LENS INHIBITOR PROTEINS AND CATARACTOGENESIS

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Many investigators have suggested a role for sunlight (specifically UV-B light) in the formation of cataract. UV-B has been identified as a risk factor for cataract in epidemiology studies, and laboratory data on the irradiation of lenses or lens crystallins in vitro supports a photo- oxidative mechanism for protein damage. Many features of UV photodamage in vitro, however, are inconsistent with what is known about senile or brunescent cataract. These conflicting observations are addressed in this grant, and a new hypothesis for UV and oxidative damage is presented. This involves the idea that proteins are modified solely within the confines of the super-aggregates which make up the water-insoluble fraction in the lens nucleus. This permits oxidative chemistry to be carried out in a protected and nonpolar environment. Several different approaches will be taken to prove this hypothesis by carrying out the following specific aims: 1) Determine the structure and aggregate state of the water-insoluble fraction from bovine and human lenses. 2) Compare the UV-induced oxidation of native alpha-crystallin and alpha- crystallin in super-aggregates both with and without in vivo levels of protective agents. Studies are also proposed on proteolysis, and will continue the characterization of lens proteases and inhibitors. This will include: 1) Continued studies on the role of native and aggregated alpha-crystallins as inhibitors of proteolytic enzymes. 2) Characterization of a new lens elastase enzyme, and the initiation of a search for the enzyme(s) which catalyze the endogenous cleavage of alpha- crystallin.