AMINO-CARBONYL REACTIONS IN THE AGING HUMAN LENS

PI研究的目的是确定 氨基-羰基反应发生在还原糖和 蛋白质氨基（所谓的美拉德反应）在老化的 人类的倾斜 在体外，该反应导致蛋白质的形成 荧光团、发色团、交联剂和光敏剂。 相当大的进展，包括我们自己的实验室， 近年来取得的成就，现在将牵连和美拉德反应， 透镜晶体蛋白正常老化时的分子变化， 糖尿病发病率加快。 简言之，透镜晶体蛋白的孵育 与还原糖或抗坏血酸被认为是微妙的最，如果没有 在老化和白内障的人透镜中观察到的所有变化。 提出了三个具体目标。 具体目标我将阐明 戊二赖氨酸的形成机制，以及高级美拉德 我们实验室发现的反应产物， 对中度高血糖应激的反应能力 糖尿病在倾斜，与戊糖苷相反， 透镜中的产品仅对高血糖应激反应。 具体目标二是建立抗坏血酸代谢图谱 在透镜中使用一种新的，明确的方法， 氟标记抗坏血酸和无创磁共振成像 成像与NMR和GC/MS相结合。这些实验 将与氟化学专家合作进行 也是固体光谱学和核磁共振成像的专家 他们是 期望提供一个深入了解的问题， 氧化产物在体内被解毒，并帮助检验假设 抗坏血酸加工的损伤形成了 加速晶状体老化和白内障的发生。 最后，在具体目标III中，主要研究者将启动对 抗坏血酸的内源性和药理学机制 解毒 特别是，他将测试新的假设， 高反应性抗坏血酸催化剂可通过以下方法化学失活 H2 O2和谷胱甘肽，或被N-乙酰基的胍基捕获 精氨酸和氨基胍，它们都被发现具有 抗白内障特性。 这些试剂的反应产物将是 表征并用作抗白内障治疗中的标记物。

The objective of the PI's research is to define the contribution of amino-carbonyl reactions which occur between reducing sugars and protein amino groups (so-called Maillard reaction) in the aging of the human leans. In vitro, this reaction leads to the formation of protein fluorophores, chromophores, crosslinks and photosensitizers. Considerable progress, including from our own laboratory, As been achieved in recent years will now implicates and Maillard reaction in molecular changes in normal aging of lens crystallins, and at an accelerated rate in diabetes. In short, incubation of lens crystallins with reducing sugar or ascorbic acid was found to delicate most if not all the changes observed in the aging and cataractous human lens. Three specific aims are proposed. Specific aim I will be to elucidate the mechanism of formation of pentodilysine, and advanced Maillard reaction product discovered in our laboratory which has the unique ability to respond to moderate hyperglycemic stress induced by diabetes in the leans, in contrast to pentosidine, a glycoxidation product which in the lens responds only to high glycemic stress. Specific aim II will be to establish a metabolic map of ascorbate catabolites in the lens using a novel, unequivocal methodology based on fluorine labeled ascorbate and noninvasive magnetic resonance imaging in combination with NMR and GC/MS. These experiments will be carried out in collaboration with an expert in fluorine chemistry and an expert in solid state spectroscopy and MRI imaging. They are expected to provide an insight into the question of how ascorbate oxidation products are detoxified in vivo, and help test the hypothesis that impairment in ascorbate processing forms the basis for accelerated lenticular aging and cataractogenesis in some individuals. Finally, in specific aim III, the PI will initiate research into the endogenous and pharmacological mechanisms of ascorbate detoxification. In particular, he will test the novel hypothesis that the highly reactive ascorbate catabolites can be chemically deactivated by H202 and glutathione, or trapped by the guanidino groups of N-acetyl arginine and aminoguanidine both of which have been found to have anticataract properties. The reaction products of these agents will be characterized and utilized as markers in anticataract therapy.