Genetic model of retinal pigment epithelium degeneration

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已被广泛认识。RPE细胞的原发性变性被认为是几种重要的人类视网膜疾病的核心病因，包括年龄相关性黄斑变性（AMD）和与线粒体功能障碍相关的色素视网膜病变，但目前还没有RPE细胞原发性变性的动物遗传模型。本提案描述了一种利用小鼠遗传学创建这样一个模型的策略。将产生一种小鼠品系，其中RPE细胞逐渐退化并因RPE特异性线粒体功能丧失而死亡。RPE细胞变性应引起继发性感光细胞变性和脉络膜萎缩。对不同年龄的RPE细胞损失对RPE和邻近组织的影响进行详细的结构和功能分析。在退化的适当阶段，模型将受到调制光照射的扰动。原发性RPE细胞变性模型将有助于理解RPE与感光细胞以及RPE与脉络膜的相互依赖性，有助于理解继发于RPE细胞死亡的致病过程，有助于在RPE细胞功能逐渐受损的情况下研究潜在的治疗方法。

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.