving their physiological role unknown. The accessibility of GPCRs on the plasma membrane and their tissue-selective distribution make them excellent pharmacological targets. Studying these GPCRs, namely orphan GPCRs, will advance the understanding of their role, and explore how they might be exploited as drug targets.
GPR75 (retinal GPCR) is an orphan GPCR that is highly expressed in human retinal pigment epithelial (RPE) cells. Six variants of GPR75 have been identified; however, their functional significance has yet to be determined. Our lab has begun to elucidate the function of GPR75 by creating GPR75 over-expressing HEK-293 cells, using CRISPR/Cas technology in-vitro and in-vivo and developing a screen to identify ligands. Uncovering ligands or developing functional or neutralising antibodies would provide useful research tools to target GPR75 and even offer potential therapeutics in the future.
Using cutting edge technologies such as molecular biology, signalling and G-protein binding assays, CRISPR/Cas technology, antibody generation, chemistry to synthesis and modify ligands and relevant animal mouse models, the specific aims of the studentship are to:
1. Uncover the pharmacology of GPR75, in part through the identification of ligands and the generation of functional or neutralising GPR75 antibodies.
2. Investigate the significance of the GPR75 variants on receptor function by site-directed mutagenesis of wild-type GPR75.
3. Determine the physiological relevance of GPR75 in RPEs in a mouse model using CRISPR/Cas GPR75-knockout mice, novel ligands and GPR75 functional antibodies.
This proposed PhD project brings together areas of expertise in pharmacology, immunology, chemistry and the blood-ocular barrier from the University of Aberdeen with those from local industry. Expertise and training in the generation of an antibody targeting GPR75 will be given by Elasmogen, a biologics drug discovery company that specialises in antibody-like proteins called soloMERs, which due to their small size allows for both site-specific delivery and penetration, which is ideal to cross the ocular barrier in-vivo. Completion of the specific aims will reveal the pharmacology of GPR75 and functional effects of receptor variants. Furthermore, understanding the role of GPR75 in RPE cells could uncover the biological mechanisms of the ageing process in the eye that predispose patients to diseases such as age-related macular degeneration, thereby highlight this receptor as a new target for the disease, thus providing translational impact.