Genetic Modifiers of Photoreceptor Development and Maintenance

光感受器发育和维持的基因修饰

• 批准号: 8895944
• 负责人: Neena B Haider
• 金额: $ 48.27万
• 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/8895944
• 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; Genomic approach; Goals; Health; 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; genetic approach; improved; insight; mouse model; novel; photoreceptor degeneration; pre-clinical; preclinical study; prevent; 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批遗传性异质性疾病，当整体认为是世界上失明的主要原因时。这些疾病的范围包括疾病，例如色素炎（RP），影响每1000人中的一个人和1000个人的黄斑变性，这会影响65岁以上3个患者中的1人。显然，疾病的严重程度受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产生和维护的转录网络，以确定可能适合改善视网膜疾病治疗策略的新目标。 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。我们以前的研究和其他研究表明，在多个转录网络中，核受体NR2E3在调节视网膜发育和功能中起着至关重要的作用。 NR2E3突变患者的疾病严重程度显着差异 表型。这些表型差异强调了影响视网膜疾病的人类修饰基因的重要性。我们假设NR2E3及其辅因子NR1D1是能够调节许多IRD中影响视网膜疾病的基因网络的主调节器，从而成为视网膜变性的有效修饰。这项研究的目标是确定核受体NR2E3和NR1D1在营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和基因组方法来实现这些目标。具体而言，我们将1）确定NR2E3和NR1D1在五个不同的视网膜变性模型中改善光感受器变性的广谱疗效； 2）为NR2E3和NR1D1开发有效的临床前基因输送方法； 3）确定在多种光感受器变性模型中NR2E3和NR1D1挽救视网膜疾病的机制。初步研究表明，NR2E3和NR1D1可以营救两种不同的视网膜疾病模型。这些临床前研究将为临床研究提供宝贵的见解，并开发可行的治疗剂，以减轻或防止视网膜变性。