AMINO-CARBONYL REACTIONS IN THE AGING HUMAN LENS

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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.