PhD Study : Antidiabetic promise of combined GLP-1, glucagon and neuropeptide Y receptor signalling

Summary

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Peptide hormones are extremely important for controlling energy homeostasis and metabolism, and represent excellent drug targets for diseases such as diabetes. In this respect, dual activation of receptors for glucagon and the incretin hormone, glucagon-like peptide-1 (GLP-1) using a single unimolecular molecule, has established benefits in obesity-diabetes. In addition, neuropeptide Y receptors (NPYR), activated by Peptide YY (PYY) a hormone co-secreted with GLP-1, can augment weight loss or pancreatic islet function. At Ulster, we have developed patent protected PYY molecules that exert direct benefits on pancreatic beta-cell function, or promote reductions in energy intake. Using this initial knowledge, the following research questions will be addressed as part of this PhD project:

1. What impact will triple activation of GLP-1, glucagon and NPY receptors have on pancreatic beta-cell function?  Glucagon-like peptide-1 (GLP-1), glucagon and neuropeptide Y (NPY) each exert independent benefits of pancreatic beta-cell function and survival. Our laboratory has already developed bioactive, fully enzymatic stable, versions of all three peptides. We also have experience in designing and charactering unimolecular triple-acting peptide entities, and this expertise will be applied to the current project. Effects of triple receptor activation on secretory function as well as proliferation and survival will be explored in rodent and human insulin-releasing beta cell lines as well as isolated murine islets. We will determine receptor activation balance of the GLP-1/glucagon/NPY unimolecular peptide using both established receptor antagonists as well as beta cells with  CRISPR/Cas9 KO of each individual receptor.
2. What will the therapeutic benefit of sustained triple activation of GLP-1, glucagon and NPY receptors be in diabetes?  Using knowledge gained from Question 1, the lead molecule will be progressed to preclinical therapeutic efficacy trials in models of type 2 diabetes with different aetiologies. Novel unimolecular molecules will be compared head-to-head against clinically approved antidiabetic drugs, with a primary endpoint of superiority over these established agents. Our laboratory has established expertise in small rodent antidiabetic efficacy studies and generating data packages of significant interest.
3. How does the islet and enteroendocrine hormone secreting cell peptidome alter following sustained activation of GLP-1, glucagon and NPY receptors in diabetic rodents? A peptidomic approach will be utilised to specifically examine changes in islet peptidome following sustained triple activation of GLP-1, glucagon and NPY receptors in diabetes. Whole islets and fluorescent-activated cell sorted islet alpha- and beta-cells will be analysed.  Given the origin and direct effects of GLP-1, glucagon on PYY peptidomic analysis of enteroendocrine cells and pancreatic islets will also be conducted.

Expected Results: Based on pilot studies we expect to observe likely additive or synergistic benefits of triple receptor activation on beta-cell function. Generation of an enzyme-resistant long-acting GLP-1/glucagon/NPY unimolecular peptide should allow for assessment of this approach as a potential new therapeutic option for diabetes, with efficacy equivalent or superior to currently approved antidiabetic drugs. Question 3 will provide valuable information of how the gut and islet peptidome is altered in response to metabolic stress, as well as sustained treatment with GLP-1, glucagon and NPY receptor activation. ​

Please note: Applications for more than one PhD studentships 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
• 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)

The following scholarship options are available to applicants worldwide:

• Full Award: (full-time tuition fees + £19,000 (tbc))
• Part Award: (full-time tuition fees + £9,500)
• Fees Only Award: (full-time tuition fees)

These scholarships will cover full-time PhD tuition fees for three years (subject to satisfactory academic performance) and will provide a £900 per annum research training support grant (RTSG) 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.

Please note: you will automatically be entered into the competition for the Full Award, unless you state otherwise in your application.

Department for the Economy (DFE)

The scholarship will cover tuition fees at the Home rate and a maintenance allowance of £19,000 (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