Genetic Modifiers of Retinal Disease

视网膜疾病的基因修饰

基本信息

批准号：
10375022
负责人：
Patsy M Nishina
金额：
$ 60.3万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10375022
关键词：
Ablation Address Adult Affect Age of Onset Alleles Animal Model Appearance Atrophic Automobile Driving Biological Blindness CRISPR/Cas technology Cells Characteristics Child Clinical Coats&apos disease Cystoid Macular Edema Development Diagnosis Disease Enhancers Environmental Exposure Environmental Risk Factor Family Genes Genetic Genome Genotype Heritability Human Knock-out Knowledge Lead Leber&apos s amaurosis Leber&apos s disease Mediating Mendelian disorder Microphthalmos Modification Molecular Monoclonal Antibodies Mus Mutation Onset of illness Optic Disk Drusen Pathogenicity Pathologic Pathology Pathway Analysis Pathway interactions Patients Pattern Phenotype Pigmentation physiologic function Pigments Population Progressive Disease Protein Isoforms Public Health Reporting Resources Retina Retinal Detachment Retinal Diseases Retinitis Pigmentosa Retinoschisis Role Severities Severity of illness Specificity Telangiectasis Testing Therapeutic Therapeutic Intervention Tissues Treatment outcome Variant arteriole blind cell type cone-rod dystrophy differential expression disease phenotype disease prognosis early onset effective therapy gene augmentation therapy improved insight macula mouse model mutant personalized medicine pre-clinical precision medicine preservation prevent response targeted treatment therapeutic evaluation therapeutic target treatment response

项目摘要

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.

项目概要/摘要通常无法获得有效治疗的遗传性视网膜疾病导致了 1.02 美国有 100 万成年人失明。在儿童中，遗传性疾病 - 莱伯先天性黑蒙，占失明的20%，其中10-15%是由CRB1基因突变引起的。此外 LCA、CRB1 突变还可引起先天性或早发性视网膜色素变性 (RP)，这是一种更缓慢的疾病进行性疾病。 CRB1 RP 变异有时与独特的疾病特征相关，例如视网膜毛细血管扩张，伴或不伴渗出性视网膜脱离（Coat 病）、RPE 色素沉着丧失除了近小动脉（保留小动脉旁 RPE 或 PPRPE）、静脉旁脉络膜视网膜色素萎缩、视锥杆营养不良、纳米眼球伴视盘玻璃膜疣、视网膜劈裂、黄斑囊样水肿和黄斑营养不良性疾病。与多种疾病表型相关的原因 CRB1 突变的情况尚不完全清楚。可以解释这种疾病的基因型-表型相关性在携带 CRB1 突变的患者中尚未检测到谱系，这表明环境因素因素或遗传背景修饰因素导致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贡献者是 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，理解变异性的原因和观察到的病理学背后的机制对于开发有效的疗法。在本提案中，我们将检验以下假设：Crb1 突变引起的病理变化取决于受影响的亚型及其发生的遗传背景，以及它们潜在的相互作用。我们将确定增强或抑制 Crb1rd8 相关疾病表型的遗传修饰剂的分子基础或位于 Crb1rd8 上位。通过使用具有亚型特异性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及其机制它们通过它们发挥作用。这些研究解决了获取开发所需的基本生物学知识这一未满足的关键需求可以针对症状前阶段以预防、延迟发作或减轻严重程度的有效疗法这种疾病。动物模型在加深我们对遗传的理解方面发挥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的资源无法轻易在人体中进行的治疗测试。