BIOCHEMISTRY & RADIOPROTECTION FROM RADIATION CATARACT

生物化学

• 批准号: 3263873
• 负责人: JOHN C LIVESEY
• 金额: $ 17.55万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-01 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3263873
• 关键词: cataract; fiber cell; glutathione; high performance liquid chromatography; laboratory mouse; laboratory rat; lens proteins; linear energy transfer; oxygen tension; radiation carcinogenesis; radiation dosage; radiation sensitivity; radiobiology; radioprotective agents; thiols

Cataracts are the world's leading cause of blindness; a non-surgical preventative is badly needed in many regions of the world. Cataracts are an iatrogenic complication of therapeutic irradiation for the treatment of malignancies involving the eye or orbit. Experimental radiation-induced cataracts are a useful model system for studying both cataractogenesis and mechanisms of radioprotector action. Cataractogenesis involves a defined sequence of biochemical and histological changes in irradiated lenses, including alterations in the glutathione concentrations of the lens, lens proteins precipitation, and the formation of high molecular weight protein aggregates. Our previous work has shown that S-3-amino-2- hydroxypropylphosphorothioic acid (WR77913) is effective in preventing or inhibiting radiation cataractogenesis in rats. This proposal is directed at quantitatively determining whether certain factors in the lens environment are important in determining the susceptibility to radiation cataract. The biochemistry of the lens and its physiological environment determine the quantitative reaction to lens irradiation. Surprisingly few prior investigations have determine the interaction between oxygen and reducing species (glutathione, aminoalkylthiol drugs) in enhancing or inhibiting the process of cataractogenesis. The aims of this project include defining the roles of the aqueous humor oxygen tension and the lens thiol concentrations in determining the susceptibility to radiation damage in the lens. Using independent measurements of oxygen and thiols, correlative experiments will determine the quantitative importance of these factors in the susceptibility of rats to radiation cataracts. The degree to which changes in thiol or oxygen status in the lens influence lens transparency will indicate the relative importance of these factors in radiation cataractogenesis; the degree to which they alter the efficacy of cataract inhibitory drugs may indicate the mechanisms of action of these drugs in the lens. In addition to functional measures of radiation damage (assessment of transparency), we will also determine the influence of radiation and radioprotective drugs on lens proteins, both in terms of the distribution of soluble and insoluble forms and the separate proteins (crystallines) which make up the bulk of the lens fiber cell matrix. The generality of these findings will be tested by determining the relative importance of both oxygen and thiols in explaining a previously determined rat strain difference in the sensitivity to radiation cataract. Furthermore, since drug prevention of many types of cataract may involve similar mechanisms, the importance of the biochemical and physiological environment on the efficacy of cataract-inhibitory drugs is important in the rational design of more effective methods of preventing cataracts.

白内障是世界上最主要的致盲原因， 世界上许多地区都迫切需要预防措施。 白内障是 放射治疗的医源性并发症 涉及眼睛或眼眶的恶性肿瘤。 实验辐射诱导 白内障是研究白内障发生和 辐射防护剂的作用机制。 白内障发生涉及一种定义明确的 受照射晶状体的生物化学和组织学变化顺序， 包括改变透镜、透镜 蛋白质沉淀，并形成高分子量蛋白质 集料. 我们以前的工作表明，S-3-氨基-2- 羟丙基硫代磷酸（WR 77913）可有效预防或 抑制大鼠辐射性白内障的发生。 该提案针对 在定量确定透镜中的某些因素是否 环境在确定对辐射的敏感性方面很重要 白内障 透镜的生物化学和生理环境决定了 对透镜照射的定量反应。 令人惊讶的是， 研究已经确定了氧和还原性之间的相互作用 药物（谷胱甘肽，氨基烷基硫醇药物）在增强或抑制 白内障形成的过程。 该项目的目标包括： 房水氧分压和透镜巯基的作用 在确定对辐射损伤的敏感性的浓度 透镜。 使用氧和硫醇的独立测量， 实验将确定这些因素的定量重要性， 老鼠对辐射性白内障的易感性。 的程度 透镜中硫醇或氧状态的变化影响透镜的透明度 将表明这些因素在辐射中的相对重要性 白内障发生;它们改变白内障疗效的程度 抑制药物可能表明这些药物的作用机制， 透镜。 除了辐射损伤的功能性措施外， （透明度评估），我们还将确定 辐射和辐射防护药物对透镜蛋白的影响， 可溶性和不溶性形式的分布以及分离的蛋白质 （晶体），其构成透镜纤维细胞基质的主体。 的 这些发现的一般性将通过确定相对 氧和硫醇在解释先前确定的 大鼠对放射性白内障敏感性的品系差异。 此外，由于许多类型的白内障的药物预防可能涉及 类似的机制，生物化学和生理学的重要性， 环境对白内障抑制药物疗效的影响很重要， 合理设计更有效的预防白内障的方法。