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Insights into eye disease: understanding the molecular basis of age-related macular degeneration

Faculty of Biology, Medicine and Health

About the Project

Dysregulation of innate immunity has been implicated as playing a key role in the development of age-related macular degeneration (AMD) – a major form of blindness in the industrialised world (see [1-5]). Loss of central vision results from the destruction of the macula, which is preceded by the accumulation of particulate matter within this central region of the retina; this is associated with local inflammation and tissue damage [4]. A common polymorphism (Y402H) in the gene encoding human complement factor H (CFH) has been identified as a major risk factor for AMD. CFH is an important regulator of the complement system (part of innate immunity) where it is thought to localise on host tissues (and thus suppress complement activation) via its binding to negatively charged sugar molecules known as GAGs [1-5]. In our recent work we have found that the Y402H polymorphism has a profound affect on the GAG-binding specificity of CFH [1-3]. This change in GAG recognition affects the localisation of the disease-associated form of CFH in the human eye [2,3] and thus likely contributes directly to the pathogenesis of AMD (i.e. due to impaired immune regulation) [4]. We have also discovered that there is a large reduction in the amount of GAG (and thus binding sites for CFH) within the human eye as a consequence of normal aging [5]; this perhaps explains why AMD only affects people late in life. Further research is now needed to better understand the initiation/progression of AMD so as to facilitate the design of novel treatments for this devastating disease.

This project will form part of an on-going programme of work in Professor Day’s lab (in collaboration with Professor Paul Bishop, University of Manchester) aimed at understanding the molecular basis of AMD. This research project may include fluorescent microscopy, cell biology, molecular biology and protein biochemistry.

Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

Informal enquiries may be made directly to the primary supervisor.


Prosser, B.E., Johnson, S., Roversi, P., Herbert, A.P., Blaum, B.S., Tyrrell, J., Jowitt, T.A., Clark, S.J., Tarelli, E., Uhrin, D., Barlow, P.N., Sim, R.B., Day, A.J. & Lea, S.M. Structural basis for complement factor H linked age-related macular degeneration. (2007) J. Exp. Med. 204, 2277-2283.

Clark, S.J., Perveen, R., Hakobyan, S., Morgan, B.P., Sim, R.B., Bishop, P.N. & Day A.J. Impaired binding of age-related macular degeneration-associated complement factor H 402H allotype to Bruch’s membrane in human retina. (2010) J. Biol. Chem. 285, 30192-30202.

Clark, S.J., Ridge, L.A., Herbert, A.P., Hakobyan, S., Mulloy, B., Lennon, R., Wurzner, R., Morgan, B.P., Urhin, D., Bishop, P.N. & Day, A.J. Tissue-specific host recognition by complement factor H is mediated by differential activities of its glycosaminoglycan-binding regions. (2013) J. Immunol. 190, 2049-2057.

Langford-Smith, A., Keenan, T.D.L., Clark, S.J., Bishop, P.N. & Day, A.J. The role of complement in Age-related Macular Degeneration: heparan sulphate, a ZIP code for complement factor H? (2014) J. Innate Immunity 6, 407-416.

Keenan, T.D.L., Pickford, C.E., Holley, R.J., Clark, S.J., Lin, W., Dowsey, A.W., Merry, C.L., Day, A.J. & Bishop, P.N.* Age-dependent changes in heparan sulfate in human Bruch’s membrane: implications for age-related macular degeneration. (2014) Invest. Ophthalmol. Vis. Sci. 55, 5370-5379.

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