The long-term goal of this project is to test proteasome inhibitors as potential therapeutic agents for ocular lens disorders. Posterior capsular opacification (PCO) and anterior polar and subcapsular cataract manifest abnormal proliferation or apoptosis. The proteasome is a key factor in proliferation and apoptosis in many cell types. Several classes of powerful anti-proteasome drugs are under development or in clinical trial for treatment of disparate diseases. Proteasome inhibition may stop abnormal proliferation or apoptosis in PCO and cataractogenesis, and prevent or delay opacification.
The specific aims are to answer the following questions about PCO and anterior polar and subcapsular cataracts: Is there altered Ubiquitin-Proteasome pathway activity? Proteolytic activity will be quantitated using chromogenic and/or fluorescent substrates. Are levels of pro- or anti-apoptotic proteasome substrates altered? Expression and function of regulatory proteins will be determined and correlated with apoptosis and markers of cataract. Do proteasome inhibitors prevent changes associated with opacification? Well-defined classes of proteasome inhibitors will be tested for the ability to prevent or delay changes associated with cataract formation. TGF-beta will be used to induce PCO and cataract like changes in an eye bank donor lens capsular bag model, a rat lens explant model, and in cultured HLE B-3 cells. Anterior capsules obtained during cataract surgery will be analyzed for markers of cataract and apoptosis. These experiments will for the first time address the role of the proteasome in lens pathology. If an abnormal balance between proliferation and apoptosis is part of opacification, the proteasome is an important therapeutic target, and these studies may provide the basis for a novel, effective pharmacological treatment of PCO and cataract.
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