Molecular Basis of Syndromic Retinitis Pigmentosa

色素性视网膜炎的分子基础

• 批准号: 6727032
• 负责人: SUSAN J HAYFLICK
• 金额: $ 38.26万
• 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 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6727032
• 关键词: DNA damage; alcohol phosphotransferase; apoptosis; clinical research; coenzyme A; disease /disorder model; electroretinography; enzyme deficiency; gene mutation; genetically modified animals; human subject; immunocytochemistry; laboratory mouse; macular degeneration; magnetic resonance imaging; model design /development; molecular pathology; retinitis pigmentosa

DESCRIPTION (provided by applicant): The overall goal of this project is to delineate the molecular pathogenesis of a form of syndromic retinitis pigmentosa called pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome) and characterized by abnormal electroretinogram, lipofuscin accumulation in the retinal pigment epithelium, and early, rapidly progressive pigmentary retinopathy. This autosomal recessive disorder includes extrapyramidal dysfunction and iron accumulation in the basal ganglia. PKAN is caused by mutations in PANK2, one of four human genes to encode a key regulatory enzyme in coenzyme A (CoA) biosynthesis, called pantothenate kinase. Since PANK2 is uniquely associated with mitochondria, we hypothesize that defects lead to CoA deficiency, energy and lipid metabolic abnormalities, oxidative damage and apoptosis in susceptible tissues. We propose to investigate how PANK2 defects cause retinal and neuronal degeneration. Our specific aims are: 1) to create Pank2 defective mouse mutants representing a spectrum of disease severity and delineate their associated phenotypes; 2) to identify metabolic and molecular perturbations in pantothenate kinase 2 deficiency in vivo and in vitro; and 3) to determine whether mutations in PANK2 are associated with age-related macular degeneration or idiopathic pigmentary retinopathy. Knowledge about the genetic basis of PKAN has enabled delineation of a clinically recognizable disease, as well as the development of a molecular diagnostic test and new ideas for rational therapies. This discovery has linked a previously unsuspected metabolic pathway with retinopathy and neurodegeneration and has illuminated a possible role for defects in this pathway in related, more common disorders that share pathologic features with PKAN, including age-related macular degeneration, retinitis pigmentosa and Parkinson disease.

描述（由申请人提供）：该项目的总体目标是描述一种称为泛酸激酶相关神经变性（PKAN，以前称为Hallervorden-Spatz综合征）的综合征性视网膜色素变性的分子发病机制，其特征是视网膜电图异常，视网膜色素上皮内脂褐素积聚，以及早期，快速进展的色素视网膜病变。这种常染色体隐性遗传病包括锥体外系功能障碍和基底神经节铁积累。PKAN是由PANK2突变引起的，PANK2是编码辅酶a （CoA）生物合成关键调节酶的四个人类基因之一，称为泛酸激酶。由于PANK2与线粒体有独特的关联，我们推测其缺陷会导致CoA缺乏、能量和脂质代谢异常、易感组织的氧化损伤和凋亡。我们建议研究PANK2缺陷是如何引起视网膜和神经元变性的。