Genetic Modifiers of Retinal Disease

项目摘要/摘要 根据2014年全国健康调查，美国有2250万人患有失明或 许多原因导致的失明，包括遗传性视网膜疾病，通常都有有效的治疗方法 不可用。CRB1变异导致可遗传的视网膜退行性表型，从Leber先天性 以先天性或早发性失明为特征的黑色素沉着性视网膜炎，进展较慢 进行性疾病。CRB1RP变异通常与独特的疾病特征有关，如视网膜 毛细血管扩张伴或不伴渗出性视网膜脱离(Coat‘s病)，RPE色素丧失 除近小动脉(保留小动脉旁RPE或PPRPE)外，色素旁脉络膜视网膜 视盘萎缩、视锥-视杆细胞营养不良、纳米眼伴视盘玻璃疱疹和黄斑营养不良疾病。有限 已检测到携带CRB1突变的患者中存在基因-表型相关性的证据。这 提示突变的CRB1与环境因素或遗传修饰物的相互作用是可能的 观察到的疾病表型变异的原因。 在这项提案中，我们将具体解决CRB1相关疾病潜在的遗传复杂性。 通过致敏的化学诱变筛选，我们已经鉴定出12个新的小鼠模型 与Crb1rd8突变相关的上位性遗传修饰物。这些模型基于已定义的基因 在受控环境中提出的背景将使我们能够回答以下问题：1)什么是 与Crb1rd8相互作用导致包括视网膜在内的临床表型的遗传修饰物 发育不良、视力下降和视网膜电反应减弱？2)什么细胞类型 导致这种疾病的表型？3)遗传诱导的致病机制是什么？ 导致这些表型的修饰物？4)能否确定可能起到 未来治疗干预以延缓、预防或逆转疾病的蓝图？ 这项建议的目标是确定遗传修饰物和致病基因的分子基础。 它们导致的疾病表型的潜在机制。这些研究解决了一个关键的 对开发有效疗法的需求尚未得到满足，这些疗法可以针对症状前阶段进行预防、延误 出现或减轻疾病的严重程度。动物模型发挥着重要而独特的作用，以进一步推动我们的 了解疾病的遗传基础，并将其作为检查组织病理学和 进行临床前治疗试验，而这些试验不能轻易在人体上进行。

PROJECT SUMMARY/ABSTRACT According to the 2014 National Health Survey, 22.5 million people in the US suffer from vision loss or blindness from many causes, including heritable retinal disorders, for which effective treatments are generally unavailable. CRB1 variants cause heritable retinal degenerative phenotypes ranging from Leber congenital amaurosis, characterized by congenital or early-onset blindness, to retinitis pigmentosa, a more slowly progressive disease. CRB1 RP variants are often associated with unique disease features, such as retinal telangiectasia with or without exudative retinal detachment (Coat's disease), a loss of RPE pigmentation except near arterioles (preservation of para-arteriolar RPE or PPRPE), pigment paravenous chorioretinal atrophy, cone-rod dystrophy, nanophthalmos with optic disc drusen, and macular dystrophic disease. Limited evidence for genotype-phenotype correlations in patients bearing CRB1 mutations has been detected. This suggests that interactions of mutant CRB1 with either environmental factors or genetic modifiers are the likely cause of the variability in disease phenotypes observed. In this proposal, we will specifically address the genetic complexities underlying CRB1-associated disease. Through a sensitized chemical mutagenesis screen, we have identified 12 novel mouse models bearing epistatic genetic modifiers associated with the Crb1rd8 mutation. These models on defined genetic backgrounds, raised in controlled environments will allow us to answer the following questions: 1) What are the genetic modifiers that interact with Crb1rd8 to cause the clinical phenotypes observed including retinal dysplasia, reduction in visual acuity and diminished electroretinographic response? 2) What cell types contribute to the disease phenotypes? 3) What are the pathogenic mechanisms that are induced by the genetic modifiers that lead to these phenotypes? 4) Can shared mechanisms be identified that might serve as a blueprint for future therapeutic intervention to delay, prevent, or reverse the disease? The goal of this proposal is to determine the molecular basis of the genetic modifiers and the pathogenic mechanisms underlying the disease phenotypes to which they contribute. These studies address a critical unmet need for developing effective therapies that can target the pre-symptomatic stage to prevent, delay onset or decrease severity of the disease. Animal models serve an important and unique role to further our understanding of the genetic underpinnings of disease and as a resource to examine tissue pathology, and to perform pre-clinical therapeutic tests that cannot be readily conducted in humans.