Exploring G Protein-Coupled Receptor signaling in pancreatic islets as targets for diabetes and its complications

Summary

The prevalence of type 2 diabetes has risen dramatically during recent decades and there is an urgent need to develop new approaches for therapeutic treatment that provide a combination of benefits, with fewer side effects and better patient outcomes. When diabetes is not managed, it can lead to serious complications including cardiovascular disease (CVD), stroke, blindness, kidney disease and premature mortality. CVD is a major cause of death and disability in diabetes, accounting for 52% of fatalities in those with type 2 diabetes.

New treatments are necessary due to the increasing prevalence of diabetes and its complications. In recent years, therapies that target the actions of glucagon-like peptide-1 (GLP-1) which stimulate insulin secretion through activation of beta cell G protein-coupled receptors (GPCRs) have been successful. This has resulted in substantial interest in targeting other islet GPCRs for diabetic therapies [1-3]. GPCRs are a superfamily of transmembrane receptors that transduce extracellular signals into intracellular responses.

GPCRs are the target of approximately 50% of all recently developed pharmaceutical agents. Our research has shown that targeting GPCRs can counteract defective insulin secretion, low beta cell mass, insulin resistance and inflammation which are key characteristics of diabetes and CVD [1-3]. In this project, G protein-signalling cascades will be characterised in islets using western blotting, peptide assays, cAMP imaging by fluorescence confocal microscopy and GPCR gene knockout studies using CRISP-R (Clustered regularly interspaced short palindromic repeats) gene editing.

Precision proteomics and mass spectrometry will enable the characterization of signalling events including at the levels of post-translational modifications. The effects of specific GPCR agonist therapy on the regulation of glucose tolerance, insulin resistance and inflammation will be determined in vivo. This PhD project represents a significant step in the validation of these islet targets for improved diabetes treatment and care.

Project aims are:

1. To investigate the mechanism of action and receptor-mediated intracellular signalling events activated by islet GPCRs and determine their role in the regulation of pancreatic function, cellular proliferation and islet cell mass.
2. To use gene knockout of GPCRs using CRISP-R gene editing, fluorescence confocal microscopy and mass spectrometry to investigate the common downstream signalling molecules activated in diabetes and cardiovascular disease.
3. To investigate GPCR cross-talk and the effect of signals on islet signalling and function.
4. To evaluate the anti-diabetic and anti-inflammatory effects of GPCR agonists in monotherapy and in combination in vivo with other known antidiabetic drugs.

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
• Clearly defined research proposal detailing background, research questions, aims and methodology

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.

• Completion of Masters at a level equivalent to commendation or distinction at Ulster
• Experience using research methods or other approaches relevant to the subject domain
• Sound understanding of subject area as evidenced by a comprehensive research proposal
• Work experience relevant to the proposed project
• Publications record appropriate to career stage
• Experience of presentation of research findings
• A comprehensive and articulate personal statement
• Relevant professional qualification and/or a Degree in a Health or Health related area

Funding and eligibility

The University offers the following levels of support:

Vice Chancellors Research Studentship (VCRS)

Full award (full-time PhD fees + DfE level of maintenance grant + RTSG for 3 years).

This scholarship will cover full-time PhD tuition fees and provide the recipient with £18,000 (tbc) maintenance grant per annum for three years (subject to satisfactory academic performance).

This scholarship also comes with £900 per annum for three years as a research training support grant (RTSG) allocation to help support the PhD researcher.

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.

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.

Vice-Chancellor’s Research Bursary (VCRB)

Part award (full-time PhD fees + 50% DfE level of maintenance grant + RTSG for 3 years).

This scholarship will cover full-time PhD tuition fees and provide the recipient with £8,000 maintenance grant per annum for three years (subject to satisfactory academic performance). This scholarship also comes with £900 per annum for three years as a research training support grant (RTSG) allocation to help support the PhD researcher.

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.

Vice-Chancellor’s Research Fees Bursary (VCRFB)

Fees only award (PhD fees + RTSG for 3 years).

This scholarship will cover full-time PhD tuition fees for three years (subject to satisfactory academic performance). This scholarship also comes with £900 per annum for three years as a research training support grant (RTSG) allocation to help support the PhD researcher.

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.

Department for the Economy (DFE)

The scholarship will cover tuition fees at the Home rate and a maintenance allowance of £18,000 (tbc) per annum for three years (subject to satisfactory academic performance).

This scholarship also comes with £900 per annum for three years as a research training support grant (RTSG) allocation to help support the PhD researcher.

• Candidates with pre-settled or settled status under the EU Settlement Scheme, who also satisfy a three year residency requirement in the UK prior to the start of the course for which a Studentship is held MAY receive a Studentship covering fees and maintenance.
• Republic of Ireland (ROI) nationals who satisfy three years’ residency in the UK prior to the start of the course MAY receive a Studentship covering fees and maintenance (ROI nationals don’t need to have pre-settled or settled status under the EU Settlement Scheme to qualify).
• Other non-ROI EU applicants are ‘International’ are not eligible for this source of funding.
• 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.

Due consideration should be given to financing your studies. Further information on cost of living