Several significant findings from this laboratory during the current funding period indicate that regulation of iron (Fe) availability is a crucial component of ocular homeostasis, and that availability of Fe may play a pivotal role in ocular pathology. In the current proposal, we plan to investigate these observations in greater detail and to elucidate the mechanisms involved in Fe storage in the lens in normal and pathological conditions. The hypothesis to be addressed is that lenticular uptake and storage of Fe is essential for ocular homeostasis under normal conditions. This ability is compromised in inflammation or cataractogenesis, resulting in increased lenticular Fe concentration. Deleterious changes in lenticular function then occur due to Fe-catalyzed oxidative reactions. Because of the demonstrated importance of Fe to ocular pathophysiology and because virtually nothing is presently known about ocular Fe homeostasis, experiments in this proposal are designed to fill this gap. These studies will begin with experiments using lens epithelial cell cultures and then will be extended to whole lens cultures and finally to the in vivo situation. Mechanisms for Fe transport and storage in the lens will be defined using both whole rabbit lenses and epithelial cell cultures from normal rabbit and canine lenses, and canine cataractous lenses. The limits of lenticular capacity for transport and storage of Fe will be determined. The effects of exceeding capacity on lens function and the mechanisms underlying these alterations will then be determined. Since the lens is likely to be an important regulator of ocular Fe homeostasis in vivo, the effects of aphakia on ocular Fe homeostasis in normal and inflamed eyes will be determined. The results of these experiments will provide essential information about lenticular Fe homeostasis and about the contributions of the lens to ocular Fe homeostasis. Detailed information about the functions of Fe in ocular pathology is likely to provide important insights for rational design of new and more effective therapeutic regimes.
