MOLECULAR BASIS OF SYNDROMIC RETINITIS PIGMENTOSA

色素性视网膜炎的分子基础

• 批准号: 6138219
• 负责人: SUSAN J HAYFLICK
• 金额: $ 26.68万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6138219
• 关键词: clinical research; disease /disorder model; electroretinography; gene expression; gene mutation; genetic disorder diagnosis; genetic mapping; genetic markers; genotype; human genetic material tag; human subject; immunocytochemistry; in situ hybridization; magnetic resonance imaging; model design /development; molecular cloning; molecular genetics; molecular pathology; northern blottings; nucleic acid sequence; phenotype; pleiotropism; polymerase chain reaction; retinitis pigmentosa; single strand conformation polymorphism; southern blotting

The goal of this project is to isolate and characterize the gene for a form of syndromic retinitis pigmentosa (RP), called Hallervorden-Spatz syndrome (HSS) and characterized by abnormal electroretinogram, lipofuscin accumulation in the retinal pigment epithelium, and early, rapidly progressive pigmentary retinopathy. This autosomal recessive disorder of childhood includes extrapyramidal dysfunction with iron accumulation in the basal ganglia. Though lipid peroxidation is an hypothesized mechanism leading to the HSS phenotype, no knowledge exists of the molecular or biochemical defect. We propose a molecular genetic approach to understanding this syndromic form of RP. Our specific aims are to 1) identify the gene for HSS, designated NBIA1 (Neurodegeneration with Brain Iron Accumulation, type 1) by completing the physical map of the critical region, identifying and screening candidate genes, and demonstrating deleterious mutations; 2) develop the molecular diagnosis of HSS using mutation studies and genotype-phenotype correlation; 3) characterize the HSS gene and its protein product at the tissue, cellular, subcellular and molecular levels using homology to model organisms, sequence analysis, histopathology, immunohistochemistry and studies of tissue expression patterns; and 4) isolate the murine homolog of the HSS gene and develop a mouse model for HSS in order to study its pathophysiology. Knowledge about the HSS gene will allow molecular diagnosis in individuals suspected to have this disease. As well, prenatal diagnosis of this fatal condition will be feasible. By delineating the pathophysiologic process in HSS, we may begin to develop rational therapies, which may be of benefit in treating other forms of RP, as well. Rare diseases often illuminate the mechanisms at work in common, related disorders. An advantage to studying syndromic RP is that the pleiotropic manifestations provide a context to help delineate the mechanism of retinopathy. The HSS gene is not retina-specific, and a defect in it must account for rod photoreceptor degeneration as well as regional brain iron accumulation. Furthermore, since defects in this non-retina- specific process may cause other forms of syndromic and isolated RP and may be integral in disorders of lipofuscin accumulation, including aging macular degeneration, identification of the HSS gene may lead to greater understanding of RP as well as the macular dystrophies associated with senescence.

这个项目的目标是分离和鉴定一种 综合征性视网膜色素变性(RP)的形式，称为哈勒沃登-斯帕茨 综合征(HSS)，以视网膜电信号异常为特征， 脂褐素在视网膜色素上皮中积聚，早期， 快速发展的色素性视网膜病变。这种常染色体隐性遗传 儿童期障碍包括伴有铁的锥体外系功能障碍 积聚在基底节。尽管脂质过氧化是一种 导致HSS表型的假设机制，尚不存在知识 分子或生化缺陷。我们提出了一种分子遗传学 了解这一RP综合征形式的方法。 我们的具体目标是：1)确定HSS的基因，命名为NBIA1 (伴有脑铁积聚的神经退行性变，类型1)通过完成 关键区域的物理地图，识别和筛选 候选基因，并显示有害突变；2)开发 应用突变研究和基因表型进行HSS的分子诊断 相关性；3)HSS基因及其蛋白产物在 组织、细胞、亚细胞和分子水平使用同源性 模式生物，序列分析，组织病理学，免疫组织化学 和组织表达模式的研究；4)分离小鼠 HSS基因同源并建立HSS小鼠模型 研究它的病理生理学。 对HSS基因的了解将使分子诊断成为可能 被怀疑患有这种疾病的个人。同样，产前诊断 这种致命疾病的治疗将是可行的。通过勾勒出 在HSS的病理生理过程中，我们可能会开始发展理性 治疗，这可能是有益于治疗其他形式的RP，如 井。 罕见疾病经常阐明共同的、相关的工作机制 精神错乱。研究综合征RP的一个优势是多效性 表现形式提供了一个背景，帮助描绘了 视网膜病变。HSS基因不是视网膜特有的，它是一个缺陷 必须考虑杆状感光细胞退化以及区域性 脑铁积聚。此外，由于这种非视网膜的缺陷- 特定的过程可能会导致其他形式的综合征和孤立的RP和 可能在包括衰老在内的脂褐素积聚障碍中是不可或缺的 黄斑变性，鉴定HSS基因可能导致更大 对RP以及与黄斑营养不良相关的黄斑营养不良的理解 衰老。