Chronic inflammation of the gastric mucosa (chronic gastritis) may occur from Helicobacter pylori infection or bacterial overgrowth in the hypochlorhydric stomach. The central question posed in this Subproject is how does reduced stomach acid trigger the reversion of the gastric epithelium to cells with small bowel characteristics? Recently, we have confirmed in a hypochlorhydric mouse model that reduced stomach acid coincides with bacterial overgrowth and changes in the epithelium reminiscent of H. pylori infection in patients. Since bacterial colonization of the stomach induces an inflammatory response, it is difficult to study the contribution from bacterial gene products versus the inflammation. Therefore to distinguish between these two components of chronic gastritis, we will study transgenic mice expressing the H. pylori gene product CagA and wild type mice treated with the pro-inflammatory cytokine interferon gamma (INF-gamma). INF-gamma was selected since it is the major Th1 cytokine secreted during H. pylori infection. Recently, CagA was shown to translocate into the cytoplasm of human gastric cells suggesting that this event may be one signal triggering the cascade of events. However, the role of a specific bacterial virulence factor on the pathogenesis that is observed has not been studied. Over time, the inflammatory process progresses and alteration of the epithelial cell population occurs which includes gradual loss of parietal cells with increased infiltration and proliferation of mucous cells. Proliferation of the mucous cell types and evidence of an intestinal phenotype with villin expression (intestinal metaplasia) is a major precursor lesion for gastric cancer. Overall, the specific goals of this project are to understand the impact of bacterial infection on gastric epithelial cell differentiation.
The specific aims of the project are: 1) Study how H. pylori CagA modulates the pattern of gastric epithelial cell differentiation in vivo. 2) Study how cytokines modulate gastric epithelial cell differentiation in vivo. 3) Dissect the signaling pathways activated by CagA that regulate cell survival. 4) Study aberrant expression of villin in the stomach after bacterial colonization. The studies proposed will advance our understanding of how cell differentiation is regulated in vitro and in vivo by bacterial gene products and cytokines. Further, clues as to how modulating the pattern of gastric epithelial cell differentiation is linked to the development of pre-neoplastic lesions in the stomach will be examined. In this manner, we hope to gain significant insight into how common pathologic influences affect gastric cell identity.
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| Mills, Jason C; Samuelson, Linda C (2018) Past Questions and Current Understanding About Gastric Cancer. Gastroenterology 155:939-944 |
| Merchant, Juanita L (2018) Parietal Cell Death by Cytokines. Cell Mol Gastroenterol Hepatol 5:636-637 |
| El-Zaatari, Mohamad; Bass, Adam J; Bowlby, Reanne et al. (2018) Indoleamine 2,3-Dioxygenase 1, Increased in Human Gastric Pre-Neoplasia, Promotes Inflammation and Metaplasia in Mice and Is Associated With Type II Hypersensitivity/Autoimmunity. Gastroenterology 154:140-153.e17 |
| Merchant, Juanita L; Ding, Lin (2017) Hedgehog Signaling Links Chronic Inflammation to Gastric Cancer Precursor Lesions. Cell Mol Gastroenterol Hepatol 3:201-210 |
| Al Menhali, Asma; Keeley, Theresa M; Demitrack, Elise S et al. (2017) Gastrin induces parathyroid hormone-like hormone expression in gastric parietal cells. Am J Physiol Gastrointest Liver Physiol 312:G649-G657 |
| Sahoo, Nirakar; Gu, Mingxue; Zhang, Xiaoli et al. (2017) Gastric Acid Secretion from Parietal Cells Is Mediated by a Ca2+ Efflux Channel in the Tubulovesicle. Dev Cell 41:262-273.e6 |
| Companioni Nápoles, Osmel; Tsao, Amy C; Sanz-Anquela, José Miguel et al. (2017) SCHLAFEN 5 expression correlates with intestinal metaplasia that progresses to gastric cancer. J Gastroenterol 52:39-49 |
| Demitrack, Elise S; Samuelson, Linda C (2017) Notch as a Driver of Gastric Epithelial Cell Proliferation. Cell Mol Gastroenterol Hepatol 3:323-330 |
| Saqui-Salces, Milena; Tsao, Amy C; Gillilland 3rd, Merritt G et al. (2017) Weight gain in mice on a high caloric diet and chronically treated with omeprazole depends on sex and genetic background. Am J Physiol Gastrointest Liver Physiol 312:G15-G23 |
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