PhD Study : Utility of combined GLP-1 and neurotensin receptor signalling, and/or related hybrid peptides, for type 2 diabetes therapy

Summary

Glucagon-like peptide-1 (GLP-1) is an incertin hormone secreted postprandially from intestinal L-cells with established actions to increase glucose-dependent insulin secretion and reduce appetite [Irwin & Flatt 2015]. Similarly, neurotensin (NT), is a 13 amino acid neuropeptide secreted by pancreatic nerves and enteroendocrine cells in response to a meal, with established effects on energy balance [Khan et al. 2017]. Both peptide hormones have also been shown to possess proliferative actions on pancreatic beta-cells and augment beta-cell function [Irwin & Flatt 2015; Khan et al. 2017].

Thus, there is clear potential for additive or synergistic benefits of these two hormones in obesity-diabetes. In full agreement with this, neurotensin has recently been revealed to synergise with the clinically approved GLP-1 analogue, liraglutide, to help reverse obesity in high fat fed mice [Ratner et al. 2019]. In a related theme, our laboratory has also recently shown clear antidiabetic synergy between other similar gut derived peptide hormones, namely glucose-dependent insulinotropic polypeptide (GIP) and xenin [Martin et al. 2012].

These observations later lead to the development of a single GIP/xenin hybrid peptide capable of simultaneously activating both receptor pathways [Hasib et al. 2017]. Indeed, this novel GIP/xenin hybrid displayed prominent antidiabetic therapeutic potential in rodent models of diabetes [Hasib et al. 2017].  Notably, GIP is the sister incretin of GLP-1, while xenin-25 and neurotensin share considerable homology. Thus, the established GIP/xenin axis [Craig et al. 2018] may be broadly similar to the postulated GLP-1/neurotensin interaction that will be investigated within the current research project. Moreover, given that GLP-1-based treatments are already clinically approved, unlike GIP, the potential therapeutic impact of GLP-1/NT peptides is more credible.

As such, this PhD project will build on initial exciting findings with GLP-1 and neurotensin peptides, akin to previous published work on GIP and xenin from our laboratory, with the possibility of progressing to generation of a GLP-1/NT hybrid peptide that would have considerable therapeutic promise for type 2 diabetes.

Therefore, the core objectives of this PhD research project are:

• Fully establish GLP-1 and NT interactions at the level of the pancreatic beta-cell, including aspects of insulin secretion and related mechanisms, as well as effects on beta-cell growth and survival
• Determine benefits of combined GLP-1 and NT administration in normal and diabetic rodents
• Synthesis and characterise a range of novel GLP-1/NT hybrid peptides
• Assess the in vitro enzymatic stability as well as in vitro and in vivo biological actions of novel peptides as outlined above *Determine duration of in vivo biological action of hybrid peptides through assessment of pharmacodynamic and/or pharmacokinetic profiles
• Assess the beneficial effects of novel GLP-1/NT hybrid peptides alone, and in combination with established anti-diabetic drugs, in different aetiologies of type 2 diabetes.

Applicants should note that Laboratory bench fees of £6,000.00 per annum are required for this self-funded PhD 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