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Title: Complement Factor B and pathological angiogenesis in age-related macular degeneration
Author: Pilotti, Camilla
ISNI:       0000 0004 7429 2237
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Age-related macular degeneration (AMD) is the leading cause of vision loss in the global ageing population. The growth of new blood vessels in the subretinal tissue, a hallmark of wet AMD, causes loss of central vision. Complement Factor B (CFB) is a secreted positive regulator of the alternative pathway of the complement system. Mice lacking Cfb exhibit reduced pathological ocular angiogenesis after laser-induced choroidal neovascularisation (CNV). However, polymorphisms in human CFB (32W and 32Q) have been linked to a decreased risk of developing AMD. The primary objectives in this study was to find out whether CFB is implicated in the pathological formation of new blood vessels leading to neovascular AMD, and to evaluate the roles of the different risk variants of CFB in angiogenesis. This work was carried out using three experimental systems: in vitro techniques were employed to generate the three human CFB variants as recombinant proteins, via stable transfection in mammalian 293T cells; the ex vivo fetal metatarsal assay explant model of angiogenesis was used to investigate the roles of the human CFB variants, and in vivo studies were performed using two novel mouse models, the endothelial- and RPE-specific Cfb knockouts. The work done in this thesis showed that i) the three CFB variants have different biological activities in the mouse metatarsal assay, ii) CFB can modulate macrophage phenotype. iii) Tie2Cre Cfb KO mice have an unaltered retinal phenotype in the development of CNV and iv) Cfb produced in mouse RPE-choroid is involved in pathological neovascularization. In summary, these are the first studies to demonstrate different biological activities of the three known human CFB variants, and provide mechanistic insight into the relationship between CFB genotype and AMD risk.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available