APOLIPOPROTEIN ISOFORMS AND RETINAL DEGENERATION

载脂蛋白异构体和视网膜变性

• 批准号: 7014983
• 负责人: Steven J. Fliesler
• 金额: $ 18.38万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7014983
• 关键词: aging; alleles; apolipoproteins; genes; human; retina

DESCRIPTION (provided by applicant): The long-range goal of this study is to understand the biology of apolipoproteins in the retina, particularly the mechanism by which specific apoE isoforms may exert (or lack) neuroprotective effects. The immediate goal of this 2-year exploratory project is to develop and characterize the requisite genetically altered mouse strains to pursue the long-range goal. ApoE is a protein involved in cholesterol metabolism and transport. In the brain, the apoES isoform is thought to be neuroprotective and to play an important role in recovery following CNS injury. In contrast, the apoE4 isoform is a risk factor for dementias, such as Alzheimer's disease. Paradoxically, the exact opposite trend seems to prevail in age-related macular degeneration (AMD), where apoE4 correlates with reduced incidence of disease. The reason for this paradox remains a mystery, and will require appropriate new model systems to elucidate the molecular mechanisms involved. As a first step toward that goal, we will develop novel mouse strains and assess whether apoE can modulate the severity and time course of hereditary retinal degeneration in an isoform-specific manner. Mutant mice harboring the rds (retinal degeneration slow) mutation and lacking the apoE gene will be cross-bred with mice that selectively express either the human apoES or apoE4 isoform. Genotype will be confirmed by PCR. ApoE expression will be assessed as a function of age using Western blot analysis and immunocytochemistry, in comparison with age-matched rds and non-transgenic (wild-type) control mice. Retinal degeneration will be assessed by light and electron microscopy; retinal function will be assessed by electroretinography (ERG). The clinical relevance of this study lies in the potential to modulate the expression of neuroprotective isoforms of apoE in the retina as a novel therapy to retard or ameliorate human retinal degenerations of various origins. As such, this project has the potential to impact several aspects of the NEI's mission: to help prevent and treat eye diseases and other disorders of vision; reduce visual impairment and blindness; improve the quality of life for people of all ages; and advance our knowledge of how the visual system functions in health and disease.

描述（由申请人提供）：这项研究的远距离目标是了解视网膜中载脂蛋白的生物学，尤其是特定的APOE同工型可能发挥（或缺乏）神经保护作用的机制。这个为期两年的探索项目的直接目标是开发和表征所需的遗传改变的小鼠菌株以追求远距离目标。 APOE是一种参与胆固醇代谢和运输的蛋白质。在大脑中，顶座同工型被认为是神经保护作用，并且在CNS损伤后恢复中起重要作用。相反，APOE4同工型是痴呆症的危险因素，例如阿尔茨海默氏病。矛盾的是，与年龄相关的黄斑变性（AMD）似乎完全相反的趋势，其中APOE4与疾病发病率降低相关。这种悖论的原因仍然是一个谜，将需要适当的新模型系统来阐明所涉及的分子机制。作为朝着该目标的第一步，我们将开发新型的小鼠菌株，并评估APOE是否可以以同工型特异性方式调节遗传性视网膜变性的严重性和时间过程。带有RDS（视网膜变性慢）突变和缺乏APOE基因的突变小鼠将与小鼠杂交，这些小鼠有选择地表达人顶或ApoE4同工型。基因型将通过PCR确认。与年龄匹配的RD和非转基因（野生型）对照小鼠相比，使用Western印迹分析和免疫细胞化学的APOE表达将作为年龄的函数评估。视网膜变性将通过光和电子显微镜评估；视网膜功能将通过视网膜图（ERG）评估。这项研究的临床相关性在于可能调节视网膜中APOE的神经保护同工型的表达，作为一种延迟或改善各种起源的人类视网膜退化的新疗法。因此，该项目有可能影响NEI使命的几个方面：帮助预防和治疗眼病和其他视力疾病；减少视力障碍和失明；改善各个年龄段的人们的生活质量；并促进我们对视觉系统在健康和疾病中如何发挥作用的知识。