Genetic Modifiers of Retinal Disease

项目摘要/摘要 遗传性视网膜疾病，通常没有有效的治疗方法，导致1.02 美国有数以百万计的成年人失明。在儿童中，遗传性疾病--莱伯氏先天性巨结肠， 占失明的20%，其中10%-15%是由CRB1基因突变引起的。除了……之外 LCA、CRB1突变也可导致先天性或早发性视网膜色素变性(RP)， 进行性疾病。CRB1RP变异有时与独特的疾病特征有关，例如 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 萎缩，视锥-视杆细胞营养不良，小眼球伴视盘玻璃疣，视网膜劈裂，黄斑囊样水肿，以及 黄斑营养不良性疾病。与多种疾病表型相关的原因 与CRB1突变的关系尚不完全清楚。可以解释这种疾病的基因-表型相关性 在携带CRB1突变的患者中没有检测到光谱，这表明环境 因素或遗传背景修饰物有助于观察到的疾病表型的变异性。 疾病表现表型变异的另一个潜在因素是Crb1亚型，它具有 最近被证明具有空间和时间上不同的表达模式。显然，理解 变异的原因和观察到的病理基础的机制对于 开发有效的治疗方法。 在这个建议中，我们将检验这样一个假设，即由于Crb1突变引起的病理变化取决于 受影响的异构体及其发生的遗传背景，以及它们之间的潜在相互作用。我们将确定 增强或抑制Crb1rd8相关疾病表型或 在Crb1rd8上是上位的。通过使用具有同型特异性基因敲除等位基因的小鼠模型 受控的遗传背景，我们将确定它们对疾病变异性的贡献和机制 它们通过这一点发挥作用。 这些研究解决了一个关键的未得到满足的需求，即获取发展所需的基本生物学知识 可以针对症状前阶段的有效治疗，以预防、推迟发病或减轻严重程度 这种疾病。动物模型对加深我们对基因的理解起着重要而独特的作用。 疾病的基础，并作为检查组织病理学和进行临床前研究的资源 不能轻易在人体上进行的治疗性试验。

PROJECT SUMMARY/ABSTRACT Heritable retinal disorders, for which effective treatments are generally unavailable, contributes to the 1.02 million adults who are blind in the US. Among children, the heritable disease - Leber Congenital Amaurosis, accounts for 20% of blindness, and 10-15%of those are caused by mutations in the CRB1 gene. In addition to LCA, CRB1 mutations can also cause congenital or early-onset retinitis pigmentosa (RP), a more slowly progressive disease. CRB1 RP variants are sometimes 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, retinoschisis, cystoid macular edema, and macular dystrophic disease. The cause of the wide range of disease phenotypes associated with CRB1 mutations is not fully understood. Genotype-phenotype correlations that could explain the disease spectrum have not been detected among patients bearing CRB1 mutations, suggesting that environmental factors or genetic background modifiers contribute to the variability in the disease phenotypes observed. Another potential contributor to the phenotypic variability in disease presentation are Crb1 isoforms which have recently been shown to have spatially and temporally distinct expression patterns. Clearly, understanding the reasons for the variability and the mechanisms underlying the observed pathologies is extremely important for developing effective therapies. In this proposal, we will test the hypothesis that pathological changes due to Crb1 mutations depend upon the isoform affected and the genetic background on which it occurs, and their potential interactions. We will identify the molecular basis of genetic modifiers that enhance or suppress Crb1rd8 associated disease phenotypes or are epistatic upon Crb1rd8. Through the use of mouse models with isoform specific knockout alleles and controlled genetic backgrounds, we will determine their contribution to disease variability and the mechanisms through which they function. These studies address a critical unmet need for acquiring the basic biological knowledge necessary to develop 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.