Functional Analysis of Novel Genes in Eye Development and Vision

老年性黄斑变性（AMD）是视力丧失的主要原因。我们已经证明，干性AMD与补体因子H和纤维蛋白3在RPE基础上富含胆固醇的区域内的特定沉积有关。质谱已被用于鉴定与AMD中蛋白质沉积形成有关的复合物的进一步组分。AMD中应激相关过程的细胞培养模型显示，rpe来源细胞的特异性应激导致AMD重要通路的基因表达改变，特别是胆固醇合成和运输的上调以及细胞内游离锌的减少。该模型已被用于确定缓解应激反应的血清因子，并可能具有治疗潜力。

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.