NUCLEAR CATARACT: ROLE OF UV FILTERS AND LENS BARRIER

描述(申请人提供)：老年性核性白内障是一种 世界失明的主要原因。我们的国家发生了一场革命 近1~2年ARN白内障的认识在那之前， 基本上，我们所知道的就是ARN白内障与 深度氧化，并伴随着不溶解、变色 以及晶状体蛋白质的交联性。目前还不清楚为什么会有如此大规模的氧化 这些晶状体的核发生了变化。 最近的进展表明，ARN白内障的发生是由于 晶状体随年龄增长而发生的变化。其中包括发现了 晶状体变色的可能原因以及可能的生化/物理基础 允许晶状体中心的氧化进行；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)从其在皮质合成或还原的部位进入晶状体 细胞核，在老年个体中形成。因此，老年正常人的细胞核 晶状体容易受到氧化应激的影响。 此外，人类晶状体紫外线过滤化合物本质上是不稳定的， 经过脱氨基反应生成反应酮。一旦屏障形成，这些 有时间分解，然后很容易与晶状体晶体反应。这 结合似乎是年龄相关的人类晶状体着色的基础 可能是ARN白内障。 这些发现表明，ARN白内障的大部分特征，如果不是全部的话 可以根据中年时晶状体BAMER的发病来解释，以及 核蛋白随后的氧化和与紫外线滤光片的反应。 这项拨款申请的目的是调查这项建议。如果 经证实，这将对未来的白内障治疗产生重大影响， 因为它提供了希望，药物干预可能会预防，或者 延迟，ARN白内障。具体目标是： 1.确定紫外线滤光片、犬尿氨酸、 3-羟基犬尿氨酸和3-羟基犬尿氨酸葡萄糖苷对晶状体蛋白的影响 老年正常，以及ARN白内障晶状体和 2.建立完整的人类晶状体的长期培养设施，并使用 这是为了调查：a)沐浴者对老式镜片的扩散，b)结合 紫外线滤光剂对完整晶状体中晶体蛋白的影响以及c)抑制 紫外线滤器生物合成途径作为预防核的药理策略 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.