The oxygen supply chain and wet AMD
Research details
- Type of funding: MRC / Fight for Sight Clinical Research Training Fellowship
- Grant Holder: Mr Sidath Liyanage
- Institute: UCL Institute of Ophthalmology
- Region: London
- Start date: July 2012
- End Date: June 2015
- Priority:
- Eye Category:
Overview
Age-related macular degeneration, also known as AMD, is the most common cause of sight loss in industrialised countries. More than half a million people are affected in the UK. This serious condition affects the macula - the part of the retina which deals with seeing central vision, colours and fine detail.
There are two main types of AMD, known as 'dry' and 'wet'. In wet AMD, unhealthy blood vessels grow behind the macula and can bleed or leak. This quickly causes loss of central vision. About 1 in 10 people with AMD have the wet form.
In wet AMD, the eye produces a molecule known as 'vascular endothelial growth factor' or VEGF. It encourages the growth of these blood vessels.
Anti-VEGF treatments, such as Lucentis, can help but are not completely effective. They also mean repeated eye injections and there is risk of side effects.
VEGF is important for eye development and maintaining healthy blood vessels. But we don’t know exactly what causes AMD or why unhealthy amounts of VEGF are produced.
We do know that VEGF and other substances in the body are controlled by switching various genes on or off. One of these genes is called ‘hypoxia inducible factor’ or HIF.
In this project the researchers are using various ways to switch the HIF gene on and off, to find out what this does to VEGF and blood vessel growth. The results should help make it easier to develop effective treatments for wet AMD.-
Scientific summary
Hypoxia-inducible factors in age-related macular degeneration
This fellowship will investigate the hypothesis that hypoxia-inducible factor (HIF) activation in myeloid cells is responsible for neovascular age-related macular degeneration (AMD). By defining the role of HIF in myeloid cells in the development of experimental choroidal neovascularisation (CNV), the aim is to identify new opportunities to improve the efficacy of therapeutic intervention.
Having developed gene and cell therapy approaches for a wide range of ocular disorders and demonstrated proof of principle in clinical application, the research team has the relevant expertise and infrastructural resources to translate relevant findings into new interventions for the benefit of people at risk of sight loss. It is anticipated that development of a new molecular intervention from preclinical proof of concept to clinical application will take approximately 5 years.
Aim: to define the molecular and cellular processes responsible for choroidal neovascularisation by investigating the role of HIFs in myeloid cells during experimental CNV.
Objectives
- To determine the distribution of myeloid cells in the normal retina and in experimental CNV
- To characterize these cells by immunophenotyping in vitro and in vivo
- To determine the impact of HIF activation on the extent of CNV
- To determine the role of HIF activation in recruitment of myeloid cell populations to CNV
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Research update
Results from the project were unexpected. The team was studying HIF because it’s part of a system that control the body’s response to a lack of oxygen. If not enough oxygen is getting through to where it’s needed, HIF can turn on and and activate new blood vessel growth via VEGF. The blood vessels would carry a new supply of oxygen.
That was the idea, anyway. But it turns out in this case that the source of excess VEGF is not coming from HIF being active in the type of cells that were studied. Although this is a surprise, it’s a useful one, as it means researchers can rule this out and start looking at other sources of VEGF. -
Publications
- Chu, C. J. et al. Multimodal analysis of ocular inflammation using the endotoxin-induced uveitis mouse model. Disease Models and Mechanisms 9, 473–481 (2016).
- Liyanage, S. E. et al. Myeloid-Derived Vascular Endothelial Growth Factor and Hypoxia-Inducible Factor Are Dispensable for Ocular Neovascularization—Brief Report. Arterioscler Thromb Vasc Biol 36, 19–24 (2016).
- Herrmann, P. et al. Cd59a deficiency in mice leads to preferential innate immune activation in the retinal pigment epithelium–choroid with age. Neurobiology of Aging 36, 2637–2648 (2015).
- Sim, D. A. et al. A simple method for in vivo labelling of infiltrating leukocytes in the retina using Indocyanine green dye. Disease Models and Mechanisms dmm.019018 (2015).
- Wu, W. et al. IL-4 Regulates Specific Arg-1+ Macrophage sFlt-1–Mediated Inhibition of Angiogenesis - The American Journal of Pathology. (2015).
- Chu, C. J. et al. Assessment and In Vivo Scoring of Murine Experimental Autoimmune Uveoretinitis Using Optical Coherence Tomography. PLOS ONE 8, e63002 (2013).