EASTBIO CASE: Orphan GPCRs: Cracking the Function Code - No Ligand Required! University of Aberdeen in United Kingdom

This fully funded, 4-year PhD project is part of a competition funded by the BBSRC EASTBIO Doctoral Training Partnership .

This is a CASE studentship (Collaborative Awards in Science and Engineering). CASE studentships involve students enhancing their training by spending three to 18 months with a CASE partner in a workplace outside of the academic environment. The CASE partner for this project is Melio Bio . Please note, your application may be shared with any external partners of this PhD Studentship.

G protein-coupled receptors (GPCRs) are a major focus for drug discovery due to their membrane localization, tissue-specific expression, role in amplifying cellular signals and association with disease. Orphan GPCRs, receptors for which the endogenous ligand remain unknown, represent an untapped resource in the pharmaceutical industry. Deorphanization of GPCRs is challenging, labour-intensive, and in many cases fruitless, highlighting potential gaps in our understanding of how GPCRs are regulated and limitations in current ligand-screening. Our lab focuses on the orphan GPCR, GPR75, which is an exciting new target for metabolic disease: mutations in GPR75 are directly correlated to BMI and diabetes.  We have shown GPR75 to be constitutively active (signalling in the absence of ligand), which we believe provides a novel pharmacological handle to uncover its function. GPCRs are conformationally dynamic proteins, and it is recognised that conserved sequences, intracellular and extracellular loops and structural motifs contribute to constitutive activity, signalling and receptor trafficking: profiling GPR75 mutants would provide structure-function insight into ligand-independent activity. Furthermore, it is now recognised that membrane composition and the microenvironment play a role in modulating GPCRs, which adds another layer to the control of constitutive activity. Using a variety of molecular and pharmacological approaches, such as mutagenesis, novel biosensors, cell signalling assays, immunofluorescence and proteomics, the goal of this PhD studentship is to dissect the role of structure, the cellular microenvironment and interacting partners of GPR75, to uncover its ligand-independent signalling and function, which will contribute to the development of new pharmacological tools and advance GPR75-ligand screens. These outcomes have direct relevance for the discovery and development of molecules to target GPR75 in disease. This PhD studentship brings together areas of expertise in GPCR pharmacology and molecular biology from the University of Aberdeen and industry experience in drug discovery and screening platforms to offer an optimal training environment and provide the student with a set of highly desirable skills. It is expected that completion of the aims will advance our understanding of GPR75 constitutive activity and form the basis of developing a screen to uncover drugs to target this orphan GPCR in disease.

For further project information please contact the lead project supervisor by selecting the first listed name at the top of this advert and sending your enquiry.

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ELIGIBILITY:

Applicants should hold a minimum of a 2:1 UK Honours degree (or international equivalent) in a relevant subject. Those with a 2:2 UK Honours degree (or international equivalent) may be considered, provided they have (or are expected to achieve) a Distinction or Commendation at master’s level.

We encourage applications from all backgrounds and communities, and are committed to having a diverse, inclusive team.

All students must meet the eligibility criteria as outlined in the UKRI guidance on funding for postgraduate training and development . This guidance should be read in conjunction with the Terms and conditions for training funding – UKRI .

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APPLICATION PROCEDURE:

• Please visit this page for full application information: https://biology.ed.ac.uk/eastbio/how-to-apply
• Please send your completed EASTBIO application form, along with academic transcripts and certificates to [email protected]
• Please ensure that two references are submitted by the deadline using the EASTBIO reference form ( available here ). If the references are not included with your application, they must be sent directly to [email protected] with the subject line: "EASTBIO Reference – [Your Name]".
• It is the applicant’s responsibility to ensure that references are submitted by the deadline (17 ^th January). We will not request academic references on your behalf.
• Please ensure you submit all the required information and documentation. Due to workload constraints, we are unable to follow up on missing documents or process incomplete applications.
• If you require any additional assistance in submitting your application or have any queries about the application process, please don't hesitate to contact us at [email protected]