Genetic Modifiers of Photoreceptor Development and Maintenance

光感受器发育和维持的基因修饰

• 批准号: 7941446
• 负责人: Neena B Haider
• 金额: $ 28.05万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941446
• 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; 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; Vertebrate Photoreceptors; cofactor; congenic; disease phenotype; improved; in vivo; mouse model; novel; photoreceptor degeneration; positional cloning; prevent; public health relevance; 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）：视网膜退化是一组遗传性异构疾病，通常可以根据在杆和锥形感受器中观察到的病理类型进行分类。这些疾病每4000名患者中有一个，很明显疾病的严重程度受遗传因素的强烈影响。这大批疾病包括色素性视网膜炎，黄斑变性，Bardet-Biedl综合征，Usher综合征和增强的S-Cone综合征（ESC），每种综合征（ESC）都具有光感受器变性，是疾病表型的主要成分。我们的长期目标是了解调节光感受器产生和维护的转录网络，这将使我们能够确定可能适合改善视网膜疾病治疗策略的新颖目标。我们的研究和其他研究表明，核受体NR2E3在多个转录网络中起作用，以调节感光细胞的发育和维持。 PI是第一个报告人NR2E3中的突变会导致隐性ESC，而小鼠NR2E3中的突变导致过量产生蓝色的Opsin表达锥细胞，并具有渐进的视网膜变性。最近的发现还表明，人NR2E3中的突变在表型表现上可能具有显着差异，从而导致ESC型表型，高盛综合征或显性视网膜炎色素。这强调了NR2E3指导的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的存在。该建议的目的是确定小鼠模型NR2E3RD7/RD7中视网膜变性的遗传修饰符。我们采用了两种方法：一种遗传映射策略，以及一种候选基因方法来执行我们的研究。目的1是使用位置克隆方法在AKR/J菌株背景上识别NR2E3RD7/RD7的遗传修饰符，称为MOR7。我们已经绘制了这个修饰符基因，并开发了一种先天线（N9），该线路可以改善NR2E3RD7/RD7相关的视网膜变性。 AIM 2是确定核受体NR1D1是NR2E3的辅因子是否可以修改NR2E3RD7/RD7相关的视网膜变性。我们将通过在新生儿NR2E3RD7/RD7小鼠中过度表达NR1D1来测试我们的假设，以确定NR1D1是否可以挽救视网膜退化和视网膜外植体实验，以确定NR2E3或NR1D1对ROD或CONE CONE CONE PENSE感染者细胞fate的影响的影响。我们的研究将极大地增强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多种形式的视网膜疾病的疗法提供了潜在的强大靶标，这些疗法涉及光感受器变性。公共卫生相关性：视网膜疾病正在使影响全球数百万人的疾病使人衰弱，并且通常会导致完全失明。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。这些基因将是潜在的强大靶标，可用于治疗一种而不是多种形式的视网膜疾病。