CATARACTOGENESIS IN HYPERFERRITINEMIA CATARACT SYNDROME

高铁蛋白血症白内障综合征的白内障发生

• 批准号: 6178348
• 负责人: DAVID G BROOKS
• 金额: $ 18.2万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6178348
• 关键词: SDS polyacrylamide gel electrophoresis; autoradiography; blood proteins; cataract; clinical research; denaturing gradient gel electrophoresis; disease /disorder etiology; enzyme linked immunosorbent assay; ferritin; gel mobility shift assay; gene environment interaction; gene expression; genetic disorder; genetically modified animals; human subject; in situ hybridization; ion exchange chromatography; iron disorder; laboratory mouse; lens; organ culture; orphan disease /drug; proteolysis; syndrome; western blottings

Hyperferritinemia cataract syndrome (HCS) is a recently discovered genetic disease defined by elevated serum ferritin and cataracts. Dysregulation of L ferritin gene expression is the basis of this human disorder. Specifically, mutations in a discrete regulatory region of the L ferritin gene, the iron' response element, lead to over production of wild type L ferritin protein. Although ferritin is found at high levels in all tissues and extracellular fluids examined to date, cataracts are the only proven pathologic consequence of this constitutive over expression of ferritin. The mechanism of cataract formation in hyperferritinemia cataract syndrome (HCS) is unknown. Understanding the pathobiology of cataractogenesis in HCS is essential to design a rational approach to cataract prevention and treatment. The objective 9f this proposal is to determine the mechanism of HCS cataractogenesis with a long term goal of developing effective preventive and/or therapeutic strategies for these cataracts. The mechanism of cataract formation in HCS will likely have broader implications for cataract formation in general. The specific aims of this proposal all involve investigation of ferritin in eye. First, the normal expression of ferritin in lens and lens cell lines will be determined. Second, over expression of L ferritin in human cell lines and in mouse will be generated as models of HCS. Third, quantitative expression and distribution of L ferritin in HCS lens material will be determined. An animal model that reproduces cataract promises opportunity to 1investigate cataract formation as a function of the interaction of HCS genotype with environmental factors including iron, antioxidants and UV light. This proposal describes a 4 year training program in which the applicant will acquire the requisite experience to become an independent clinician scientist. The sponsor and collaborator's extensive experience in clinical ophthalmology, eye histopathology, genetic cataract and mouse genetics will complement the applicant's prior training in molecular biology, internal medicine and clinical genetics. A strong ophthalmology research program will provide the requisite environment in which to transition the applicant to being an independent physician/researcher in genetics and eye disease.

高铁蛋白血症白内障综合征（HCS）是最近发现的一种遗传性疾病，其定义为血清铁蛋白升高和白内障。 L 铁蛋白基因表达失调是这种人类疾病的基础。具体而言，L 铁蛋白基因的离散调节区域（铁反应元件）的突变会导致野生型 L 铁蛋白的过量产生。尽管迄今为止检查的所有组织和细胞外液中都发现铁蛋白含量很高，但白内障是铁蛋白这种组成性过度表达的唯一已证实的病理后果。高铁蛋白血症白内障综合征（HCS）中白内障形成的机制尚不清楚。了解 HCS 中白内障发生的病理学对于设计合理的白内障预防和治疗方法至关重要。该提案的目标 9f 是确定 HCS 白内障发生的机制，长期目标是为这些白内障制定有效的预防和/或治疗策略。 HCS 中白内障形成的机制可能对一般白内障形成具有更广泛的影响。该提案的具体目标均涉及眼部铁蛋白的研究。首先，确定晶状体和晶状体细胞系中铁蛋白的正常表达。其次，将生成人类细胞系和小鼠中 L 铁蛋白的过度表达作为 HCS 模型。第三，将确定HCS晶状体材料中L铁蛋白的定量表达和分布。重现白内障的动物模型有望为研究白内障形成作为 HCS 基因型与环境因素（包括铁、抗氧化剂和紫外线）相互作用的函数提供了机会。该提案描述了一个为期 4 年的培训计划，申请人将在其中获得成为独立临床科学家所需的经验。申办者和合作者在临床眼科、眼组织病理学、遗传性白内障和小鼠遗传学方面的丰富经验将补充申请人之前在分子生物学、内科和临床遗传学方面的培训。强大的眼科研究计划将为申请人转变为遗传学和眼病领域的独立医生/研究员提供必要的环境。