Cataracts are the world's leading cause of blindness; a non-surgical preventative is badly needed in many regions of the world. Cataracts are an iatrogenic complication of therapeutic irradiation for the treatment of malignancies involving the eye or orbit. Experimental radiation-induced cataracts are a useful model system for studying both cataractogenesis and mechanisms of radioprotector action. Cataractogenesis involves a defined sequence of biochemical and histological changes in irradiated lenses, including alterations in the glutathione concentrations of the lens, lens proteins precipitation, and the formation of high molecular weight protein aggregates. Our previous work has shown that S-3-amino-2- hydroxypropylphosphorothioic acid (WR77913) is effective in preventing or inhibiting radiation cataractogenesis in rats. This proposal is directed at quantitatively determining whether certain factors in the lens environment are important in determining the susceptibility to radiation cataract. The biochemistry of the lens and its physiological environment determine the quantitative reaction to lens irradiation. Surprisingly few prior investigations have determine the interaction between oxygen and reducing species (glutathione, aminoalkylthiol drugs) in enhancing or inhibiting the process of cataractogenesis.
The aims of this project include defining the roles of the aqueous humor oxygen tension and the lens thiol concentrations in determining the susceptibility to radiation damage in the lens. Using independent measurements of oxygen and thiols, correlative experiments will determine the quantitative importance of these factors in the susceptibility of rats to radiation cataracts. The degree to which changes in thiol or oxygen status in the lens influence lens transparency will indicate the relative importance of these factors in radiation cataractogenesis; the degree to which they alter the efficacy of cataract inhibitory drugs may indicate the mechanisms of action of these drugs in the lens. In addition to functional measures of radiation damage (assessment of transparency), we will also determine the influence of radiation and radioprotective drugs on lens proteins, both in terms of the distribution of soluble and insoluble forms and the separate proteins (crystallines) which make up the bulk of the lens fiber cell matrix. The generality of these findings will be tested by determining the relative importance of both oxygen and thiols in explaining a previously determined rat strain difference in the sensitivity to radiation cataract. Furthermore, since drug prevention of many types of cataract may involve similar mechanisms, the importance of the biochemical and physiological environment on the efficacy of cataract-inhibitory drugs is important in the rational design of more effective methods of preventing cataracts.
