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.
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