The human lens is continually under photooxidative and oxidative stress. Although light and active oxygen species have been implicated in long term changes in the human lens that lead to aging and cataractogenesis, almost nothing is known about the actual mechanism(s) by which those reactions occur. In addition the mechanism(s) by which endogenous glutathione decreases photooxidative and oxidative reactions have yet to be completely defined. The experiments outlined here will provide basic information concerning those reactions. This is an especially timely question since decreases in the ozone layer would increase photochemical stress on the lens and possibly increase the incidence of cataractogenesis. The effect of light on human lens will be thoroughly investigated by first, developing an action spectrum for the constituents of the human lens. This spectrum presents the relative photochemical damage as a function of wavelength impinging on the sample. These studies will not only given the absorbing species that initiate photochemical reactions in the lens but will also determine if there is a change in that sensitivity with age. From these studies we will ascertain the wavelengths of light that must be filtered out in order to minimize damage to the human lens. The other goals of this proposal are to define the role of light and other oxidative processes in the specific molecular changes that occur in the human lens with age as well as to determine the mechanism by which they were formed. This involves the detailed investigation of the photochemistry of the main absorbing species in the human lens, the O- beta glucoside of 3-hydroxy kynurenine and the comparison of those photooxidations with the actual molecular changes that occur in the human lens with aging. The last goal is to develop methods by which those photooxidative and oxidative changes can be retarded by supplementing the lens with glutathione mimics. These studies will be performed on the molecular (amino acid) and macromolecular (protein) levels. This type of multidimensional approach has the best chance of elucidating the role of various photooxidative and oxidative processes in aging and cataractogenesis in the human lens and the development of methods to retard them.
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