Genetic Modifiers of Photoreceptor Development and Maintenance

光感受器发育和维持的基因修饰

• 批准号: 8773985
• 负责人: Neena B Haider
• 金额: $ 49.25万
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8773985
• 关键词: ARRB1 gene; Advanced Development; Affect; Age of Onset; Attenuated; Bardet-Biedl Syndrome; Behavior assessment; Blindness; Cell Proliferation; Cell physiology; ChIP-seq; Clinical Research; Complete Blindness; Cone; DNA; Data; Development; Disease; Elderly; Electroretinography; Exhibits; Funding; Fundus; Gene Delivery; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Goals; Hematoxylin and Eosin Staining Method; Human; Immunohistochemistry; Individual; Inherited; Lasers; Lead; Leber' s amaurosis; Longitudinal Studies; Macular degeneration; Maintenance; Methods; Modeling; Molecular; Molecular Genetics; Mus; Mutation; Nuclear Receptors; Ophthalmoscopy; Patients; Phenotype; Photoreceptors; Phototransduction; Production; Reporting; Retina; Retinal; Retinal Cone; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Role; SW opsin; Severities; Severity of illness; Staining method; Stains; Syndrome; Technology; Testing; Therapeutic; Variant; Visual Acuity; Work; cofactor; disease phenotype; gene therapy; improved; insight; mouse model; novel; photoreceptor degeneration; pre-clinical; preclinical study; prevent; public health relevance; ranpirnase; retinal progenitor cell; retinal rods; rho; treatment strategy

DESCRIPTION (provided by applicant): Inherited retinal diseases are a large group of genetically heterogeneous disorders, that when considered as a whole are the leading cause of blindness in the world. These diseases range to include disorders such as retinitis pigmentosa (RP) which affects one in every 1000 individuals, and macular degeneration, which affects 1 in 3 individuals over the age of 65. It is clear that the severity of disease is strongly influenced by genetic factors. Our long-term goal is to understand the transcriptional networks regulating photoreceptor generation and maintenance, in order to identify novel targets that may be amenable for improved treatment strategies for retinal disease. 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. Our previous studies and the work of others demonstrate a crucial role for the nuclear receptor Nr2e3 in multiple transcriptional networks to regulate the retinal development and function. Patients with Nr2e3 mutations show significant variability in severity of the disease phenotype. These phenotypic disparities underscore the significance of human modifier genes influencing retinal diseases. We hypothesize that Nr2e3 and its cofactor Nr1d1 are master regulators able to modulate the network of genes that influence retinal disease in many IRDs and thereby serve as potent modifiers of retinal degeneration. The goals of this study are to determine the efficacy and capacity of nuclear the receptors Nr2e3 and Nr1d1 in rescuing multiple forms of retinal disease. We will accomplish these goals using modern molecular genetic and genomic approaches. Specifically we will 1) determine the broad-spectrum efficacy of Nr2e3 and Nr1d1 to ameliorate photoreceptor degeneration in five distinct retinal degeneration models; and 2) develop an effective preclinical gene delivery method for Nr2e3 and Nr1d1; and 3) determine the mechanism by which Nr2e3 and Nr1d1 rescue retinal disease in multiple models of photoreceptor degeneration. Preliminary studies show that Nr2e3 and Nr1d1 can rescue two disparate models of retinal disease. These preclinical studies will provide valuable insight leading to clinical studies and the development of viable therapeutics to attenuate or prevent retinal degeneration.

描述（由申请人提供）：遗传性视网膜疾病是一大组遗传异质性疾病，当作为一个整体考虑时，是世界上失明的主要原因。这些疾病的范围包括诸如视网膜色素变性（RP）和黄斑变性的病症，视网膜色素变性（RP）影响每1000个个体中的一个，黄斑变性影响65岁以上的3个个体中的1个。很明显，疾病的严重程度受到遗传因素的强烈影响。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，以确定可能适用于改善视网膜疾病治疗策略的新靶点。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。我们以前的研究和其他人的工作证明了核受体Nr 2 e3在多个转录网络中调节视网膜发育和功能的关键作用。具有Nr 2 e3突变的患者在疾病的严重程度上显示出显著的变异性 表型这些表型差异强调了人类修饰基因影响视网膜疾病的重要性。我们假设Nr 2 e3及其辅因子Nr 1d 1是能够调节影响许多IRD视网膜疾病的基因网络的主调节因子，从而作为视网膜变性的有效调节剂。本研究的目的是确定核受体Nr 2 e3和Nr 1d 1在挽救多种形式的视网膜疾病中的功效和能力。我们将使用现代分子遗传学和基因组学方法来实现这些目标。具体而言，我们将1）确定Nr 2 e3和Nr 1d 1在五种不同视网膜变性模型中改善感光细胞变性的广谱功效; 2）开发Nr 2 e3和Nr 1d 1的有效临床前基因递送方法; 3）确定Nr 2 e3和Nr 1d 1在多种感光细胞变性模型中挽救视网膜疾病的机制。初步研究表明，Nr 2 e3和Nr 1d 1可以挽救两种不同的视网膜疾病模型。这些临床前研究将提供有价值的见解，导致临床研究和可行的治疗方法的发展，以减轻或预防视网膜变性。