The investigator seeks to define the mechanism for the progressive insolubilization of lens proteins which occurs with age/cataract. The fundamental hypothesis is that environmental insults result in covalent changes in lens proteins. These, in turn, affect protein conformation and short range interaction among proteins in the very concentrated environment of the lens. The result is loss of solubility. The first phase of the proposal will identify and define types of covalent changes which occur in Emory mouse and human cataracts. The second phase will look at recombinant and mutant alpha crystallin protein as an in vitro model for testing the central hypothesis that these modifications lead to insolubilization. The effects of mixed disulfides, photo-oxidation and advanced glycation will be studied. Physical biochemical approaches will be used to measure changes in conformation, protein-protein interaction, and the chaperon activity of the alpha crystallin. Site specific mutagenesis will be used to modify the alpha.
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