Age-related macular degeneration (AMD) is the commonest cause of blindness in the developed world. AMD is a progressive disorder of the outer retina characterised by the accumulation of extracellular deposits and chronic inflammation at the level of Bruch’s basement membrane. Photoreceptor cell death is the result of progressive (‘geographic’) atrophy of supporting retinal pigment epithelium (RPE), or disruption by pathological neovascularisation that arises from the choroid and penetrates defects in Bruch’s membrane. Choroidal neovascularisation (CNV) develops in response to the up-regulation of multiple pro-angiogenic cytokines, including vascular endothelial growth factor (VEGF), in the context of an abnormal extracellular matrix. The outcome of neovascular AMD can be improved by intraocular delivery of VEGF inhibitors but this is incompletely effective, indicating the involvement of additional parallel pathways or compensatory mechanisms. There is a clear unmet need for more effective treatments. In this fellowship I will investigate the hypothesis that HIF activation in myeloid cells is responsible for neovascular AMD. By defining the role of HIF in myeloid cells in the development of experimental CNV I aim to identify new opportunities to improve the efficacy of therapeutic intervention.
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