AMINO-CARBONYL REACTIONS IN THE AGING HUMAN LENS

尽管人们付出了巨大的努力， 在老化的透镜中积累的黄色和荧光化合物 晶体蛋白大部分仍未阐明。 我们假设 这些结构至少部分是由于 非酶糖基化的蛋白质在美拉德反应。 然而，由于缺乏合适的模型化合物和缺乏 一个实验动物模型，试图证明 美拉德反应在这些年龄相关的变化一直到目前为止 基于间接证据 为了填补这一空白，我们提出了一种新的方法，基于（1） 发展对化学的透彻理解， 生理条件下的美拉德反应和（2）发育 糖介导的加速衰老的动物模型， 美拉德反应对透镜的病理后果。 生理条件下美拉德反应的化学 将使用一个简单的模型系统来研究条件，该模型系统包括 葡萄糖和新戊胺。 将进行结构解析 NMR、GC-质谱、FAB-质谱、IR、UV和荧光 谱 有了这个模型系统， 成功地表征了一些吡咯衍生物， 葡萄糖 新的细菌的存在和原位定位 确定的美拉德发色团和交联将是 在化学和免疫学上建立在衰老，正常， 糖尿病和白内障的人类晶状体。 美拉德反应对透镜稳定性的影响 晶体蛋白将在一种新的实验动物模型中进行研究， 基于慢性半乳糖血症的加速衰老大鼠喂食 一种醛糖还原酶抑制剂。 如果这些老鼠的晶状体显示 的确增加了白内障形成的易感性，我们将尝试 为了防止透镜中的美拉德反应， 药理学操作 我们预计，在这个五年期结束时，我们将拥有 带来了确凿的证据， 在透镜中的美拉德反应的产物，并澄清了 这一反应是否起主要或次要作用的问题， 年龄相关的晶状体蛋白变化的发病机制。

In spite of intense efforts research the structure and role of the yellow and fluorescent compounds which accumulate in aging lens crystallins remain largely unelucidated. We hypothesized that these structures are at least in part due to browning of nonenzymatically glycosylated proteins during Maillard reaction. However, due to lack of appropriate model compounds and lack of an experimental animal model, attempts to incriminate the Maillard reaction in these age-related changes have been so far based on circumstantial evidence. To fill this gap we propose a novel approach based on (1) developing a thorough understanding of the chemistry of the Maillard reaction under physiological conditions and (2) developing an animal model of sugar-mediated accelerated aging to study pathological consequences of the Maillard reaction on the lens. The chemistry of the Maillard reaction under physiological conditions will be studied using a simple model system comprising glucose and neopentylamine. Structure elucidation will be made with NMR, GC-Mass, FAB-Mass, IR, UV and fluorescence spectroscopy. With this model system we have already successfully characterized a number of pyrrole derivatives from glucose. The presence and in situ localization of the newly identified Maillard chromophores and crosslinks will be established chemically and immunologically in aging, normal, diabetic and cataractous human lenses. The effects of the Maillard reaction on the stability of lens crystallins will be studied in a novel experimental animal model of accelerated aging based on chronic galactosemia in rats fed with an inhibitor of aldose reductase. If lenses of such rats show indeed increased susceptibility to cataract formation, we will try to prevent the Maillard reaction in the lens through pharmacologic manipulation. We expect that, at the end of this five-year period, we will have brought conclusive evidence for the occurrence of the late products of the Maillard reaction in the lens and clarified the question of whether this reaction plays a major or minor role in the pathogenesis of the age-related changes in crystallins.