Exploiting chronic GIP receptor antagonism for treatment of obesity, diabetes and related disorders

Summary

Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino acid polypeptide hormone secreted from intestinal K-cells of the duodenum and proximal jejunum. Like glucagon-like peptide-1 (GLP-1), its younger and better-known incretin hormone, GIP is released into the circulation in response to ingestion of macronutrients, it is degraded by DPPIV and accounts for a major part of the ‘incretin-effect’ by enhancing glucose-stimulated insulin secretion.

Pioneering studies conducted at Ulster in early 2000s revealed that agonism or antagonism of the GIP receptor might represent promising approaches to the treatment of obesity-diabetes.

Although a disruptive suggestion which was opposed by many in the scientific community at the time, the recent approval of the dual GIP/GLP-1 receptor agonist, Mounjaro (tirzepatide), for the management of type 2 diabetes mellitus (T2DM) has reinvigorated interest in exploitation of GIP receptor (GIPR) pathways.

Furthermore, the idea that GIPR antagonism might also be beneficial is substantiated by late-stage clinical trials with Maritide (AMG133) which is a dual GLP-1 agonist/GIPR antagonist.

Difficulties with using early peptide antagonists include possible lack of specificity and relatively short half-life. Application of new technology to the production of monoclonal antibodies to the GIP receptor which antagonise GIP action overcomes these difficulties.

Such monoclonal GIPR antibodies represents both an exciting research tool as well as opening-up the path to possible new improved therapeutic approaches.

This project will use monoclonal GIPR antibodies in laboratory and pre-clinical studies to delineate the physiology of GIP, its role in obesity-diabetes and related conditions such as infertility and neurodegenerative disease.

The project will also carefully evaluate the therapeutic value of monoclonal GIPR antibodies both alone and in combination with known antidiabetic drugs and novel agents in development.

Important Information: Applications for more than one PhD studentship are welcome, however if you apply for more than one PhD project within Biomedical Sciences, your first application on the system will be deemed your first-choice preference and further applications will be ordered based on the sequential time of submission.

If you are successfully shortlisted, you will be interviewed only on your first-choice application and ranked accordingly. Those ranked highest will be offered a PhD studentship.

In the situation where you are ranked highly and your first-choice project is already allocated to someone who was ranked higher than you, you may be offered your 2nd or 3rd choice project depending on the availability of this project.

Essential criteria

Applicants should hold, or expect to obtain, a First or Upper Second Class Honours Degree in a subject relevant to the proposed area of study.

We may also consider applications from those who hold equivalent qualifications, for example, a Lower Second Class Honours Degree plus a Master’s Degree with Distinction.

In exceptional circumstances, the University may consider a portfolio of evidence from applicants who have appropriate professional experience which is equivalent to the learning outcomes of an Honours degree in lieu of academic qualifications.

• Sound understanding of subject area as evidenced by a comprehensive research proposal
• A comprehensive and articulate personal statement

Desirable Criteria

If the University receives a large number of applicants for the project, the following desirable criteria may be applied to shortlist applicants for interview.

• First Class Honours (1st) Degree
• Completion of Masters at a level equivalent to commendation or distinction at Ulster
• Practice-based research experience and/or dissemination
• Experience using research methods or other approaches relevant to the subject domain
• Work experience relevant to the proposed project
• Publications record appropriate to career stage
• Experience of presentation of research findings

Equal Opportunities

The University is an equal opportunities employer and welcomes applicants from all sections of the community, particularly from those with disabilities.

Appointment will be made on merit.

Funding and eligibility

This project is funded by:

• Department for the Economy (DfE)

Our fully funded PhD scholarships will cover tuition fees and provide a maintenance allowance of £21,000 (approximately) per annum for three years* (subject to satisfactory academic performance).  A Research Training Support Grant (RTSG) of £900 per annum is also available.

These scholarships, funded via the Department for the Economy (DfE), are open to applicants worldwide, regardless of residency or domicile.

Applicants who already hold a doctoral degree or who have been registered on a programme of research leading to the award of a doctoral degree on a full-time basis for more than one year (or part-time equivalent) are NOT eligible to apply for an award.

*Part time PhD scholarships may be available to home candidates, based on 0.5 of the full time rate, and will require a six year registration period.

Due consideration should be given to financing your studies.