We recently discovered that the drug U18666A, an inhibitor of cholesterol synthesis, when given at a low dose to neonatal rats can lead to development of cataracts of the lens of the eye. This new model may offer some advantages over existing models, since the drug is well tolerated by the rat, the cataracts are rapidly induced, they appear primarily to involve the nucleus of the lens and to some extent the cataracts appear reversible. Preliminary work in our laboratory indicates that both lens lipids and proteins are altered by U18666A and, in particular, the observed changes in proteins are similar to those reported to occur in human cataracts of senile origin. Specifically, in U18666A induced cataractous lens the relative content of soluble proteins decrased in insoluble proteins increase. The overall objectives of the proposed research are to clearly describe this new model of cataracts and to determine the basic mechanism of cataractogenesis. More specifically, in the proposed studies we will examine the morphology of the eye during cataract development and reversal, measure and correlate changes in lens lipids and proteins, and measure synthesis de novo of sterols and proteins in normal and cataractous lenses. Standard histological technics using a variety of stains will be used for the studies of morphology. Lipids extracted from the lens will be separated by thin-layer chromatography and subsequently quantiated by gas-chromatography and colorimetric assays. Proteins will be fractionated and identified by Sephadex G-200 and DEAE cellulose chromatography and SDS and alkaline urea polyacrylamide-gel-electrophoresis. By correlating the sequence of changes in lens lipids versus proteins during cataract development and reversal we should be able to critically evaluate the relative importance of effects upon lipids versus proteins in explaining the etiology of the cataracts induced by U18666A. The proposed project promises to develop a new model for the study of cataracts and will provide new information on the biochemistry of cataracts which could contribute to a greater understanding of human lens disorders.
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