Arachidonic acid is converted to prostaglandins by cyclooxygenase (Cox). There are two isoforms , Cox-1 constitutive enzyme; whereas Cox-2 is inducible by inflammatory cytokines. There is a body of literature demonstrating the protective effects of prostaglandins on the gastrointestinal epithelium but the mechanism of these protective effects are not known. Crypt stem cells play a central role in the epithelial response to injury. The ability of stem cells to survive and proliferate after injury is affected by the genes they express and by the extracellular environment and exogenous agents. We have found that prostaglandins play an important role in regulating the ability of stem cells to respond to injury. Using the irradiated mouse intestine model and irradiated I407 cells, a human intestinal epithelial cell line, we have developed data demonstrating the influence of both the expression of cyclooxygenases nd the administration of exogenous prostaglandins on this process. We have also developed data suggesting that some of the effects of prostaglandins in this stem cell response to injury are mediated through effects on apoptosis. In particular we he found that the response of the Cox-1 knockout mouse to radiation is marked by decreased stem cell survival nd increased apoptosis when compared to its wild type littermates. The central hypothesis os this proposal is that prostaglandins regulate the response of gastrointestinal stem cells to injury. We propose to use the radiation injury model in the mouse small intestinal and in I407 cells to test this hypothesis under the following Specific Aims. 1. To define the mechanism by which prostaglandins are radioprotective; and 2. To determine the role of prostaglandins and/or apoptosis in the effects of other radioprotective (LPS, IL-1, IL-11, TGF-beta3), or radiosensitizing (IL-12) agents.
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