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.

References

Craig SL, Gault VA, Irwin N. Emerging therapeutic potential for xenin and related peptides in obesity and diabetes. Diabetes Metab Res Rev. 2018 34(6):e3006.

Hasib A, Ng MT, Gault VA, Khan D, Parthsarathy V, Flatt PR, Irwin N. An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice.Diabetologia. 2017 60(3):541-552.

Irwin N, Flatt PR. New perspectives on exploitation of incretin peptides for the treatment of diabetes and related disorders. World J Diabetes. 2015 6(15):1285-95.

Khan D, Vasu S, Moffett RC, Gault VA, Flatt PR, Irwin N. Locally produced xenin and the neurotensinergic system in pancreatic islet function and β-cell survival. Biol Chem. 2017 399(1):79-92.

Ratner C, He Z, Grunddal KV, Skov LJ, Hartmann B, Zhang F, Feuchtinger A, Bjerregaard A, Christoffersen C, Tschöp MH, Finan B, DiMarchi RD, Leinninger GM, Williams KW, Clemmensen C, Holst B. Long-Acting Neurotensin Synergizes With Liraglutide to Reverse Obesity Through a Melanocortin-Dependent Pathway. Diabetes. 2019 68(6):1329-1340.


Essential criteria

  • To hold, or expect to achieve by 15 August, an Upper Second Class Honours (2:1) Degree or equivalent from a UK institution (or overseas award deemed to be equivalent via UK NARIC) in a related or cognate field.
  • 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
  • Sound understanding of subject area as evidenced by a comprehensive research proposal
  • 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

This is a self-funded PhD opportunity.


Other information


The Doctoral College at Ulster University


Reviews

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Kamin Hau - PhD in Biomedical Sciences


Profile picture of Kieran O'Donnell

My experience has been great and the people that I have worked with have been amazing

Kieran O'Donnell - 3D printing of biological cells for tissue engineering applications

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Profile picture of Michelle Clements Clements

Completing the MRes provided me with a lot of different skills, particularly in research methods and lab skills.

Michelle Clements Clements - MRes - Life and Health Sciences

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Profile picture of Sarah Craig

I completed my undergraduate studies at Ulster University, where I graduated in 2017 with first class honours in Biomedical Science with a Diploma in Professional Practice . I joined the Diabetes Research group as a PhD researcher in September 2017 and completed my PhD studies in June 2020.I am proud to say I not only completed my PhD studies within 3 years, but also became the World Champion (with a perfect score!) in Irish Dance during my PhD studies. My favourite memory was the opportunity to present my PhD work at the EASD conference in 2019. If I could speak to myself at the start of my PhD, the best piece of advice I would give myself would be to enjoy every single minute as the time flies in. I really would do another PhD!

Sarah Craig - PhD in Biomedical Sciences


Profile picture of Natalie Klempel

I completed my undergraduate studies in America at Texas Woman’s University where I majored in Kinesiology. I then moved to Scotland to successfully complete my Masters with Merit in Human Anatomy at the University of Dundee.My proudest moment was when I passed my viva! My favourite memory was …the dissections. I’ll never forget the friends I made and the good times we had together. I couldn’t have got through this without the support of my family, friends, lab colleagues, supervisors, and my boyfriend. If I could speak to myself at the start of my PhD, the best piece of advice I would give myself would be to write up after every experiment, keep a lot of back up copies of the work, and to enjoy the experience.

Natalie Klempel - PhD in Biomedical Sciences


Profile picture of Poonam Singh Nigam

I joined Ulster university in Jan 1990 after completing Postdoctoral research in Germany (1986-88) and PhD in India (1985). DSc degree in Applied Microbial-Biotechnology has been awarded after the evaluation of my thesis based on Research, Publication & related activities, completed as a research-active academic member of staff (1990-2019). DSc thesis summarised my scientific outputs and contributions (183 research papers, 3 biotechnology reference-books, 43 research-informed book-chapters, 26 research-informed review-articles, 90 conference-abstracts,1 European Patent and 2 Technology-transfers; Supervision of National & International researchers-18 Postdoctoral/Exchange and 12 PhD; and affiliations as Examiner of 58 PhD researchers globally, and Fellow & Member of nine scientific & academic societies.My message to all researchers is that "Chase your Aspirations and Never Give up". I couldn’t have got through my long academic & Professional journey without

Poonam Singh Nigam - DSc in Biomedical Sciences


Profile picture of Karl Smith

I started my PhD after I completed my undergraduate in Biology at Ulster University in 2016, with a dissertation project that focused on genetic variations in bacterial species. I continued using some of these techniques in my doctoral research, which primarily involved the investigation and development of mass spectrometry imaging in vitamin D treated prostate cancer, looking at the metabolic and genetic variations upon treatment. I worked with international collaborators at the University of Edinburgh and Maastricht University, where I got to learn and develop mass spectrometry techniques that have not previously been carried out in Northern Ireland. I now work as a postdoctoral researcher at the National High Magnetic Field Laboratory at Florida State University in Tallahassee, Florida, where I am helping to develop and implement a mass spectrometry imaging facility for users across the world with the super powerful 21T FT-ICR mass spectrometer.A PhD is a demanding process but when

Karl Smith - PhD in Biomedical Sciences


Profile picture of William Crowe

Throughout my PhD I’ve been provided with continuous support and guidance by my supervisors and the staff at the University.I’ve also received many opportunities to further enhance my professional development in the form of teaching experience and presenting my work at conferences which will aid in my pursuit of a career in academia or industry.

William Crowe


Profile picture of Ryan Kelsey

I graduated Ulster University in 2016 with a degree in Biomedical Science with DPP (Pathology). I was then offered a PhD studentship with Dr Catriona Kelly and Professor Neville McClenaghan at CTRIC which I started in September 2016. My PhD explored the pathophysiology of Cystic Fibrosis-Related Diabetes, the most common co-morbidity associated with Cystic Fibrosis.My proudest moment was undoubtedly passing my Viva (via Skype!), but I was also proud to be given the opportunity to present my work at the UK Cystic Fibrosis Trust Conference in 2018. Through this conference, I was able to meet with people with CF and the challenges they face which was important reminder that the research I was doing mattered. I couldn't have got through this without the unwavering support of my family, who were always there for me in the good times and the bad. I am also extremely grateful for the support and mentorship of my supervisors Dr Catriona Kelly, Professor Neville McClenaghan and Dr Dawood Khan

Ryan Kelsey - PhD in Biomedical Sciences


Profile picture of Ahmed Abuelhana

My proudest moment was when I knew the possibility of the full transfer of my PhD project to Ulster University, the University which I loved and started my first steps towards my PhD in, and also being a PhD graduate from one of the highly reputable universities such as Ulster is a big thing which I should always be proud of. I think there is no that word that can ever express my deepest thanks and sincere appreciation to my supervisor Professor Kathryn Burnett for her ideal supervision, valuable guidance, encouragement, generous help and ultimate support throughout my PhD project. I have been really lucky to have her as a supervisor. Also my deepest gratitude to Mr Linden Ashfield, Principal Clinical Pharmacist, Antrim Area Hospital (NHSCT) for his help and endless support throughout the whole research project. Also, I could not have got through this without the support of my beloved family (my father ”Sayed”, my mother ”Gamila”, my wife “Nermeen”

Ahmed Abuelhana - PhD in Biomedical Sciences


Profile picture of Ryan Lafferty

I graduated from Queen's University Belfast with a Master's in pharmacy in 2014 and subsequently began working as a community pharmacist in the Greater Belfast area. My career began to take an unusual turn when I got involved with a small startup company who developed a novel blood glucose monitor for diabetic patients. From here, my interest in diabetes was piqued and I applied for a PhD project (somewhat optimistically!) in the Diabetes Research Group at Ulster. Nearly four years later, I'm still there working as a postdoctoral researcher. Not bad considering I never thought I had a chance of getting a PhD spot!My time within the DRG has been, and still is, fantastic. I've made life-long friends (and surprisingly few enemies!) who have been patient, helpful and a joy to collaborate with. I couldn't have got through it without them (you know who you are). Likewise, the guidance from my supervisors, Prof. Peter Flatt and Dr. Nigel Irwin, has been invaluable. I'm probably most proud of

Ryan Lafferty - PhD in Biomedical Sciences