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.

项目摘要/摘要可遗传的视网膜疾病通常不可用，这有助于1.02 在美国盲人的成年人。在儿童中占失明的20％，其中10-15％是由CRB1基因突变引起的。此外 LCA，CRB1突变也可能引起先天性或早期发作性视网膜炎色素（RP），较慢进行性疾病。 CRB1 RP变体有时与独特的疾病特征有关，例如视网膜毛细血管扩张，有或没有透明性视网膜脱离（外套病），RPE色素沉着丧失除了附近的小动脉（保存para-arteriolar rpe或pprpe）外萎缩，锥杆性营养不良，纳米果皮，带有视盘drusen，视叶片，囊状黄斑水肿和黄斑营养不良疾病。相关疾病表型的广泛原因使用CRB1突变尚不完全了解。基因型 - 表型相关性，可以解释该疾病在带有CRB1突变的患者中尚未检测到频谱，这表明环境因素或遗传背景修饰符有助于观察到的疾病表型的变异性。疾病表现中表型变异性的另一个潜在贡献者是CRB1同工型，具有最近被证明具有空间和时间上不同的表达模式。显然，理解可变性的原因和观察到的病理学基础的机制对于开发有效的疗法。在此提案中，我们将检验以下假设：CRB1突变引起的病理变化取决于同工型受到影响及其发生的遗传背景及其潜在相互作用。我们将确定增强或抑制CRB1RD8相关疾病表型或对CRB1RD8表示同义。通过使用与同工型特异性基因敲除等位基因的鼠标模型和受控的遗传背景，我们将确定它们对疾病变异性和机制的贡献通过它们的功能。这些研究涉及获得开发必要的基本生物学知识的关键需求有效的疗法可以针对症状前阶段，以防止，延迟发作或减少严重程度疾病。动物模型发挥了重要而独特的作用，可以进一步了解我们对遗传的理解疾病的基础和作为检查组织病理学并进行临床前的资源无法在人类中进行的治疗测试。