Control by Oxygen of Lens Metabolism and Cataract Formation

氧对晶状体代谢和白内障形成的控制

• 批准号: 7341674
• 负责人: DAVID CY BEEBE
• 金额: $ 52.1万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-05 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7341674
• 关键词: Affect; Age; Age-Months; Animal Model; Animals; Applications Grants; Biochemistry; Blindness; Blood Circulation; Cataract; Cell Nucleus; Condition; Crystalline Lens; Data; Diabetes Mellitus; Diabetic Retinopathy; Disease; Environment; Enzymes; Epithelial; Exposure to; Eye; Gel; Gene Expression; Gene Proteins; Genes; Genetic Models; Growth; Human; Hyperoxia; Hypoxia; Intervention; Knockout Mice; Lead; Lens Opacities; Measurement; Measures; Mediator of activation protein; Medicare; Metabolic; Metabolism; Microarray Analysis; Molecular; Mus; Nuclear; Operative Surgical Procedures; Oxygen; Pathway interactions; Patients; Polymerase Chain Reaction; Property; Rate; Research Personnel; Retina; Retinal; Retinal Diseases; Risk; Risk Factors; Shapes; Testing; Transcript; Vitrectomy; Vitreous Chamber; Vitreous body structure; Vitreous humor; age related; base; cost; diabetic; eye chamber; fiber cell; glutathione peroxidase; in vivo; lens; lens transparency; non-diabetic; normal aging; oxidation; prevent; programs; protein expression; research study; response; retinal ischemia; transcription factor

Cataract (opacification of the lens of the eye) is the primary cause of blindness in the world and costs the US Medicare program nearly $5 billion annually. Nuclear cataract (opacification of the center of the lens) is the most common form of age-related cataract. However, the causes of this disease are not well understood. Previous studies showed that exposure of the body to increased oxygen is a risk factor for nuclear cataracts in humans. The lens normally exists in a severely hypoxic environment. We found that changes in oxygen levels in the eye influence lens gene and protein expression. We also found that loss of the gel structure of the vitreous body is an important risk factor for nuclear cataracts and increases oxygen levels around the lens. Based on these and other observations described in this proposal, we propose that exposure of the lens to molecular oxygen is the primary cause of age-related nuclear cataracts and the gradual opacification of the lens nucleus that occurs with age. We will test the predictions of this hypothesis in two specific aims. In the first, we will identify the mechanisms by which oxygen regulates lens gene expression and whether oxygen levels directly contribute to the formation of nuclear cataracts. Mouse lenses that are wild type or that express stable forms of the transcription factor HIF1a will be exposed to different levels of oxygen in vivo and then microarray analysis and qPCR will be used to document changes in gene expression. This will reveal the molecular pathways by which oxygen alters lens gene expression, allowing the lens to survive in a hypoxic environment. We will also determine whether reducing the oxygen levels around the lens protects against nuclear cataract formation. This will be done by maintaining genetically modified mice that develop nuclear cataracts beginning at 6 months of age in lower levels of ambient oxygen, which lowers the oxygen levels around the lens by -50%. If molecular oxygen contributes to lens oxidative damage, this treatment will delay the formation of lens oxidative damage and opacification. By measuring oxygen levels in the eyes of patients undergoing retinal surgery we found that oxygen around the lens is elevated after vitrectomy and decreased in patients with diabetic retinopathy. Based on these data, we will test the prediction that, in patients with diabetes (lower oxygen in the vitreous body), post- vitrectomy cataracts will progress more slowly than in patients with non-ischemic retinopathy. We also observed that patients with long-standing, unilateral retinal hypoxia have less nuclear opacity in their affected (hypoxic) eye. We will compare nuclear opacity in both eyes of patients with long-standing, unilateral retinal ischemia. This study will test our prediction that oxygen from the retina is responsible for the "normal," age- related opacification of the lens nucleus.

白内障（眼睛晶状体混浊）是世界上导致失明的主要原因，造成了 美国医疗保险计划每年近 50 亿美元。核性白内障（晶状体中心混浊）是 最常见的与年龄有关的白内障。然而，这种疾病的原因尚不清楚。 先前的研究表明，身体暴露在氧气增加的环境中是核病的危险因素。 人类白内障。晶状体通常存在于严重缺氧的环境中。我们发现变化 眼睛中的氧气水平影响晶状体基因和蛋白质的表达。我们还发现凝胶的损失 玻璃体结构是核性白内障的重要危险因素，并会增加氧含量 镜头周围。根据本提案中描述的这些和其他观察结果，我们建议 晶状体暴露于分子氧是导致与年龄相关的核性白内障的主要原因 随着年龄的增长，晶状体核逐渐混浊。我们将检验这个假设的预测 有两个具体目标。首先，我们将确定氧气调节晶状体基因的机制 表达以及氧水平是否直接导致核性白内障的形成。鼠标镜片 野生型或表达稳定形式的转录因子 HIF1a 的细胞将暴露于不同的环境中。 体内氧水平，然后使用微阵列分析和 qPCR 记录基因变化 表达。这将揭示氧气改变晶状体基因表达的分子途径，从而允许 晶状体能在缺氧环境中生存。我们还将确定是否降低氧气含量 晶状体周围可防止核性白内障的形成。这将通过维持基因来完成 改良小鼠在较低环境浓度下从 6 个月大开始出现核性白内障 氧气，可使镜片周围的氧气含量降低 -50%。如果分子氧对晶状体有贡献 氧化损伤，这种治疗会延缓晶状体氧化损伤和混浊的形成。 通过测量接受视网膜手术的患者眼内的氧气水平，我们发现氧气 玻璃体切除术后晶状体周围升高，而糖尿病视网膜病变患者则降低。基于 根据这些数据，我们将测试以下预测：在糖尿病患者（玻璃体内含氧量较低）中，术后 玻璃体切除术白内障的进展速度比非缺血性视网膜病变患者慢。我们也 观察到长期单侧视网膜缺氧的患者受影响的视网膜核混浊较少 （缺氧）眼睛。我们将比较患有长期单侧视网膜病变的患者双眼的核混浊情况 缺血。这项研究将检验我们的预测，即视网膜中的氧气是造成“正常”年龄的原因。 相关的晶状体核混浊。