Oxidative damage is associated with cataractogenesis. The lens epithelium is one of the primary targets of different types of stresses to the lens. Lens epithelial cells have protective and repair systems to cope with oxidative stress. In many types of cells, the ubiquitin dependent pathway (UDP) is one of the repair mechanisms because it is involved in selective degradation of damaged proteins and in DNA repair. The principal investigator has demonstrated that 1) lens epithelial cells have an active UDP; 2) about 50 percent of the intracellular proteolysis in the lens epithelial cells is performed by the UDP; and 3) some oxidized lens proteins are degraded to a large extent via the UDP. The preliminary data indicate that the activity of the UDP in bovine lens epithelial cells increases during recovery from oxidative stress and that ubiquitin activating enzyme (E1) is rate-limiting in the UDP. Based on this information, the principal investigator hypothesizes that the UDP in lens epithelial cells plays an important role in recovery from oxidative stress and that the regulation of UDP activity may be essential for the cells to withstand stress. The broad goal of this project is to elucidate the role of UDP in lens epithelial cells during recovery from oxidative stress. First the principal investigator will manipulate the activity of the UDP via regulation of the E1 activity and test if the activity of the UDP is essential for the cells to recover from oxidative stress. He will then characterize and/or identify some of the proteins conjugated to ubiquitin. Finally he will elucidate the mechanisms which underlie the increased UDP activity during recovery from oxidative stress. The information obtained will enhance our understanding of the role of the UDP in lens cells and may be used for future regulation of the UDP activity to promote the recovery of lens epithelial cells from stress.
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