Genetic Modifiers of Photoreceptor Development and Maintenance

光感受器发育和维持的基因修饰

• 批准号: 8204535
• 负责人: Neena B Haider
• 金额: $ 41.9万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204535
• 关键词: Affect; Alleles; Bardet-Biedl Syndrome; Biological; Candidate Disease Gene; Cell Cycle; Cells; Chromosome Mapping; Chromosomes, Human, Pair 11; Complete Blindness; Data; Defect; Development; Disease; Electroporation; Gene Expression Profiling; Generations; Genes; Genetic; Genetic Identity; Goals; Health; Hereditary Disease; Human; Individual; Lead; Macular degeneration; Maintenance; Maps; Mitotic; Molecular Profiling; Mus; Mutant Strains Mice; Mutation; Newborn Infant; Nuclear Receptor Gene; Nuclear Receptors; Outcome; Pathology; Pathway interactions; Phenotype; Photoreceptors; Production; Reporting; Retina; Retinal; Retinal Cone; Retinal Defect; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; SW opsin; Severities; Severity of illness; Syndrome; Testing; Transgenic Organisms; Usher Syndrome; cofactor; congenic; disease phenotype; improved; in vivo; mouse model; novel; photoreceptor degeneration; positional cloning; prevent; research study; retinal progenitor cell; retinal rods; treatment strategy

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.

描述（由申请人提供）：视网膜变性是一组遗传异质性疾病，通常可根据在视杆和视锥光感受器中观察到的病理类型进行分类。这些疾病影响每4000人中的一个，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综合征和增强的S-视锥综合征（ESCS），其中每一种都具有作为疾病表型的主要组成部分的光感受器变性。我们的长期目标是了解调节光感受器生成和维持的转录网络，这将使我们能够确定可能适用于改善视网膜疾病治疗策略的新靶点。我们的研究和其他人的研究表明，核受体Nr 2 e3的功能在多个转录网络，以调节感光细胞的发育和维护。PI是第一个报告人Nr 2 e3突变导致隐性ESCS，而小鼠Nr 2 e3突变导致表达蓝色视蛋白的视锥细胞过量产生并伴有进行性视网膜变性的人。最近的研究结果还表明，在人类Nr 2 e3突变可以有显着的变异性表型表现，导致较温和的ESCS表型，戈德曼Favre综合征，或显性视网膜色素变性。这强调了Nr 2 e3定向转录途径在视网膜疾病中的重要性，并表明存在影响这些疾病的人类修饰基因。本提案的目的是在小鼠模型Nr 2 e3 rd 7/rd 7中鉴定视网膜变性的遗传修饰剂。我们利用两种方法：遗传作图策略，和候选基因的方法来执行我们的研究。目的1是使用定位克隆方法在AKR/J菌株背景上鉴定Nr 2 e3 rd 7/rd 7的遗传修饰因子，称为Mor 7。我们已经绘制了这个修饰基因，并开发了一个同类系（N9），改善Nr 2 e3 rd 7/rd 7相关的视网膜变性。目的2是确定核受体Nr 1d 1，Nr 2 e3的辅因子，是否可以修改Nr 2 e3 rd 7/rd 7相关的视网膜变性。我们将通过在新生Nr 2 e3 rd 7/rd 7小鼠中过表达Nr 1d 1来测试我们的假设，以确定Nr 1d 1是否可以挽救视网膜变性和视网膜外植体实验，以确定改变的Nr 2 e3或Nr 1d 1表达对视杆或视锥感光细胞命运的影响。我们的研究将大大提高对影响视网膜疾病严重程度的遗传因素的理解，并为改善治疗或预防涉及感光细胞变性的多种形式的视网膜疾病提供潜在的强大靶点。公共卫生关系：视网膜疾病是一种使人衰弱的疾病，影响全球数百万人，通常会导致完全失明。我们建议使用小鼠模型来鉴定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。