NUCLEAR CATARACT: ROLE OF UV FILTERS AND LENS BARRIER

描述（由申请人提供）：视网膜相关核性（ARN）白内障是一种 世界失明的主要原因。我们的社会发生了革命 在过去的1 - 2年里对ARN白内障的认识。在那之前， 基本上所有已知的是ARN白内障与 深刻的氧化，这是伴随着不溶解，着色， 和透镜蛋白的交联。目前还不清楚为什么如此大规模的氧化 这些晶状体的核发生了变化。 最近的进展表明，ARN白内障的发展是以下因素的直接结果： 透镜随年龄的变化。其中包括发现 透镜着色的可能原因以及可能 允许透镜中心的氧化进行;最终导致 白内障简单地说，抗氧化剂谷胱甘肽的运动障碍 (GSH)从其在皮质中的合成或还原部位进入透镜 核，在老年人中形成。因此老年正常人的细胞核 透镜变得对氧化应激敏感。 此外，人透镜UV滤光剂化合物本质上是不稳定的， 进行脱氨基作用以形成反应性酮。一旦屏障形成， 有时间分解，然后容易与透镜晶体蛋白反应。这 结合似乎是年龄依赖性人类透镜着色的基础， 可能是ARN白内障。 这些发现表明，ARN白内障的大多数（如果不是全部）特征 可以根据中年时透镜损坏的发生来解释， 随后的氧化和核蛋白与UV过滤剂的反应。 本补助金申请的目的是调查这一建议。如果 证实，这将对未来的白内障治疗产生重大影响， 因为它提供了药物干预可能预防的希望， 延迟，ARN白内障。具体目标是： 1.确定UV过滤剂、犬尿氨酸 3-羟基犬尿氨酸和3-羟基犬尿氨酸葡糖苷与透镜晶体蛋白 老年人正常，以及ARN白内障晶状体， 2.建立一个长期培养完整人类晶状体的设施， 这是为了研究：a）在旧晶状体中扩散的bather，B） UV过滤剂对完整晶状体中晶状体蛋白的抑制作用以及c） 紫外线过滤生物合成途径作为一种药理学策略，以防止核 白内障

DESCRIPTION (provided by applicant): Age-related nuclear (ARN) cataract is a major cause of world blindness. There has been a revolution in our understanding of ARN cataract in the past 1-2 years. Up until that time, essentially all that was known was that ARN cataract is associated with profound oxidation and that this is accompanied by insolubilisation, coloration and cross-linking of lens proteins. It was unclear why such massive oxidative changes occurred in the nuclei of these lenses. Recent advances suggest that ARN cataract develops as a direct result of changes in the lens that occur with age. These include the discovery of the probable reason for lens coloration and the biochemical/physical basis that may allow oxidation in the centre of the lens to proceed; resulting ultimately in cataract. Briefly, a barrier to the movement of the antioxidant, glutathione (GSH) from its site of synthesis or reduction in the cortex, into the lens nucleus, forms in older individuals. Thus the nucleus of the older normal human lens becomes susceptible to oxidative stress. In addition, human lens UV filter compounds are intrinsically unstable and undergo deamination to form reactive ketones. Once the barrier forms, these have time to breakdown and then readily react with lens crystallins. This binding appears to be the basis for age-dependent human lens coloration and possibly ARN cataract. These findings suggest that most, if not all, of the features of ARN cataract may be explained on the basis of the onset of the lens bamer in middle age, and the subsequent oxidation and reaction of the nuclear proteins with UV filters. It is the aim of this grant application to investigate this proposal. If confirmed, this would have major implications for future cataract treatment, since it offers hope that drug intervention may be possible to prevent, or delay, ARN cataract. The specific aims are to: 1. identify the sites of attachment of the UV filters, kynurenine, 3-hydroxykynurenine and 3-hydroxykynurenine glucoside to lens crystallins from older normal, as well as ARN cataract lenses and 2. establish a long-term culture facility for intact human lenses and to employ this to investigate: a) the bather to diffusion in older lenses, b) the binding of UV filters to crystallins in intact lenses as well as c) inhibition of the UV filter biosynthetic pathway as a pharmacological strategy to prevent nuclear cataract.