Abstract
Age-related macular degeneration (AMD) is one of the commonest causes of sight loss in the elderly population and to date there is no intervention that slows or prevents early AMD disease progressing to blinding neovascularization or geographic atrophy. AMD is a complex disease and factors proposed to contribute to the development and progression of disease include aging, genetics, epigenetics, oxidative stress, pro-inflammatory state, and life-style factors such as smoking, alcohol, and high fat diet. Here, we generate a knowledge repository of pathways and protein–protein interaction (PPI) networks likely to be implicated in AMD pathogenesis, such as complement activation, lipid trafficking and metabolism, vitamin A cycle, oxidative stress, proteostasis, bioenergetics, autophagy/mitophagy, extracellular matrix (ECM) turnover, and choroidal vascular dropout. Two disctinct clusters ermerged from the networks for parainflamation and ECM homeostasis, which may represent two different disease modules underlying AMD pathology. Our analyses also suggest that the disease manifests primarily in RPE/choroid and less in neural retina. The use of standardized syntax when generating maps of these biological processes (SBGN standard) and networks (PSI standard) enables visualization of complex information in graphical programs such as CellDesigner and Cytoscape and enhances reusability and extension of data. The ability to focus onto subnetworks, multiple visualizations and simulation options will enable the AMD research community to computationally model subnetworks or to test experimentally new hypotheses arising from connectivities in the AMD pathway map.
Highlights
By the age of 65, it is thought that 1 in every 3 people will have some form of vision loss due to an eye disease.[1,2] The most common of these diseases is age-related macular degeneration (AMD).[3]
We included compartments relevant to AMD pathogenesis including sub-retinal pigment epithelium (RPE) deposits such as drusen and macrophages which are seen as part of the inflammatory landscape of AMD.[25]
To assign processes implicated in AMD pathogenesis to each compartment and to build the SBGN model, several strategies to select information from the literature were adopted
Summary
By the age of 65, it is thought that 1 in every 3 people will have some form of vision loss due to an eye disease.[1,2] The most common of these diseases is age-related macular degeneration (AMD).[3]. The only early abnormality in AMD may be the presence of small drusen, between the retinal pigment epithelium (RPE) and Bruch’s membrane. These are associated with a relatively low risk of disease progression. If blood vessels migrate from the choroid (or more rarely the retina) into the sub-RPE and/or subretinal space the fibrovascular tissue and associated fluid leakage can distort vision and if hemorrhage occurs, visual loss can be sudden. Reticular pseudodrusen (sometimes called subretinal drusenoid deposits, but these may not be precisely the same thing) are a relatively recently defined phenotype[5] that is seen in AMD as well as other outer retinal degenerations characterized by Bruch’s membrane/ RPE pathology
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