Funded PhD Opportunity Development of gene-editing technologies to aid diagnosis of type 1 diabetes
This opportunity is now closed.
Subject: Biomedical Sciences
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.
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.
- Upper Second Class Honours (2:1) Degree or equivalent from a UK institution (or overseas award deemed to be equivalent via UK NARIC)
- Sound understanding of subject area as evidenced by a comprehensive research proposal
- A comprehensive and articulate personal statement
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
Vice Chancellors Research Scholarships (VCRS)
The scholarships will cover tuition fees and a maintenance award of £15,009 per annum for three years (subject to satisfactory academic performance). Applications are invited from UK, European Union and overseas students.
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 fees component of the studentship (no maintenance award is provided). For Non EU nationals the candidate must be "settled" in the UK.
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