Genetic Modifiers of Photoreceptor Development and Maintenance

描述(申请人提供)：遗传性视网膜疾病是一大类遗传异质性疾病，作为一个整体被认为是世界上导致失明的主要原因。这些疾病包括视网膜色素变性(RP)和黄斑变性等疾病，每1000人中就有一人受到影响，65岁以上的人中有1人受到黄斑变性的影响。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控光感受器生成和维持的转录网络，以便识别可能适用于改善视网膜疾病治疗策略的新靶点。PI是第一个报道人类Nr2e3基因突变导致隐性ESCs，而小鼠Nr2e3基因突变导致表达蓝色视蛋白的锥体细胞过度产生进行性视网膜变性。我们之前的研究和其他人的工作证明了核受体Nr2e3在多个转录网络中调节视网膜发育和功能的关键作用。携带Nr2e3基因突变的患者在疾病严重程度上表现出显著的差异性 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Nr2e3及其辅助因子Nr1d1是主要的调节者，能够调节影响许多IRD中视网膜疾病的基因网络，从而成为视网膜退行性变的有效修饰物。这项研究的目的是确定核受体Nr2e3和Nr1d1在抢救多种形式的视网膜疾病方面的有效性和能力。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。具体地说，我们将1)确定Nr2e3和Nr1d1在五种不同的视网膜变性模型中改善光感受器退化的广谱疗效；2)开发针对Nr2e3和Nr1d1的有效的临床前基因传递方法；以及3)确定Nr2e3和Nr1d1在多种光感受器退化模型中拯救视网膜疾病的机制。初步研究表明，Nr2e3和Nr1d1可以挽救两种截然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，以减轻或防止视网膜退化。

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.