PhD Study : Xenin: exploring its role in physiology and pathophysiology of diabetes

Summary

The gastrointestinal tract (GIT) harbours numerous important peptide hormones that regulate normal physiology. One such GIT-derived hormone, known as xenin, is secreted from intestinal K-cells in response to feeding. Interestingly, the well-characterised incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is also released postprandially from K-cells, and there is evidence that the biological actions of xenin and GIP are complementary.

Therefore, the present studies are designed to delineate the full physiological role of xenin, with observations likely to have significant therapeutic relevance. Initially, liquid chromatography mass spectrometry/mass spectrometry (LC-MS/MS) will be used to quantify time- and nutrient-dependent changes in xenin secretory profiles using suitable GIT cell lines and in vivo in mice.

Previous research at Ulster has revealed various xenin metabolites are present in blood, and each will be quantified. In addition, receptor interactions (SGLTs, FFAs, GLUTs etc.) and related signalling pathways activated during xenin release will be analysed. Immunohistochemical techniques and scanning electron microscopy will be employed to uncover the exact location of xenin secretory granules within GIT cells. Further published evidence from Ulster reveals local pancreatic synthesis and secretion of xenin.

To validate this, we will determine the expression of COPA (xenin precursor), the proteolytic cleavage enzyme cathepsin E, and then concentrations of xenin peptides in pancreatic beta-cell lines and isolated mouse islets under normal and stressed (high or low glucose/lipid) conditions. Further to this, the biological actions of xenin, and related fragment peptides, will be investigated at pancreatic and extra-pancreatic sites. In brief, effects on pancreatic beta-cell insulin secretion, proliferation and apoptosis will be studied, alongside gene and protein expression of key beta-cell markers involved in insulin secretion and beta-cell survival.

Similar investigations on glucagon secretion and alpha-cell signalling will also be conducted. Since GIP has well characterised positive effects on bone, the impact of xenin on bone physiology will be examined. Effects of xenin peptides on in vitro osteoblast proliferation, and secretion of TGF-beta, IGF-I and FGF-2, as well as alkaline phosphatase activity, will be assessed. Osteoclast cultures will be used to determine effects of xenin on osteoclast formation. Furthermore, 3T3-L1 adipocytes will be utilised to uncover the role of xenin and related peptides in lipid metabolism.

Studies will involve measurement of key processes in lipid synthesis as well as glucose uptake. Xenin effects on the modulation of adipogenic-specific genes/proteins during adipocyte differentiation will also be studied. Finally, the action of xenin on muscle and liver will be investigated, including glucose transport in L6 myocytes and effects on primary murine hepatocyte-viability, steatosis, ER stress and autophagy.

Together, this PhD project will provide excellent training in a wide range of state-of-the-art research techniques.

We are seeking an applicant with good practical laboratory, computer and communication skills and enthusiasm and commitment to work diligently on all aspects of the research project. A background in biomedical sciences, pharmacology or a related subject would be desirable. This is one of three top priority projects for Ulster’s Diabetes Research Group. Informal enquiries to Dr Irwin (n.irwin@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