Control by Oxygen of Lens Metabolism and Cataract Formation

白内障(眼睛晶状体混浊)是世界上致盲的主要原因， 美国联邦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，身体暴露在氧气增加的环境中是核辐射的危险因素 人类的白内障。晶状体通常存在于严重缺氧的环境中。我们发现，这些变化 眼睛中的氧气水平会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，并增加氧气水平。 在镜头周围。根据这些和本提案中描述的其他观察结果，我们建议 晶状体暴露于分子氧是老年性核性白内障的主要原因 晶状体核随年龄增长而逐渐浑浊。我们将检验这一假设的预测。 有两个具体的目标。首先，我们将确定氧调节晶状体基因的机制。 以及氧气水平是否直接导致核性白内障的形成。小鼠晶状体 野生型或表达稳定形式转录因子HIF1a将暴露于不同的 体内的氧气水平，然后微阵列分析和qPCR将被用来记录基因的变化 表情。这将揭示氧气改变晶状体基因表达的分子途径，从而 在低氧环境中生存的晶状体。我们还将确定是否降低氧气水平 在晶状体周围防止形成核性白内障。这将通过保持遗传上的 在较低水平的环境中，6个月龄开始发生核性白内障的改良小鼠 氧气，这会使晶状体周围的氧气水平降低-50%。如果分子氧对晶状体有贡献 氧化损伤，这种处理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睛的氧气水平，我们发现氧气 玻璃体切割术后晶状体周围升高，糖尿病视网膜病变患者下降。基于 这些数据，我们将测试预测，在糖尿病患者(玻璃体中氧气含量较低)，后- 玻璃体切割术白内障的进展将比非缺血性视网膜病变的患者慢。我们也 观察到长期单侧视网膜低氧的患者在其所受影响的患者中有较少的核混浊 (缺氧性)眼睛。我们将比较长期单侧视网膜病变患者双眼的核混浊。 缺血症。这项研究将检验我们的预测，即视网膜中的氧气是导致正常年龄的原因-- 晶状体核相关混浊。

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.