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

基本信息

批准号：
7545429
负责人：
DAVID CY BEEBE
金额：
$ 54.23万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-05 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7545429
关键词：
Affect Age Age-Months Animal Model Animals Applications Grants Biochemistry Blindness Blood Circulation Cataract Cell Nucleus 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 Property 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 diabetic patient fiber cell glutathione peroxidase in vivo lens lens transparency non-diabetic normal aging oxidation oxidative damage prevent programs protein expression research study response retinal ischemia transcription factor

项目摘要

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（眼睛镜头的不良）是世界上失明的主要原因，付出了代价美国医疗保险计划每年将近50亿美元。核白内障（镜头中心的不良）为与年龄有关的白内障最常见的形式。但是，这种疾病的原因尚不清楚。先前的研究表明，人体暴露于增加的氧气是核的危险因素人类白内障。镜头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透镜基因和蛋白质表达。我们还发现凝胶的损失玻璃体的结构是核白内障的重要危险因素，并增加了氧气水平镜头周围。基于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与年龄相关的核白内障的主要原因，并且随着年龄的增长而发生的透镜核的逐渐渗透。我们将测试该假设的预测在两个具体目标中。首先，我们将确定氧调节晶状体基因的机制表达以及氧气水平是否直接导致核白内障的形成。老鼠镜头野生型或表达转录因子HIF1A的稳定形式将暴露于不同体内氧气水平，然后使用微阵列分析和QPCR来记录基因的变化表达。这将揭示氧气改变镜头基因表达的分子途径，从而在低氧环境中生存的镜头。我们还将确定是否降低氧气水平镜头周围可预防核白内障形成。这将通过基因维护来完成修饰的小鼠在较低的环境中从6个月大的核白内障开始氧气，将镜头周围的氧气水平降低-50％。如果分子氧有助于晶状体氧化损伤，这种治疗将延迟形成晶状体氧化损伤和不透明的。通过测量正在进行视网膜手术的患者眼中的氧气水平，我们发现氧气玻璃体切除术后晶状体周围升高，糖尿病性视网膜病患者降低。基于这些数据，我们将测试以下预测：在糖尿病患者（玻璃体中较低的氧气）中，玻璃体切除术的性白内障的进展比非缺血性视网膜病患者的进展更慢。我们也是观察到患有长期，单侧视网膜缺氧的患者的受影响较小（低氧）眼睛。我们将比较长期，单侧视网膜的患者的两只眼睛的核不透明度缺血。这项研究将测试我们的预测，即来自视网膜的氧气负责“正常”，年龄 - 晶状体核的相关无粘性。