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: 7038514
• 负责人: DAVID CY BEEBE
• 金额: $ 55.22万
• 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/7038514
• 关键词: cataract; clinical research; eye; lens; metabolism; oxygen

DESCRIPTION: 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 HIF1alpha 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 approximately 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.

描述：白内障（眼睛镜头的不透明）是世界上失明的主要原因，每年付费美国医疗保险计划近50亿美元。核白内障（镜头中心的不透明）是与年龄相关性白内障的最常见形式。但是，这种疾病的原因尚不清楚。 先前的研究表明，人体暴露于氧气增加是人类核白内障的危险因素。镜头通常存在于严重缺氧的环境中。我们发现眼睛中的氧气水平的变化会影响透镜基因和蛋白质表达。我们还发现，玻璃体体的凝胶结构的损失是核白内障的重要危险因素，并增加了镜头周围的氧气水平。基于本提案中描述的这些和其他观察结果，我们建议将晶状体暴露于分子氧是与年龄相关的核白内障的主要原因，并且是随着年龄的增长而逐渐渗透的透镜核的逐渐渗透。我们将以两个具体目标来测试该假设的预测。首先，我们将确定氧调节透镜基因表达以及氧气水平是否直接促进核白内障的形成的机制。野生型或表达稳定形式的转录因子HIF1Alpha的小鼠透镜将暴露于体内不同水平的氧气，然后将使用微阵列分析和QPCR来记录基因表达的变化。这将揭示氧气改变晶状体基因表达的分子途径，从而使晶状体在低氧环境中生存。我们还将确定降低透镜周围的氧气水平是否可以防止核白内障形成。这将通过维持转基因的小鼠，该小鼠在较低的环境氧气中从6个月大时才开始发展核白内障，从而使镜头周围的氧气水平降低了约50％。如果分子氧有助于晶状体氧化损伤，则该治疗将延迟形成晶状体氧化损伤和不透明的。 通过测量正在接受视网膜手术的患者眼中的氧气水平，我们发现玻璃体切除术后晶状体周围的氧气升高，糖尿病性视网膜病患者的氧气升高。基于这些数据，我们将测试以下预测：在糖尿病患者（玻璃体中氧气较低）中，玻璃体切除术白内障的进展要比非缺血性视网膜病变患者的进展慢。我们还观察到，长期，单侧视网膜缺氧的患者的受影响（低氧）眼睛的核不动性较小。我们将比较长期，单侧视网膜缺血患者的两只眼睛的核不透明度。这项研究将测试我们的预测，即来自视网膜的氧气负责晶状体核的“正常”，与年龄相关的无情。