PhD Study : Oral delivery of insulin and other peptide therapeutics using GET technology.

Summary

Oral delivery of insulin may significantly improve the quality of life of diabetes patients who routinely receive insulin injections. In fact, compared with this administration route, oral delivery of insulin in diabetes treatment offers many advantages: higher patient compliance, rapid hepatic insulinisation, and avoidance of peripheral hyperinsulinemia and other possible adverse effects such as hypoglycemia and weight gain. However, the oral delivery of insulin remains a challenge because its passage from the gut to blood and target tissues is extremely limited.

The main barriers faced by insulin and other possible peptide therapeutics in the gastrointestinal tract are degradation by proteolytic enzymes and lack of transport across the intestinal epithelium. Several strategies to deliver insulin orally have been proposed, but without much clinical or commercial success.

We have created a method of efficiently delivering drugs into cells by targeting a ubiquitous sugar type (heparan sulphate expressed on cell membranes with a cell penetrating peptide (CPP) (Dixon et al., PNAS 19: E291-299; 2016). The delivery system is known as glycosaminoglycan-binding enhanced transduction (GET). This technology is patented by the University of Nottingham and its present application to diabetes therapeutics is a joint venture with Ulster.

This project will exploit GET peptides to promote the intracellular transduction of insulin (and other therapeutic peptides such as GLP-1) and subsequent release into the systemic circulation. We have exciting preliminary data showing modification of GET with transcytosis peptides can improve insulin delivery through biological barriers and in diabetic mice.

The core objectives of this research are:

*Optimise the GET peptide and insulin combination for optimal reduction in blood glucose

*Optimise the regime for oral delivery of oral insulin formulation

*Determine any toxicity or gastroenterological effect of oral insulin delivery

*Explore application to other diabetes therapeutic peptides such as GLP-1

*Integrate insulin delivery system with other gut peptides for therapeutic application

Training and use of a wide range of methods will be provided including HPLC purification of synthetic peptides, mass-spectrometry, in vitro insulin action/secretion studies using BRIN-BD11 or 3T3 cells, glucose assays, insulin, glucagon and GLP-1 immunoassays. Acute and long-term animal studies will involve assessing the effects of insulin-GET peptides administered subcutaneously (control) and both orally and intra-jejunally in streptozotocin-diabetic mice and other models of diabetes.

Pharmacokinetic assessment of peptide concentration and biological action, peptide-dose responses, glucose tolerance tests, peptide desensitization studies, blood biochemistry assessments will be performed. Histology, PCR and Western blotting techniques will be carried out on selective tissues (intestine, islets, sites of insulin action) to study the absorption, distribution and effects of regulatory hormone-GET peptides.

We are seeking an applicant with good practical, computer and communication skills plus enthusiasm and commitment to work diligently on all aspects of the research. A background in biomedical or biological sciences, pharmacology or a related subject would be desirable. Informal enquiries to Prof Flatt (pr.flattt@ulster.ac.uk) are welcomed.

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.

• First Class Honours (1st) Degree
• Masters at 65%
• Research project completion within taught Masters degree or MRES
• Practice-based research experience and/or dissemination
• Experience using research methods or other approaches relevant to the subject domain
• Work experience relevant to the proposed project
• Publications - peer-reviewed
• 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

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