Functional Analysis of Novel Genes in Eye Development and Vision

视网膜相关性黄斑变性（AMD）是视力丧失的主要原因。我们已经证明，干性AMD与RPE基底富含胆固醇的区域内的补体因子H和纤蛋白3的特异性沉积有关。质谱已被用于鉴定涉及AMD中蛋白质沉积形成的复合物的其他组分。AMD中应激相关过程的细胞培养模型显示，RPE衍生细胞的特定应激导致AMD中重要途径的基因表达变化，特别是胆固醇合成和转运的上调以及细胞内游离锌的减少。 Retbindin是一种新的视网膜光感受器蛋白。基因敲除小鼠模型显示视觉反应的进行性缺陷和外层视网膜中与年龄相关的缺陷，这些缺陷与某些形式的年龄相关性黄斑变性和青光眼有一些惊人的相似之处。该模型正在评估中，沿着还有我们合作者的其他小鼠模型。 我们还正在完成对KLPH和Lengsin的研究，这两个新基因在透镜功能和透明度中发挥作用，是年龄相关性白内障的候选基因。 我们已经完成了一项广泛的合作研究，针对一个在感觉神经元（包括光感受器和听觉毛细胞）成熟中起重要作用的miRNA簇的靶向缺失模型。该缺失具有纤毛病的特征，并为Ushers样疾病提供了可能的小鼠模型。手稿几乎完成了。

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. 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 and to glaucoma. This model is under evaluation, along with other mouse models from our collaborators. We are also completing work on KLPH and Lengsin, two novel genes that have roles in lens function and transparency and are candidates for age-related cataract. We have completed work on an extensive collaborative study of a targeted deletion model for a miRNA cluster that has an important role in maturation of sensory neurons, including photoreceptors and auditory hair cells. The deletion has aspects of ciliopathies and provides a possible mouse model for Ushers-like disease. A manuscript is almost complete.