Control by Oxygen of Lens Metabolism and Cataract Formation

白内障（眼睛的透镜混浊）是世界上失明的主要原因， 美国医疗保险计划每年近50亿美元。核性白内障（透镜中心混浊）是 最常见的老年性白内障然而，这种疾病的原因并不清楚。 先前的研究表明，身体暴露于增加的氧气是核辐射的危险因素。 人类的白内障透镜通常存在于严重缺氧的环境中。我们发现， 眼睛中的氧水平影响透镜基因和蛋白质的表达。我们还发现凝胶的损失 玻璃体的结构是核性白内障的重要危险因素， 在透镜周围。根据本提案中所述的这些和其他意见，我们建议， 透镜暴露于分子氧是年龄相关的核性白内障的主要原因， 随着年龄的增长，透镜核逐渐混浊。我们将检验这一假设的预测 两个具体目标。首先，我们将确定氧调节透镜基因的机制 表达和氧水平是否直接有助于核性白内障的形成。小鼠晶状体 野生型或表达稳定形式转录因子HIF 1a将暴露于不同的 体内氧水平，然后微阵列分析和qPCR将用于记录基因表达的变化。 表情这将揭示氧气改变透镜基因表达的分子途径， 使透镜在缺氧环境中存活。我们还将确定降低氧气水平 在透镜周围保护防止核性白内障形成。这将通过维持基因 在较低水平的环境中从6个月大开始发生核性白内障的改良小鼠 氧气，其使透镜周围的氧气水平降低约50%。如果分子氧有助于透镜 氧化损伤，这种治疗将延迟透镜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中的氧气水平，我们发现， 透镜周围的玻璃体在玻璃体切除术后升高，而在糖尿病视网膜病变患者中降低。基于 这些数据，我们将测试预测，在糖尿病患者（玻璃体中氧含量较低）， 玻璃体切除术白内障将比非缺血性视网膜病患者进展得更慢。我们也 观察到长期单侧视网膜缺氧的患者，其受影响的核混浊较少， （缺氧）眼。我们将比较长期单侧视网膜病变患者双眼的核混浊， 缺血这项研究将测试我们的预测，即来自视网膜的氧气是负责“正常”的年龄- 相关的透镜核混浊。

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.