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Dysregulation of the complement system as a model for age related macular degeneration

Herrmann, P; (2016) Dysregulation of the complement system as a model for age related macular degeneration. Doctoral thesis , UCL (University College London).

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Abstract

Age-related macular degeneration (AMD) is the most common cause of vision loss in the elderly of industrialized countries. The aetiology of AMD is not entirely understood and so far there is no evidence-based treatment for early AMD. Recent genetic studies that identified polymorphisms in the complement system as a risk factor for AMD, suggest that inflammatory, immunological processes are crucial for the development of AMD but the exact interactions between high-risk genes and local disease manifestation are still unresolved. The aim of this thesis is to investigate the links by analysing the consequences of local dysregulation of the main components of the alternative complement pathway. The first part of the thesis studies how virus mediated gene transfer of complement genes into the RPE is accomplished and analysis the effects on retinal health. It demonstrates how lentiviral constructs are produced and tested and how local read-out strategies are developed. It shows how subretinal injections affect retinal health on a structural and molecular basis concluding that they might not be the appropriate tool for local complement analysis as all injections lead to a local complement response. The second part of the work studies how ageing and knockout of cell bound complement regulator Cd59a affects retinal health in mice. It demonstrates the ageing effects in wildtype mice that include subretinal macrophage accumulation and increased expression of major complement genes in the RPE/choroid. It continuous to demonstrate how these normal age-related changes are exacerbated by Cd59a knockout. The third part of the work analyses the effects of sustained elevated light exposure on different genetic backgrounds represented by different mouse lines. It demonstrates how myeloid cell activation and increase in local complement expression coincide and how they are dependent on the genetic background.

Type: Thesis (Doctoral)
Title: Dysregulation of the complement system as a model for age related macular degeneration
Event: University College London
Language: English
Keywords: Age related macular degeneration, AMD, Complement, Innate Immunity, Eye, Retina
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/1497042
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