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

基本信息

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
项目类别：
财政年份：
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

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

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项目摘要

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.

与年龄相关的黄斑变性（AMD）是视力丧失的主要原因。我们已经表明，干燥的AMD与富含RPE的胆固醇的结构域内的补体H和Fibulin 3的特定沉积有关。质谱学已用于鉴定与AMD中蛋白质沉积形成有关的复合物的进一步成分。 AMD中应力相关过程的细胞培养模型表明，RPE衍生细胞的特定应力会导致基因表达在AMD中重要的途径变化，尤其是胆固醇合成和转运的上调以及细胞内无锌的转运。视毒素是视网膜感光体的一种新型蛋白质。敲除小鼠模型显示出视觉反应的逐渐缺陷和外部视网膜中与年龄相关的缺陷，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明显的相似性。该模型以及我们合作者的其他鼠标模型正在评估中。我们还完成了KLPH和Lengsin的工作，这是两个新型基因，它们在晶状体功能和透明度中具有作用，并且是与年龄相关性白内障的候选者。我们已经完成了针对miRNA群集的目标缺失模型的广泛协作研究，该模型在感觉神经元的成熟（包括光感受器和听觉毛细胞）中具有重要作用。缺失具有纤毛病的各个方面，并为引诱者样疾病提供了可能的小鼠模型。手稿几乎完成了。