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是必不可少的。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，包括老年性黄斑变性(AMD)和与线粒体功能障碍相关的色素视网膜病变，但尚不存在原发RPE细胞退化的动物遗传模型。这项提议描述了一种利用老鼠遗传学创建这样一个模型的策略。将产生一种小鼠品系，在该品系中，由于RPE特异性线粒体功能的丧失，RPE细胞在出生后逐渐退化和死亡。RPE细胞变性可导致继发性光感受器细胞变性和脉络膜萎缩。将在不同年龄对RPE细胞丢失对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，模型将受到光曝光调制的扰动。原代RPE细胞变性模型将有助于理解RPE与感光细胞、RPE与脉络膜之间的相互依赖关系，有助于了解继发于RPE细胞死亡的致病过程，并有助于在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.