We seek to determine the role of survivin, the recently identified member of the inhibitor of apoptosis protein family, in ethanol (ETOH)-induced gastric mucosal injury healing and adaptive cytoprotection. Adaptive cytoprotection is the phenomenon whereby low 'mild irritant' ETOH concentrations protect the gastric mucosa against injury from subsequent exposure to concentrated ETOH. Survivin inhibits apoptosis and controls cell proliferation by regulating cell cycle progression. Our preliminary studies indicate that survivin is important for ETOH-induced gastric mucosal injury healing and adaptive cytoprotection; and, that this requires the MAP (ERK) kinase and PI 3-kinase/Akt signaling pathways. Based on current literature and our preliminary studies, we propose the following hypotheses: 1) ETOH-induced injury up-regulates gastric mucosal survivin expression and this is required for unimpaired healing. 2) Survivin mediates adaptive cytoprotection induced in the gastric mucosa by mild irritant ETOH concentrations. To address the first hypothesis, we will determine the temporal and spatial expression of survivin following ETOH-induced gastric mucosal injury and whether this correlates with ERK, PI 3-kinase and Akt activation, cell proliferation and apoptosis. We will determine whether ERK and/or PI 3-kinase/Akt signaling mediate(s) survivin upregulation by ETOH-induced injury and whether survivin mediates mucosal resistance to ETOH-induced injury. To address the second hypothesis, we will determine whether survivin expression is up-regulated by mild irritant ETOH concentrations that produce adaptive cytoprotection and whether this correlates with degree of protection. We will determine, using transfection studies, whether inhibition of survivin expression/function abolishes adaptive cytoprotection and whether adaptive cytoprotection requires ERK, PI 3-kinase and/or Akt. Significance: Clinical studies from our VA Medical Center demonstrated that ETOH, especially in combination with nonsteroidal anti-inflammatory agents, is the most frequent cause of erosive gastritis and upper gastrointestinal (Gl) bleeding. Upper Gl bleeding is a severe clinical condition resulting in approximately 600 thousand hospitalizations per year and an estimated cost of $12 billion. Information gained from these studies will lead to better understanding of the mechanisms underlying ETOH-induced injury and will provide for the development of better therapeutics for treating ETOH-induced injury.
| Jung, M Katherine; Callaci, John J; Lauing, Kristen L et al. (2011) Alcohol exposure and mechanisms of tissue injury and repair. Alcohol Clin Exp Res 35:392-9 |
| Jones, M K; Padilla, O R; Zhu, E (2010) Survivin is a key factor in the differential susceptibility of gastric endothelial and epithelial cells to alcohol-induced injury. J Physiol Pharmacol 61:253-64 |
| Jones, Michael K; Padilla, Oscar R; Webb, Nicole A et al. (2008) The anti-apoptosis protein, survivin, mediates gastric epithelial cell cytoprotection against ethanol-induced injury via activation of the p34(cdc2) cyclin-dependent kinase. J Cell Physiol 215:750-64 |
