MECHANISMS OF RETINAL PHOTOTOXICITY

视网膜光毒性的机制

• 批准号: 3261583
• 负责人: ROBERT J STEPHENS
• 金额: $ 21.27万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 1988-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3261583
• 关键词: choroid uvea; cytotoxicity; electron microscopy; electroretinography; gas chromatography mass spectrometry; human tissue; light adverse effect; microscopy; oxidation; peroxidation; photoprotection; retina; retina degeneration; retinal pigment epithelium; retinoids; tocopherols; unsaturated fatty acids; visual photoreceptor; visual photosensitivity; vitamin therapy

The long-term objective of the proposed research is to identify--and eventually control--the cytotoxic molecule(s) that are formed upon irradiation of the retina with visible light and that cause photosensitive cells to degenerate. The theoretical mechanism of retinal phototoxicity is based on the concept of lipid peroxidation and the formation of intermediates that are toxic to the photosensitive cells and, under certain conditions, to the retinal pigment epithelium (RPE), causing them to degenerate. The specific aims of the proposed research are to (1) determine if light damage to the retina occurs by a mechanism of photosensitized lipid oxidation; (2) use biochemical markers of retinal damage (i.e., lipid oxidation intermediates) to assess primary sites of damage (e.g., photoreceptors vs RPE); (3) determine if nutritional vitamin E or vitamin A are able to modulate the sensitivity of the retina to photic injury; (4) determine if the biochemical markers of lipid oxidation correlate with regional patterns of retinal degeneration; (5) correlate individual animal variation in sensitivity to light damage with levels of biochemical markers; and (6) demonstrate the cytotoxicity of specific lipid oxidation intermediates. To accomplish the above aims, albino and pigmented rats will be maintained on formulated diets containing specific levels of vitamins E and A prior to exposure. Freeze-dried sections of retina will be microdissected into three specific layers: neural retina, photoreceptor cells, and RPE-choroid. Samples of each layer will be analyzed for vitamin E, unsaturated fatty acids, and products of peroxidation by gas chromatography-mass spectrometry (GC-MS). Structural analysis will include light and electron microscopy, and electroretinograms will be used to assess retinal function. As human retinal tissue becomes available from fresh autopsies or surgery, it will be used to develop procedures to handle small retinal biopsies and acquire a data base on the above parameters for possible future studies. It may be that virtually everyone is subjected to subclinical light damage to their retinas. Daily accumulated light damage appears to be aggravated by nutritional deficiencies and extended exposure to light (i.e., electric illumination). This work seeks to understand the basic mechanisms of retinal light damage in order to better evaluate its importance and to open routes to control it, and to preserve retinal health.

拟议研究的长期目标是确定——并且 最终控制——形成的细胞毒性分子 可见光照射视网膜并引起光敏 细胞退化。 视网膜光毒性的理论机制是 基于脂质过氧化的概念和形成 对光敏细胞有毒的中间体，并且在一定条件下 条件，到视网膜色素上皮（RPE），导致它们 退化。 拟议研究的具体目标是（1）确定光是否 视网膜损伤是通过光敏脂质机制发生的 氧化； (2) 使用视网膜损伤的生化标志物（即脂质 氧化中间体）来评估主要损伤部位（例如， 光感受器与 RPE）； (3)确定是营养维生素E还是维生素A 能够调节视网膜对光损伤的敏感性； (4) 确定脂质氧化的生化标志物是否与 视网膜变性的区域模式； (5) 关联个体动物 对光损伤的敏感性随生化水平的变化而变化 标记； (6) 证明特定脂质氧化的细胞毒性 中间体。 为了实现上述目标，将维持白化和色素大鼠 之前服用含有特定水平维生素 E 和 A 的配方饮食 接触。 视网膜的冻干切片将被显微解剖成 三个特定层：神经视网膜、感光细胞和 RPE-脉络膜。 每层样品将进行维生素 E 分析， 不饱和脂肪酸和气体过氧化产物 色谱-质谱（GC-MS）。 结构分析将包括 光学和电子显微镜以及视网膜电图将用于 评估视网膜功能。 随着人类视网膜组织可通过新鲜尸检或手术获得， 它将用于开发处理小型视网膜活检的程序和 获取上述参数的数据库，以供将来可能的研究使用。 几乎每个人都可能遭受亚临床光损伤 到他们的视网膜。 每日累积的光损伤似乎加剧 由于营养缺乏和长时间暴露在光下（即电 照明）。 这项工作旨在了解基本机制 视网膜光损伤，以便更好地评估其重要性并打开 控制它并保持视网膜健康的途径。