The overall objective of this proposal is to establish the chemical nature of the postsynthetic modifications occurring in aging human lens crystallins and to investigate their relationship to the cataractous process in senile lenses.
The specific aims of this competitive renewal are in essence unchanged from those we have proposed 2 1/2 years ago in that they are aimed at appreciating the possible role of the Maillard reaction in the crystallin changes antecedent to cataractogenesis. Progress has been achieved in all 4 specific aims. Four glucosederived Maillard compounds have been identified in model systems and one of them is presently under investigation in the lens. A novel fluorescent lysine-arginine crosslink that is mediated by pentoses was discovered in aging collagen and found in low amounts in the human lens. A specific fluorophore with non-tryptophan fluorescence called """"""""LM"""""""" was isolated from aging and cataractous crystallins. Finally, browning and crosslinking of crystallins that is preventable by aldose reductase inhibition was discovered in chronic experimental galactosemia. These studies will be completed as part of the 4 specific aims which are: 1) To establish the structure of the major fluorescent products of the advanced Maillard reaction that are formed under physiological conditions model systems. 2) To establish the presence and role of these model compounds in aging normal, diabetic and cataractous lenses. Interface with research on fluorophores and crosslinks from aging human collagen. 3) To isolate and elucidate the structure of the major chromophores/fluorophores of the aging, diabetic and cataractous human lens and evaluate their relationship to the Maillard reaction and other causes of browning and crosslinking reactions and 4) To further develop the rat model of senile cataract based on chronic galactosemia and investigate the nature of postsynthetic modification of crystallins in such lenses.
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