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Title: The Hypoxia-Inducible Factor pathway in myeloid cells in experimental choroidal neovascularization
Author: Liyanage, S. E.
ISNI:       0000 0004 8498 7323
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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Neovascular age-related macular degeneration (nAMD) is characterized by the development of choroidal neovascularization (CNV) and is a major cause of blindness. Infiltrating myeloid cells have been implicated in the pathogenesis of CNV and are purported to be a major source of the pro-angiogenic cytokine, vascular endothelial growth factor (VEGF). Hypoxia-inducible factors (HIFs) are transcription factors that have been shown to be integral to myeloid cell function and infiltration, and are upstream regulators of VEGF production. This thesis investigates the hypothesis that the HIF pathway in myeloid cells is a crucial link in the molecular pathogenesis of nAMD, by investigating its role in laser-induced CNV. First, an approach to analysing myeloid cell populations present in CNV using flow cytometry was validated. This was necessary to characterize the ability of the transgenic Cre-loxP conditional models used in this thesis to produce myeloid-specific targeted modulation of the HIF pathway. Flow cytometric analysis of cellular expression of green fluorescent protein in reporter lines reveals that the Lysm and Iba1 promoters drive efficient Cre-mediated recombination in infiltrating myeloid subsets and retinal microglia respectively, and are effective at targeting the HIF pathway at a genomic level, validating their use in this thesis. Angiographic quantification of CNV following laser-induction shows that regulating the HIF pathway in myeloid cells did not affect the resultant CNV size. Endotoxin-induced uveitis (EIU) was employed to further investigate the role of myeloid-derived HIF. This model of ocular inflammation is stimulated by lipopolysaccharide, a potent inducer of the HIF pathway. Analysis of myeloid cells in this model by flow cytometry reveals that modulation of HIF in these populations does not affect their infiltration. Deletion of Vegfa, a pro-angiogenic downstream target of HIF, in myeloid cells did not affect CNV. The work described in this thesis demonstrates that the HIF pathway in myeloid cells is dispensable in the development of laser-induced CNV, suggesting that this pathway does not play a major role in the contribution of myeloid cells to nAMD pathogenesis.
Supervisor: Bainbridge, J. W. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available