(Scanned from the applicant's description): In the current funding period, we have demonstrated that persistent exposure of the intestine to lipid hydroperoxides (LOOH) induces an imbalance in tissue glutathione (GSH) and glutathione disulfide (GSSG) redox status, impairs peroxide detoxication, and disrupts enterocyte turnover, independently of cell injury. GSH supplementation restores cellular redox balance and maintains normal turnover kinetics. These findings suggest that oxidative stress and the accompanying redox imbalance are important mediators of specific cellular and molecular responses in intestinal cell growth and death. We currently propose to define the role of cellular redox in intestinal apoptosis and proliferation and the mechanisms by which redox mediates these responses. Our central hypothesis is that LOOH-induced redox imbalance mediates transition of intestinal cells from a quiescent state to that of a prohferative or apoptotic state by (differential activation of cell signaling pathways. We further hypothesize that upregulation of mitochondrial MnSOD abrogates mitochondria ROS generation, restores matrix redox balance and attenuates cell apoptosis.
The aims address 4 specific hypotheses.
Aim 1. To test the hypothesis that LOOH-induced redox imbalance differentially mediates intestinal cell proliferation or apoptosis depending on the severity and duration of the redox shift.
Aim 2. To test the hypothesis that redox-mediated transition of intestinal cells to the proliferative or apoptotic states is associated with activation of proliferative or apoptotic signaling.
Aim 3. To test the hypothesis that redox-induced apoptotic or proliferative signaling is mediated through differential activation of nitrogen activated protein kinases (MAPKs), Akt, or NFkB.
Aim 4. To test the hypothesis that upregulation of mitochondrial MnSOD abrogates mitochondrial ROS generation, restores matrix redox balance and attenuates cell apoptosis. The studies will provide (a) important new information on the impact of oxidant challenge and loss of redox balance on regulation of intestinal apoptotic and proliferative responses, and (b) new insights into the potential use of antioxidant enzyme overexpression in the maintenance of metabolic integrity and turnover homeostasis of the intestinal epithelium.
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