Genetic model of retinal pigment epithelium degeneration

视网膜色素上皮变性的遗传模型

• 批准号: 6729860
• 负责人: Douglas E. Vollrath
• 金额: $ 16.01万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6729860
• 关键词: aging; albino mouse; choroid uvea; electron microscopy; electroretinography; gene expression; gene targeting; genetic models; genetically modified animals; green fluorescent proteins; immunocytochemistry; in situ hybridization; light adverse effect; macular degeneration; mitochondrial disease /disorder; model design /development; pathologic process; phenotype; polymerase chain reaction; retina degeneration; retinal pigment epithelium; visual photoreceptor

DESCRIPTION (provided by applicant): Animal genetic models have been essential to the understanding and treatment of human retinal degenerative disease. The importance of the retinal pigment epithelium (RPE) to photoreceptor function is widely recognized. Primary degeneration of RPE cells is thought to be central to the etiology of several significant human retinal disorders including age-related macular degeneration (AMD) and pigmentary retinopathies associated with mitochondrial dysfunction, yet no animal genetic model of a primary RPE cell degeneration exists. This proposal describes a strategy to create such a model using mouse genetics. A mouse strain will be generated in which RPE cells gradually and postnatally degenerate and die due to RPE specific loss of mitochondrial function. RPE cell degeneration should induce secondary photoreceptor cell degeneration and choroidal atrophy. A detailed structural and functional analysis of the effects of RPE cell loss on the RPE and adjacent tissues will be performed at various ages. At an appropriate stage in the degeneration, the model will be perturbed by modulating light exposure. A model of primary RPE cell degeneration will be useful for understanding the interdependence of RPE and photoreceptor cells and of the RPE and choroid, for understanding pathogenic processes secondary to RPE cell death, and for investigating potential therapies in a setting in which RPE cell function is progressively compromised.

描述（由申请人提供）：动物遗传模型对于理解和治疗人类视网膜退行性疾病至关重要。视网膜色素上皮（RPE）对光感受器功能的重要性得到了广泛认可。 RPE细胞的主要变性被认为是几种重要人类视网膜疾病的病因的核心，包括与年龄相关的黄斑变性（AMD）和与线粒体功能障碍相关的色素性视网膜病，但不存在原代RPE细胞变性的动物遗传模型。 该建议描述了使用鼠标遗传学创建这种模型的策略。 将产生小鼠菌株，其中RPE细胞逐渐和产后退化并因RPE特异性线粒体功能而死亡。 RPE细胞变性应诱导继发感光细胞变性和脉络膜萎缩。 对RPE细胞损失对RPE和相邻组织的影响的详细结构和功能分析将在不同年龄进行。 在变性的适当阶段，该模型将通过调节光曝光而受到干扰。 原代RPE细胞变性的模型将有助于理解RPE和感光细胞以及RPE和脉络膜的相互依赖性，用于理解继发于RPE细胞死亡的致病过程，并在RPE细胞功能逐渐逐渐降低RPE细胞功能的环境中研究潜在的疗法。