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群遗传异质性疾病，当被视为一个整体时，是世界上失明的主要原因。这些疾病的范围包括视网膜色素变性（RP）等疾病，每1000人中就有1人受其影响，而65岁以上的人每3人中就有1人受其影响。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产生和维持的转录网络，以确定可能适用于改进视网膜疾病治疗策略的新靶点。PI首次报道了人类Nr2e3突变导致隐性ESCS，小鼠Nr2e3突变导致表达蓝色视蛋白的锥体细胞过量产生并伴有进行性视网膜变性。我们之前的研究和其他人的工作证明了核受体Nr2e3在多种转录网络中调控视网膜发育和功能的关键作用。Nr2e3突变的患者在疾病的严重程度上表现出显著的差异