Summary

Type 1 diabetes (T1D) is an autoimmune disease characterized by apoptosis of insulin secreting pancreatic beta-cells. As a result, people with T1D are unable to produce insulin in response to physiological demands and treatment therefore focuses on insulin replacement strategies. T1D accounts for ~10% of all cases of diabetes equating to a global prevalence of approximately 45M people. TNFAIP3 is a negative regulator of inflammation and apoptosis and protects against beta-cell apoptosis in experimental models. Variants in TNFAIP3 are associated with type 1 diabetes (T1D) risk and poor residual beta-cell function. Furthermore, TNFAIP3 protects against beta-cell apoptosis, the primary driver of T1D development. It is unclear whether the association between variants in TNFAIP3 and T1D risk/beta-cell function result from a direct effect on beta-cell survival, whether these variants create a heightened inflammatory environment, which indirectly impacts on the beta-cell, or whether both mechanisms may have a role to play in T1D development.

AIM: The aim of this pilot study is to determine how variants in TNFAIP3 affect beta-cell function and survival and whether these variants have diagnostic and/or prognostic value for T1D.

OBJECTIVES:

1. To recruit a cohort of people with T1D from the Western Health and Social Care Trust (WHSCT) and to study the prevalence of variants in TNFAIP3 and their association with age of onset, glycaemic control (HbA1c) and residual beta cell function (C-peptide). Recruitment protocols are already in place and we have established good working relationships with clinical staff in the WHSCT. Findings from this study will be validated in data from secondary cohorts from Exeter University.  The top three ranked variants will be carried forward for further analysis (objectives 2 and 3).

2.To conduct an assessment of the direct effect of variants on the beta-cell, the top three ranked variants in TNFAIP3 will be introduced into the MIN6 beta cell line using CRISPR/Cas9 technologies. The effect on cell survival (TUNEL assay, PCR for markers of apoptosis) and function (glucose-induced insulin secretion) will be determined.

3. To conduct an assessment of the indirect effects of these variants on the beta-cell, inflammatory cells (CD4+ T cells and monocytes) isolated from individuals carrying each of the top three ranked variants will be isolated from blood samples collected during construction of our cohort (objective 1). Following stimulation (PMA activation of monocytes to macrophages; cytokine challenge of T cells) of these cells, the conditioned media will be added to MIN6 cells and primary islets, and the effects on cell survival and function assessed (as outlined in Objective 2). Many of the TNFAIP3 variants associated with T1D risk are common variants (>20% of the population) located in intergenic regions. Therefore, it is difficult to predict function. However, this is an important question to address since these variants have been reported in multiple independent studies as being predictive/associated with T1D development. To turn these variants into useful clinical biomarkers, we must understand function. Via gene-editing technologies, this project will determine the diagnostic/prognostic value of these variants in T1D.


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
  • A comprehensive and articulate personal statement

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%
  • Completion of Masters at a level equivalent to commendation or distinction at Ulster
  • Research project completion within taught Masters degree or MRES
  • 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

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


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

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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.

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