PhD Study : An investigation into the role of IL-33 and the Th17 axis on mercury associated inflammation.

Summary

Systemic lupus erythematosus (SLE) is a systemic inflammatory autoimmune disease with no known cure and an unclear aetiology, with genetic and environmental factors being implicated in the initiation and progression of disease (Crowe et al. 2016). There is considerable in vivo evidence from animal studies to support a role for MethylMercury (MeHg) as an environmental contributor to the exacerbation of autoimmunity, whilst evidence from human studies is limited (Crowe et al. 2016). MeHg is known to exert a range of toxicological effects in humans which has been suggested, in part, to be related to its role in cell death through the induction of both necrosis and apoptosis (Podolska et al. 2015).

This induction of cytotoxicity by MeHg may particularly impact SLE patients negatively as defective cell death and associated clearance of cellular debris have been suggested to contribute to secondary necrosis, subsequent self-antigen presentation and with a loss of tolerance, autoantibody production. Furthermore, the induction of necrosis stimulates the release of the alarmin cytokine IL-33, which has been shown to initiate and maintain Th2 cell-mediated inflammatory responses (Murakami et al. 2014). This enhancement of the Th2 response by necrosis derived IL-33 release could have a significant impact on SLE considering the role of Th2-driven production of autoantibody in SLE disease pathogenesis. IL-33 has also been suggested to influence the Th17 axis which has a role in autoimmunity, albeit more research is need regarding the il-33-Th17 relationship.

This PhD aims to investigate the potential role of IL-33 in MeHg associated inflammation in both healthy and autoimmune conditions.

Study 1 – An investigation into the role of IL-33 on SLE disease activity. This study will investigate the association of serum IL-33 and Th17 associated cytokine concentrations on disease activity in a Northern Ireland cohort of SLE patients. The relationship will also be investigated in a normal healthy control cohort to determine if there are any apparent differences between SLE patients and normal healthy controls.

Study 2 – An investigation into IL-33 status in high consumers of fish. This study will investigate the association of serum IL-33 and biomarkers of autoimmunity in an existing human cohort from the Seychelles where the consumption of fish on a daily basis is commonplace.

Study 3 – An ex vivo investigation into the role of MeHg on IL-33 and Th17 cytokine release in isolated peripheral blood mononuclear cells (PBMC’s). This ex vivo study will compare the inflammatory response of PBMCs isolated from SLE patients (n=12) to PBMCs from normal healthy controls (n=12) following exposure to either MeHg alone or with added n-3 poly unsaturated fatty acids (PUFA’s).

Study 4 – An investigation into the role of IL-33 in MeHg induced autoimmunity.

This study will investigate the role of IL-33 on the MeHg induced exacerbation of autoimmunity in the ZBWF1 mouse model of SLE. A range of clinical and biological markers will be monitored and compared between mice exposed to MeHg and mice unexposed. This study will also investigate the impact of IL-33 blockade on MeHg associated exacerbation of SLE in mice.

This project will be based at Ulster's Nutrition Innovation Centre for Food and Health (NICHE).

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
• 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 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