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A novel therapeutic targeting the inflammasome as a treatment for glaucoma.


Project Description

Glaucoma is the leading cause of irreversible blindness and is a global problem that affects over 60 million people. Unfortunately, there is no cure for this disease and, with the rapidly expanding aging population, the number of people diagnosed with glaucoma is predicted to exceed 100 million by 2040. Glaucoma is characterised by the progressive loss of retinal ganglion cells (RGCs). Unfortunately, there is not currently a cure for glaucoma and intraocular pressure (IOP) reduction remains the only treatment strategy for all types of glaucoma. Pseudoexfoliation glaucoma, a secondary glaucoma, presents with much higher IOP than observed in open-angle glaucoma. There is growing evidence that axon damage in the optic nerve head precedes death of the RGCs, this axon damage has been linked to glial activation and inflammation. While inflammation is normally helpful and part of the wound healing response to injury, if this inflammation is excessive or continues for a prolonged time, it can change from a helpful to harmful response that further damages the nerves in the eye. Therefore, regulating inflammation is an important therapeutic target that could prevent disease progression in patients with glaucoma. The ‘NLRP3 inflammasome’ is expressed in the optic nerve head and has been shown to become activated during glaucoma. By targeting the NLRP3 inflammasome, it may be possible to inhibit harmful inflammation against the nerves in the eye and prevent vision loss in glaucoma patients. Through the role of the NLRP3 inflammasome in many inflammatory diseases, this has led to the development of a novel therapeutic that can target the inflammasome. Promising findings have been obtained for the use of this therapeutic in both glaucoma and other inflammatory conditions.

OBJECTIVES:

This proposed study will

(i) recruit a cohort of glaucoma patients within Northern Ireland and study the expression of inflammasome proteins and their association with IOP, age of onset and type of glaucoma,

(ii) identify biomarkers of inflammation in glaucoma that will determine which patients would benefit most from an anti-inflammatory therapy that targets the inflammasome in the eye,

(iii) further characterise the therapeutic to fully understand the mechanism of action and downstream effects in vitro; this will involve the use of glaucoma relevant cell lines including astrocytes, microglia and retinal ganglion cells.

This PhD project in collaboration with Dr Gregory Ksanders at Harvard Medical School will provide the opportunity to generate a comprehensive dataset that will help move this novel glaucoma therapeutic from the pre-clinical to the clinical phase improving the treatment of glaucoma patients.

AccessNI clearance required
Please note, the successful candidate will be required to obtain AccessNI clearance prior to registration due to the nature of the project.

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
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.

Completion of Masters at a level equivalent to commendation or distinction at Ulster
Experience using research methods or other approaches relevant to the subject domain
Work experience relevant to the proposed project
Publications - peer-reviewed
Publications record appropriate to career stage
Experience of presentation of research findings
A comprehensive and articulate personal statement
Use of personal initiative as evidenced by record of work above that normally expected at career stage.
Relevant professional qualification and/or a Degree in a Health or Health related area

Funding Notes

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: see View Website

References

Krishnan A, Kocab AJ, Zacks DN, Marshak-Rothstein A, Gregory-Ksander M. A small peptide antagonist of the Fas receptor inhibits neuroinflammation and prevents axon degeneration and retinal ganglion cell death in an inducible mouse model of glaucoma.
J Neuroinflammation. 2019 Sep 30;16(1):184. doi: 10.1186/s12974-019-1576-3.

Fioravanti A, Tenti S, McAllister M, Chemaly M, Eakin A, McLaughlin J, Bjourson AJ, Frati E, McGilligan V, Cheleschi S, Gibson DS. Exploring the Involvement of NLRP3 and IL-1β in Osteoarthritis of the Hand: Results from a Pilot Study. Mediators Inflamm. 2019 Mar 10;2019:2363460. doi: 10.1155/2019/2363460.

Rea IM, Gibson DS, McGilligan V, McNerlan SE, Alexander HD, Ross OA. Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines. Front Immunol. 2018 Apr 9;9:586. doi: 10.3389/fimmu.2018.00586.

McAllister MJ, Chemaly M, Eakin AJ, Gibson DS, McGilligan VE. NLRP3 as a potentially novel biomarker for the management of osteoarthritis. Osteoarthritis Cartilage. 2018 May;26(5):612-619. doi: 10.1016/j.joca.2018.02.901.

McGilligan VE, Gregory-Ksander MS, Li D, Moore JE, Hodges RR, Gilmore MS, Moore TC, Dartt DA. Staphylococcus aureus activates the NLRP3 inflammasome in human and rat conjunctival goblet cells. PLoS One. 2013 Sep 10;8(9):e74010. doi: 10.1371/journal.pone.0074010.

How good is research at Ulster University in Allied Health Professions, Dentistry, Nursing and Pharmacy?
Biomedical Sciences

FTE Category A staff submitted: 74.10

Research output data provided by the Research Excellence Framework (REF)

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