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Funded PhD Opportunity

Targeted exendin/apelin hybrid peptides for diabetes and obesity therapy.

Subject: Biomedical Sciences


Summary

Diabetes mellitus currently affects 425 million people globally and this is set to rise significantly to 629 million by 2045 (IDF 2017 Atlas). Treating diabetes accounts for about 10% of the NHS budget (£9.8 billion) and this is expected to rise to 17% by 2035. Most of this expense relates to treatment of the complications resulting from poor glycaemic control and the adverse consequences of hyperglycaemia. Alongside abnormal insulin secretion, poor insulin action also contributes to hyperglycaemia, leading to disease complications.

In developed countries, obesity trends are closely related to a later wave of Type 2 diabetes.  Therefore drugs that can induce weight loss, as well as improve blood glucose control are much sought after. Many monotherapy drug strategies fail over time, requiring addition of other second line agents to achieve better glycaemic control. Over the past 15 years, GLP-1 mimetics (Exenatide and Liraglutide) have demonstrated improved Type 2 diabetes control when added to first line therapies such as metformin.

More recently, the additional benefits of GLP-1 dual agonists (co-agonists) have been demonstrated in clinical trials with LY3298176 (Eli Lilly, USA), but these are not yet available to patients (Frias et al. 2018). The present study will involve the evaluation of novel co-agonist exendin/apelin peptides, which activate both the GLP-1 and APJ receptors simultaneously, and promote additional synergistic beneficial metabolic effects.

The current research proposal aims to harness the biological action of stable co-agonist peptides incorporating both exendin-4 and apelin-13, which act as receptor agonists at the GLP-1 and APJ receptors, respectively.

Previous investigations in our laboratory which used apelin-13 analogues have demonstrated that this peptide technology has the potential to specifically target the pancreatic beta-cell and stimulate insulin secretion and lower hyperglycaemia when administered to diet induced obese diabetic mice and diabetic db/db mice (O’Harte et al. 2018a; 2018b).

More recently, pilot data has shown that hybrid peptides, which contain both exendin-4(1-30) linked together with apelin-13 amide in one single chain peptide (43 amino acids), operate in synergy as co-agonists of the GLP-1 and APJ receptors, providing potent antidiabetic and anti-obesity actions.  These hybrid peptides are stable in mouse plasma, potently stimulate insulin secretion and can effectively reduce food intake in trained fasted mice, when compared to either exendin-4 or apelin-13 peptide alone. A lead compound has been identified and named ELA.

The present study will build upon this lead compound by adding a fatty acid (acylation) to three separate Lys side chain sites within the ELA hybrid pepptide. Thus, we aim to extend the duration of action of our lead hybrid peptide co-agonist and produce stable and longer acting second generation drug candidates.

This project will examine the efficacy of new hybrid peptides on insulin secretion in cultured BRIN-BD11 cells and isolated mouse islets and their mechanisms of action in the presence and absence of specific receptor antagonists. The efficacy of these analogues upon cAMP production and intracellular Ca2+ fluxes will be examined in cultured cells. We will for the first time test newly derived acylated analogues of the lead co-agonist peptide, as these are likely to have an enhanced pharmacological profile resulting from a prolonged half-life profile by binding to plasma proteins. The ELA peptide and the 3 acylated versions thereof will be tested for insulin secretion and acute glucose lowering ability in mice. From here the most effective lead candidate(s) will be taken forward for efficacy testing following chronic administration in animal models of appetite control and diabetes.It is also imperative that these acylated co-agonist analogues are tested in vivo in mice using a dosage and regimen mimicking long-term treatment which mimics the human diabetic condition.

The present project aims to validate the use of these novel acylated co-agonists for diabetes therapy by direct head-to-head comparison with a clinically proven stable acylated incretin hormone mimetic (Liraglutide) and the stable acylated apelin-13 peptide. These preclinical studies will be performed in three mouse models involving, food intake studies in mice trained to eat for 3 h per day, secondly in high fat fed diet-induced obese (DIO) mice, and finally in genetically susceptible (db/db) diabetic mice. The latter two models present with different pathologies and represent relevant models of human Type 2 obesity-related diabetes. The actions of hybrid peptides on pancreatic tissue morphology and hormone content will be examined using immunohistochemistry approaches.


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
  • 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

    The University offers the following awards to support PhD study and applications are invited from UK, EU and overseas for 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 £15,000 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.

    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 £7,500 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.

    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.

    Department for the Economy (DFE)

    The scholarship will cover tuition fees at the Home rate and a maintenance allowance of £ 15,009 per annum for three years. EU applicants will only be eligible for the fee’s component of the studentship (no maintenance award is provided). For Non-EU nationals the candidate must be "settled" in the UK. 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.

    Due consideration should be given to financing your studies; for further information on cost of living etc. please refer to: www.ulster.ac.uk/doctoralcollege/postgraduate-research/fees-and-funding/financing-your-studies


Other information


The Doctoral College at Ulster University


Reviews

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 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


Key dates

Submission deadline
Friday 7 February 2020

Interview Date
09 to 20 March 2020


Applying

Apply Online  


Campus

Coleraine campus

Coleraine campus
The feeling of community at our Coleraine campus makes for a warm and welcoming student experience.


Contact supervisor

Professor Finbarr O'Harte


Other supervisors

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