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Investigating the role of Inter-alpha-inhibitor Heavy Chain 3 in age-related macular degeneration


Project Description

Age-related macular degeneration (AMD) is one of the leading causes of blindness globally. It is well established that although a multifactorial disease, AMD is largely genetically driven, with the majority of attributable genetic risk being associated with loci on chromosome 1 (Chr1) and chromosome 10 (Chr10). While AMD is now well understood at the genetic level, how genetics influences the biochemistry of the disease is much less clear. Recently we have focused on human donor eyes that were homozygous for AMD risk at Chr1 (with no risk at Chr10) and have used proteomics and immhunohistochemistry to characterise Bruch’s membrane, which forms part of the outer blood-retinal barrier and is the site where AMD develops. This study identified significant changes in the levels of Inter-alpha-Inhibitor Heavy Chain-3 (ITHI3); i.e. a protein involved in the organisation of extracellular matrix (ECM), and implicated in the regulation of innate immunity and bioavailability of signaling molecules within the ECM. As such ITIH3 has the potential to tune the structure and filtering function of Bruch’s membrane, and to control immune activation and cell proliferation/apoptosis within the retina. In this project, we will: 1) determine the localisation of ITIH3 within Bruch’s membrane and the blood vessels that lie below this (termed the choriocapillaris) in eye tissues from individuals with different genetic risk and disease subtypes, 2) identify ligands for ITIH3, 3) assess whether ITIH3 (a serum protein) is expressed locally in the retina (e.g. by analysing retinal pigment epithelium (RPE) gene transcription), and 4) investigate the effects of ITIH3 on immune and stromal cell function. This project will give us a much better understanding of the biochemistry behind the progression from early to late stage AMD and will facilitate the development of new therapeutic strategies for combating this common and debilitating condition.

Applicants are expected to hold, or about to obtain, a minimum upper second class undergraduate degree (or equivalent) in Biochemistry, Immunology or a related subject. A Masters degree in a relevant subject and/or experience in ophthalmology, retinal disease, neurodegeneration, immunology and/or matrix biology is desirable. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor.

Funding Notes

Combined grants of supervisory team:
- Macular Society, £164,042. 09/2018 – 08/2021: A comprehensive molecular analysis and iPSC model of early adult-onset macular degeneration to better understand age-related macular degeneration.
- Macular Society, £169,318. 12/2017 – 12/2020: Development and utilisation of Manchester Eye Tissue Repository to elucidate molecular pathology of AMD.
- Medical Research Council (MR/P025838/1), £492,648. 05/2017 – 04/2020: Investigating the Influence of Genetic Variation Associated with Age-Related Macular Degeneration on Plasma Levels of Compliment Regulatory Proteins.

References

[1] McHarg, S., Clark, S.J., Day, A.J. & Bishop, P.N. (2015) Age-related macular degeneration and the role of the complement system. Mol. Immunol. 67, 43-50
[2] Okroj, M., Holmquist, E., Sjölander, J., Corrales, L., Saxne, T., Wisniewski, H.-G., and Blom, A.M. (2012). Heavy chains of inter alpha inhibitor (IαI) inhibit the human complement system at early stages of the cascade. J. Biol. Chem. 287, 20100–20110
[3] Baranova, N.S., Foulcer, S.J., Briggs, D.C., Tilakaratna, V., Enghild, J.J., Milner, C.M., Day, A.J. & Richter, R.P. (2013) Inter-alpha-inhibitor impairs TSG-6 induced hyaluronan cross-linking. J. Biol. Chem. 288, 29642-29653.
[4] Clark, S.J., Perveen, R., Hakobyan, S., Morgan, B.P., Sim, R.B., Bishop, P.N. & Day A.J. (2010) Impaired binding of age-related macular degeneration-associated complement factor H 402H allotype to Bruch’s membrane in human retina. J. Biol. Chem. 285, 30192-30202.
[5] Clark, S.J. and Bishop, P.N. (2017) The eye as a complement dysregulation hotspot Semin. Immunopathol. 40, 65

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