PhD Study : Modulation of pancreatic beta-cell Neuropeptide Y (NPY) receptors as a novel therapeutic option for diabetes

Summary

We have recently published exciting work that describes the pancreatic beta-cell benefits of sustained activation of Neuropeptide Y1 receptors (NPYR1) in diabetes [Lafferty et al. 2019]. In this work, it was demonstrated that NPYR1 activation promotes potent beneficial effects on pancreatic beta-cell function, growth and survival and helps to reverse streptozotocin-induced diabetes [Lafferty et al. 2019]. Although this is very encouraging, NPYR1 receptors are also found outside the pancreas, including the brain and blood vessels [Lafferty et al. 2018]. As such, activation of these receptors can stimulate appetite or vasoconstriction, respectively [Lafferty et al. 2018], which may not be advantageous in diabetes. However, further examination of NPY receptor expression within the pancreas reveals that as well as NPYR1, there is also significant expression of NPYR4 [Persaud & Bewick 2014]. Notably, NPYR1’s and NPYR4’s are known to activate identical cell signalling pathways. Indeed, in our laboratory we have already shown positive pancreatic beta-cell benefits of NPYR4 activation [Khan et al. 2017]. Thus, the NPYR4 may prove to be a more exciting target than NPYR1 in terms of promoting pancreatic beta-cell function, growth and survival, with reduced side-effect profile.

Currently available peptide-based NPYR4-specific receptor activators are limited, with Panceratic Polypeptide (PP) classically recognised to possess this biological effect [Khan et al. 2017]. However, the therapeutic potential of PP is severely limited due to rapid plasma enzyme mediated degradation, that dramtiaclly reduces half-life of the peptide. To circumvent this, we have recently developed an enzymatically stabilised version of PP, with pilot studies confirm that this new PP analogue possesses the same biological action profile as the parent peptide, but with a much prolonged pharmacodynamic profile.

The current PhD project will build on these initial exciting findings in our laboratory with the novel PP analogue. As such, the core objectives of this PhD research project are:

* Determine the full degradation profile of PP and enzymes involved

* Based on the success of our novel PP analogue, design, purify and characterise further long-acting PP-based peptides

* Assess the in vitro enzymatic stability and biological actions of novel peptides in rodent and human insulin-releasing cell lines and isolated mouse islets

* Determine effects of PP peptides on human and rodent pancreatic beta-cell proliferation and protection against apoptosis

* Determine receptor specificity of PP peptides using beta-cells with CRISPR-Cas9 induced knockout of NPYR’s

* Establish in vivo gluco-regulatory and insulin secretory actions of novel PP peptides

* Determine in vivo biological duration of action/pharmacodynamic profile of long-acting PP peptides

* Assess beneficial effects, as well as related mechanisms, of novel PP peptides alone, and in combination with established anti-diabetic drugs, in animal models with different aetiologies of type 2 diabetes.

References

Khan D, Vasu S, Moffett RC, Irwin N, Flatt PR. Influence of neuropeptide Y and pancreatic polypeptide on islet function and beta-cell survival. Biochim Biophys Acta Gen Subj. 2017 1861(4):749-758.

Lafferty RA, Flatt PR, Irwin N. Emerging therapeutic potential for peptide YY for obesity-diabetes. Peptides. 2018 100:269-274.

Lafferty RA, Tanday N, McCloskey A, Bompada P, De Marinis Y, Flatt PR, Irwin N. PYY(1-36) peptides from phylogenetically ancient fish targeting mammalian NPY1 receptors demonstrate potent effects on pancreatic beta-cell function, growth and survival. Diabetes Obesity & Metabolism. 2019 [In Press]

Persaud SJ, Bewick GA. Peptide YY: more than just an appetite regulator. Diabetologia. 2014 57(9):1762-9.

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

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
• Work experience relevant to the proposed project
• Publications - peer-reviewed
• Publications record appropriate to career stage
• Experience of presentation of research findings
• A comprehensive and articulate personal statement
• Use of personal initiative as evidenced by record of work above that normally expected at career stage.
• 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