The human lens continually absorbs ambient radiation between ca 295-400 nm. These absorptions can lead to permanent and deleterious modifications in lens constituents. It is therefore essential to determine how the lens responds to and protects itself from this photooxidative stress and whether or not that insult leads to the aging and cataractous changes detected in the human lens. By understanding the underlying mechanisms by which those changes come about, strategis and protocols can be developed to retard or negate those aging and cataractous processes. This study proposes to investigate the photochemistry of the main absorbing chromophores in the lens (i.e. tryptophan, 3-hydroxy kynurenine glucoside and the yellow pigments formed during aging) on all levels, from the cellular to the protein and finally the molecular. Molecular studies will include the determination of the efficiency of specific destructive photochemical processes and their resultant molecular changes. This will help to predict the importance of each specific photochemical processes on more complex levels such as the protein and cell level. The effect of other important parameters on these photoprocesses (such as oxygen tension and various anti-oxidants such as glutathione) will also be investigated in molecular detail. In conjunction with the above model experiments, studies will be performed on human lenses to verify the existence of such photochemical mechanisms in that tissue and determine the location where they may be important. These conclusions will result from studies on the absorptive characteristics of the successive layers of the human lens and the continued assessment of the actual molecular changes occurring in human lens constituents as aging and cataractous processes. In conclusion, the studies outlined in this proposal will 1) determine the relative importance of various chromophores in the lens as initiators of photochemical processes, 2) determine the specific mechanisms of those events, 3) determine the location in the human lens where those processes may be important, 4) prove that those and possibly other oxidative mechanisms are operant in the lens and 5) investigate methods by which those could be negated.
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