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

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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

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

The Doctoral College at Ulster University

Key dates

Submission deadline
Friday 7 February 2020
12:00AM

Interview Date
09 to 20 March 2020

Preferred student start date
Mid September 2020

Applying

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Contact supervisor

Professor Finbarr O'Harte

Other supervisors