Functional Analysis of Novel Genes in Eye Development and Vision

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Age-related macular degeneration (AMD) is a major cause of vision loss. We have shown that dry AMD is associated with specific deposits of complement factor H and fibulin 3 within domains rich in cholesterol basal to the RPE. Mass spectroscopy has been used to identify further components of complexes that are implicated in formation of protein depositions in AMD. A cell-culture model for stress-related processes in AMD shows that specific stress of RPE-derived cells causes gene expression changes for pathways important in AMD, particularly up-regulation of cholesterol synthesis and transport and decrease in intracellular free zinc. This model has been used to identify a serum factors that relieves the stress response and may have therapeutic potential. We have also initiated collaborations to examine two mouse models with possible relevance to AMD, comparing them with the results we have observed from human donor eyes. Retbindin is a novel protein of retinal photoreceptors. A knockout mouse model shows progressive deficits in visual response and age-related defects in the outer retina that have some striking similarities to some forms of age-related macular degeneration. This model is under evaluation, along with other mouse models from our collaborators. We are also completing work on two genes of previously unknown function that have roles in lens transparency and are candidates for age-related cataract.