Functional Analysis of Novel Genes in Eye Development and Vision

眼睛发育和视力新基因的功能分析

• 批准号: 9362383
• 负责人: graeme j wistow
• 金额: $ 89.21万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9362383
• 关键词: Afferent Neurons; Age related macular degeneration; Aging; Animal Model; Auditory; Bioinformatics; Blindness; Cataract; Cell Culture Techniques; Cells; Cholesterol; Complement Factor H; Complex; Defect; Deposition; Disease; Employee Strikes; Evaluation; Eye; Eye Development; Gene Expression; Genes; Genomics; Glaucoma; Growth; Hair Cells; Human; Hybrids; Knockout Mice; Manuscripts; Mass Spectrum Analysis; MicroRNAs; Modeling; Pathway interactions; Photoreceptors; Process; Proteins; Recombinant Proteins; Retina; Retinal Photoreceptors; Role; S1-5 protein; Stress; Techniques; Tissues; Up-Regulation; Vision; Visual; Work; Yeasts; Zinc; age related; ciliopathy; gene product; lens; mouse model; novel; response; retbindin

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.

Age-related macular degeneration (AMD) is a major cause of vision loss.我们已经证明，干性 AMD 与 RPE 富含胆固醇的区域内补体因子 H 和纤维蛋白 3 的特定沉积有关。质谱已被用来鉴定与 AMD 中蛋白质沉积形成有关的复合物的更多成分。 AMD 应激相关过程的细胞培养模型表明，RPE 衍生细胞的特定应激会导致 AMD 重要通路的基因表达变化，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。 Retbindin 是一种新型的视网膜感光蛋白。基因敲除小鼠模型显示出视觉反应的渐进性缺陷和外层视网膜与年龄相关的缺陷，这些缺陷与某些形式的与年龄相关的黄斑变性和青光眼具有惊人的相似之处。该模型以及我们合作者的其他小鼠模型正在接受评估。 我们还正在完成 KLPH 和 Lengsin 的研究，这两种新基因在晶状体功能和透明度方面发挥着作用，并且是年龄相关性白内障的候选基因。 我们已经完成了对 miRNA 簇的靶向删除模型的广泛合作研究，该簇在感觉神经元（包括光感受器和听觉毛细胞）的成熟中发挥着重要作用。该缺失具有纤毛病的某些方面，并为类似 Ushers 的疾病提供了可能的小鼠模型。手稿已基本完成。