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(眼睛晶状体混浊)是世界上导致失明的主要原因，每年花费美国医疗保险计划近50亿美元。核性白内障(晶状体中心混浊)是最常见的老年性白内障。然而，这种疾病的病因还不是很清楚。以前的研究表明，人体暴露在氧气增加的环境中是人类患核性白内障的一个危险因素。晶状体通常存在于严重缺氧的环境中。我们发现，眼睛含氧量的变化会影响晶状体基因和蛋白质的表达。我们还发现，玻璃体凝胶结构的丧失是核性白内障的重要危险因素，并增加了晶状体周围的氧气水平。基于这些和本研究中所描述的其他观察结果，我们认为晶状体暴露于分子氧是老年性核性白内障的主要原因，并且随着年龄的增长，晶状体核逐渐浑浊。我们将在两个具体目标上检验这一假说的预测。首先，我们将确定氧调节晶状体基因表达的机制，以及氧水平是否直接导致核性白内障的形成。野生型或表达稳定形式转录因子HIF1α的小鼠晶状体将在体内暴露于不同水平的氧气中，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，使晶状体能够在低氧环境中生存。我们还将确定降低晶状体周围的氧气水平是否可以防止核性白内障的形成。这将通过保持转基因小鼠在6个月大的时候开始在较低水平的环境氧气中患上核性白内障来实现，这将使晶状体周围的氧气水平降低约50%。如果分子氧有助于晶状体氧化损伤，这种治疗将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的眼氧水平，我们发现玻璃体手术后晶状体周围的氧气水平上升，而糖尿病视网膜病变患者的氧气水平下降。基于这些数据，我们将检验这样一种预测，即在糖尿病患者(玻璃体中氧气含量较低)的患者中，玻璃体切除术后白内障的进展速度将比非缺血性视网膜病变患者的进展缓慢。我们还观察到，长期单侧视网膜低氧的患者其受影响(低氧)眼的核不混浊较少。我们将比较长期单侧视网膜缺血患者双眼的核混浊情况。这项研究将检验我们的预测，即来自视网膜的氧气是导致晶状体核“正常的”、与年龄相关的混浊的原因。