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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Araj, Houmam H
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Washington University
Schools of Medicine
Saint Louis
United States
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Siegfried, Carla J; Shui, Ying-Bo; Bai, Fang et al. (2015) Central corneal thickness correlates with oxygen levels in the human anterior chamber angle. Am J Ophthalmol 159:457-62.e1
Beebe, David C; Shui, Ying-Bo; Siegfried, Carla J et al. (2014) Preserve the (intraocular) environment: the importance of maintaining normal oxygen gradients in the eye. Jpn J Ophthalmol 58:225-31
Li, Qi; Yan, Hong; Ding, Tian-Bing et al. (2013) Oxidative responses induced by pharmacologic vitreolysis and/or long-term hyperoxia treatment in rat lenses. Curr Eye Res 38:639-48
Siegfried, Carla J; Shui, Ying-Bo; Holekamp, Nancy M et al. (2011) Racial differences in ocular oxidative metabolism: implications for ocular disease. Arch Ophthalmol 129:849-54
Park, Young-Hoon; Shui, Ying-Bo; Beebe, David C (2011) Comparison of two probe designs for determining intraocular oxygen distribution. Br J Ophthalmol 95:118-22
Siegfried, Carla J; Shui, Ying-Bo; Holekamp, Nancy M et al. (2010) Oxygen distribution in the human eye: relevance to the etiology of open-angle glaucoma after vitrectomy. Invest Ophthalmol Vis Sci 51:5731-8
Holekamp, Nancy M; Bai, Fang; Shui, Ying-Bo et al. (2010) Ischemic diabetic retinopathy may protect against nuclear sclerotic cataract. Am J Ophthalmol 150:543-550.e1
Beebe, David C; Truscott, Roger J W (2010) Counterpoint: The lens fluid circulation model--a critical appraisal. Invest Ophthalmol Vis Sci 51:2306-10; discussion 2310-2
Beebe, David C; Holekamp, Nancy M; Shui, Ying-Bo (2010) Oxidative damage and the prevention of age-related cataracts. Ophthalmic Res 44:155-65
Garcia, Claudia M; Shui, Ying-Bo; Kamath, Meera et al. (2009) The function of VEGF-A in lens development: formation of the hyaloid capillary network and protection against transient nuclear cataracts. Exp Eye Res 88:270-6

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