Unravelling the molecular mechanism of connective tissue growth factor (CCN2) in glaucoma

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide, and intraocular pressure (IOP) is an important modifiable risk factor. Elevated IOP in POAG is due to increased resistance to aqueous humour outflow resulting from increased extra-cellular matrix (ECM) in the trabecular meshwork (TM). None of the current pharmacological glaucoma treatments target the outflow resistance and ECM changes in the TM, rather they target the disease from the aqueous production side. These treatment approaches do not therefore halt the progressive molecular pathology in the TM, and so aqueous outflow resistance and IOP continue to increase, requiring further intervention. Elevated levels of transforming growth factor β (TGFβ) in the aqueous humour bathing the TM has been shown to alter ECM production, and is an important player in the pathogenesis of glaucoma. Inhibiting TGFß as a treatment option is deleterious and counter effective as TGFβ has multiple other roles on different cells within the same organ. Connective tissue growth factor, also known as CCN2, a downstream mediator of TGFß, presents a better option for therapy. Conditional CCN2 over-expression transgenic mouse models will be used to dissect the contribution of CCN2 in the development and progression of glaucoma and the influence of exogenous TGFβ. CCN2 expression will then be manipulated and evaluated in human and animal glaucoma models using microRNA (miRNA) based therapeutics. These data will raise the possibility for a new class of disease-modifying therapeutics using miRNA biology to halt/slow disease progression.

This is an exciting project with direct translational relevance to the treatment of glaucoma. The student will gain a varied laboratory and scientific training. Experience of in vivo and in vitro experimentation and/or cell culture/gene expression analysis would be an advantage, although training will be provided in these areas. The conditional transgenic CCN2 mice are a unique resource and the student will gain experience in transgenic models, molecular and cellular biology and a novel organ culture perfusion model of glaucoma. The field of miRNA and RNA therapeutics is an emergency and exciting technology which is entering the clinical realm. This studentship will provide an excellent basis for further career development in academia or industry.

The student will benefit from three experienced and complementary supervisors. Prof Colin E. Willoughby is Professor of Molecular Ophthalmology and a clinician-scientist with an interest in glaucoma, molecular biology and miRNAs. Prof George Bou-Gharios is Professor of Matrix Biology with a specific interest in CCN2 and transgenic models. Dr Kevin Hamill is Lecturer in Cell and Molecular Biology with an interest in the extracellular matrix and laminin biology. This is a strategic project for our groups and we are keen to appoint a highly-motivated and driven student who will benefit from an enthusiastic and stimulating training experience.

The Institute of Ageing and Chronic Disease is fully committed to promoting gender equality in all activities. In recruitment we emphasize the supportive nature of the working environment and the flexible family support that the University provides. The Institute holds a silver Athena SWAN award in recognition of on-going commitment to ensuring that the Athena SWAN principles are embedded in its activities and strategic initiatives.

The successful applicant will have (or expect to hold) a First or 2:1 Honours degree in a relevant life science/biomedical subject. A Master’s degree in a relevant area would be an advantage. We are seeking an enthusiastic individual who has experience in basic cell and molecular biology techniques to appoint to this prestigious studentship.