Genetic Modifiers of Photoreceptor Development and Maintenance

描述(申请人提供)：视网膜退行性变是一组遗传异质性疾病，通常可以根据视杆细胞和视锥细胞感光细胞中观察到的病理类型进行分类。这些疾病每4000人中就有一人受到影响，很明显，疾病的严重程度受到遗传因素的强烈影响。这一大组疾病包括视网膜色素变性、黄斑变性、Bardet-Biedl综合征、Usher综合征和增强型S视锥综合征(ESCS)，每一种疾病都以光感受器变性为疾病表型的主要组成部分。我们的长期目标是了解调控光感受器生成和维持的转录网络，这将使我们能够识别可能适用于改善视网膜疾病治疗策略的新靶点。我们和其他人的研究表明，核受体Nr2e3在多个转录网络中发挥功能，调节光感受器细胞的发育和维持。PI是第一个报道人类Nr2e3基因突变导致隐性ESCs，而小鼠Nr2e3基因突变导致表达蓝色视蛋白的锥体细胞过度产生进行性视网膜变性。最近的发现还表明，人类Nr2e3的突变在表型表现上可能有显著的差异，导致较轻微的ESCs表型、Goldman Favre综合征或显性视网膜色素变性。这强调了Nr2e3指导的转录通路在视网膜疾病中的重要性，并表明影响这些疾病的人类修饰基因的存在。这项建议的目的是在小鼠模型Nr2e3rd7/Rd7中识别视网膜变性的遗传修饰因素。我们使用两种方法：遗传作图策略和候选基因方法来执行我们的研究。目的1是利用定位克隆的方法，在AKR/J株背景上鉴定Nr2e3rd7/Rd7的遗传修饰物，称为Mor7。我们已经定位了这个修饰基因，并开发了一个同源基因系(N9)来改善Nr2e3rd7/Rd7相关的视网膜变性。目的2确定Nr2e3的辅因子核受体Nr1d1是否能改变Nr2e3rd7/Rd7相关的视网膜变性。我们将通过在新生Nr2e3rd7/Rd7小鼠中过表达Nr1d1来验证我们的假设，以确定Nr1d1是否可以挽救视网膜变性，并通过视网膜外植体实验来确定改变Nr2e3或Nr1d1表达对视杆或视锥感光细胞命运的影响。我们的研究将极大地提高对影响视网膜疾病严重程度的遗传因素的理解，并为改进治疗或预防涉及光感受器退化的多种形式的视网膜疾病提供潜在的强大靶点。与公共卫生相关：视网膜疾病是一种使人衰弱的疾病，影响全球数百万人，往往会导致完全失明。我们建议使用小鼠模型来识别可以纠正视网膜疾病的基因。这些基因将成为潜在的强大靶点，可用于治疗多种形式的视网膜疾病，而不是一种。

DESCRIPTION (provided by applicant): Retinal degenerations are a group of genetically heterogeneous disorders that can often be classified according to the type of pathology observed in rod and cone photoreceptors. These diseases affect one in every 4000 individuals and it is clear the severity of disease is strongly affected by genetic factors. This large group of disorders includes retinitis pigmentosa, macular degeneration, Bardet-Biedl syndrome, Usher syndrome, and enhanced S-cone syndrome (ESCS), each of which has photoreceptor degeneration as a major component of the disease phenotype. Our long-term goal is to understand the transcriptional networks regulating photoreceptor generation and maintenance, which will enable us to identify novel targets that may be amenable for improved treatment strategies for retinal disease. Our studies and those of others demonstrate that the nuclear receptor Nr2e3 functions in multiple transcriptional networks to regulate the development and maintenance of photoreceptor cells. The PI was the first to report that mutations in human Nr2e3 cause the recessive ESCS, and mutations in mouse Nr2e3 cause excess production of blue opsin expressing cone cells with progressive retinal degeneration. Recent findings also demonstrate that mutations in human Nr2e3 can have significant variability in phenotypic manifestation causing a milder ESCS phenotype, Goldman Favre syndrome, or dominant retinitis pigmentosa. This underscores the importance of Nr2e3-directed transcriptional pathways in retinal disease and suggests the existence of human modifier genes influencing these diseases. The objective of this proposal is to identify genetic modifiers of retinal degeneration in the mouse model Nr2e3rd7/rd7. We utilize two approaches: a genetic mapping strategy, and a candidate gene approach to perform our studies. Aim 1 is to identify the genetic modifier of Nr2e3rd7/rd7, referred to as Mor7, on the AKR/J strain background using a positional cloning approach. We have mapped this modifier gene and developed a congenic line (N9) that ameliorates Nr2e3rd7/rd7 associated retinal degeneration. Aim 2 is to determine whether the nuclear receptor Nr1d1, a cofactor of Nr2e3, can modify Nr2e3rd7/rd7 associated retinal degeneration. We will test our hypothesis by over-expressing Nr1d1 in newborn Nr2e3rd7/rd7 mice to determine if Nr1d1 can rescue retinal degeneration and retinal explant experiments to determine the effects of altered Nr2e3 or Nr1d1 expression on rod or cone photoreceptor cell fate. Our studies will greatly enhance understanding of genetic factors that influence severity of retinal disease, and, provide potentially powerful targets for improved therapies to treat or prevent multiple forms of retinal disease involving photoreceptor degeneration. PUBLIC HEALTH RELEVANCE: Retinal diseases are debilitating disorders that affect millions of individuals worldwide and can often lead to complete blindness. We propose to use mouse models to identify genes that can correct retinal disease. These genes will be potentially powerful targets that can be used to treat not one but many forms of retinal disease.