Functional and inhibitory studies of human lipoxygenase

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DESCRIPTION (provided by applicant): The scope of this research program is to expand on a small part of Aim 3 of the original R01, which had limited goals. Our current revision aims to discover over 100 lipoxygenase inhibitors, optimize their activity and provide sufficient quanitites of inhibitor to investigate them as therapeutics against cancer, type-1 diabetes and Parkinson's disease. This research will be very laborious and require additional staff and equipment in four locations across the nation- key rationales of the stimulus package. Human lipoxygenase (hLO) isozymes are potential therapeutic targets because they are involved in numerous human diseases and yet, there has been little progress in their development due to the difficulty of targeting specific hLO isozymes. We propose to rectify this problem by discovering specific inhibitors against four hLOs, 5-hLO, platelet 12-hLO, reticulocyte 15-hLO-1 and epidermal 15-hLO-2, and determining their efficacy against human diseases. There are four major aims of the grant. The first major aim is to identify all of the possible isozyme specific lipoxygenase inhibitors from our initial high through-put NIH discovery of over 1000 inhibitors. Subsequently, each of the ~100 anticipated identified inhibitors will be structurally modified to optimize their potency/selectivity. The second major aim is to determine if these inhibitors are potent/selective against cancer. Currently, we have preliminary results which demonstrate that one of our 5-hLO inhibitors is potent/selective against murine colon cancer and we plan to screen the remaining inhibitors against our suite of cancer cell lines. The third major aim is to determine if our 12-hLO inhibitors protect 2-cells from auto-immune destruction and hence protect against type-1 diabetes. Currently, we have preliminary results which show that our 12-hLO inhibitor lowers the concentration of IL-12, indicating that this inhibitor may protect 2 -cells from death. We propose to expand this result and test the efficacy of our inhibitors on non-obese diabetic (NOD) mice. The fourth major aim is to determine if our LO inhibitors protect neuronal cells from the inflammatory damage that occurs in Parkinson's disease. Currently, we have preliminary results which demonstrate that our inhibitors enter neuronal cells and protect them from glutamate induced apoptosis. We are now investigating which of the specific LO inhibitors are the most beneficial in our Parkinson's mouse model. These are very encouraging results and constitute a specific LO inhibitor "tool box" which will allow us to accelerate the tempo in understanding the role of LO in cancer, diabetes and Parkinson's disease. PUBLIC HEALTH RELEVANCE: Lipoxygenase (LO) is a critical enzyme involved in numerous human diseases. The goal of this proposal is to discover and characterize inhibitors to LO with the goal of developing possible therapeutics against cancer, type-1 diabetes and Parkinson's disease.