The goals of the current application are to understand the role of the Sonic Hedgehog (Shh) ligand and components ofthe Hh signaling apparatus Glil and Gli2 in the homeostasis and subsequent translation of chronic gastritis to metaplasia, a preneoplastic lesion. It has been reported in human epidemiologic studies as well as mouse models that the development of tumors in the gastric corpus versus the antrum emerge ostensibly in response to different signals. As a result, we have focused our attention on cellular decisions that impact the emergence of corpus versus antral tumors. Studies completed during the prior funding period confirmed regional differences in the expression and function of the Shh ligand and the Hh signaling componets Glil-expressed in myeloid cell populations;and Gli2-expressed primarily in both antral mesenchyme and a hyperplastic.antral epithelium. In the antrum, primary cilia, an organelle linked to Gli2 function, and gastrin are important to normal gastric homeostasis, characterized by gastric acidity. We previously demonstrated that gastrin null mice develop antral tumors and recently reported an increase in epithelial Gli2 expression in these hyperplastic antrums. Moreover ectopic expression of Gli2 in the gastric epithelium suppresses gastrin expression and ultimately results in antral hyperplasia. In a mouse model of Helicobacter infection, we found that the corpus exhibits greater dependency on canonical Hh signaling than the antrum. In particular during /7e//co/)ac/er infection, the corpus acutely recruits Glil-expressing myeloid cells (<2 months) that appear to modify their surface markers in the chronically inflamed stomach to markers indicative of myeloid-derived suppressor cells (MDSCs). By 6 months, corpus metaplasia has emerged correlating with Gli1+-MDSCs their secretion of IL-lp. Thus we hypothesize that the contribution of Hh signaling to gastric homeostasis and hyperplasia differs according to their location in the stomach (corpus versus antrum).
Aim 1 will examine the role of Hh signaling in antral homeostasis and in particular, its role in regulating gastrin and their relationship to primary cilia.
Aim 2 will establish whether the proinflammatory cytokine IL-ip is sufficient to induce epithelial expression of Gli2 and antral hyperplasia. Crosstalk with the Notch signaling pathway will be explored in collaboration with Subproject #3.
Aim 3 will test the hypothesis that the time lag between chronic gastritis and metaplasia in the corpus requires pathogen-related maturation of myeloid cells in the inflamed gastric environment. The role of Hh signaling through Glil will be compared to Hh signaling in the inflamed intestine in collaboration with Subproject #1.

Public Health Relevance

This Subproject will define the functional differences in Hedgehog signaling components in gastric homeostasis that ultimately alters cellular decisions in the regional response to environmental stress, e.g., chronic inflammation and preneoplastic lesions such as metaplasia.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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University of Michigan Ann Arbor
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Prakash, Ajay; Udager, Aaron M; Saenz, David A et al. (2014) Roles for Nkx2-5 and Gata3 in the ontogeny of the murine smooth muscle gastric ligaments. Am J Physiol Gastrointest Liver Physiol 307:G430-6
Udager, Aaron M; Prakash, Ajay; Saenz, David A et al. (2014) Proper development of the outer longitudinal smooth muscle of the mouse pylorus requires Nkx2-5 and Gata3. Gastroenterology 146:157-65.e10
Merchant, Juanita L; Saqui-Salces, Milena (2014) Inhibition of Hedgehog signaling in the gastrointestinal tract: targeting the cancer microenvironment. Cancer Treat Rev 40:12-21
El-Zaatari, Mohamad; Kao, John Y; Tessier, Art et al. (2013) Gli1 deletion prevents Helicobacter-induced gastric metaplasia and expansion of myeloid cell subsets. PLoS One 8:e58935
Saqui-Salces, Milena; Dowdle, William E; Reiter, Jeremy F et al. (2012) A high-fat diet regulates gastrin and acid secretion through primary cilia. FASEB J 26:3127-39
El-Zaatari, Mohamad; Daignault, Stephanie; Tessier, Art et al. (2012) Plasma Shh levels reduced in pancreatic cancer patients. Pancreas 41:1019-28
Liu, Zhiping; Demitrack, Elise S; Keeley, Theresa M et al. (2012) IFNýý contributes to the development of gastric epithelial cell metaplasia in Huntingtin interacting protein 1 related (Hip1r)-deficient mice. Lab Invest 92:1045-57
Saqui-Salces, Milena; Keeley, Theresa M; Grosse, Ann S et al. (2011) Gastric tuft cells express DCLK1 and are expanded in hyperplasia. Histochem Cell Biol 136:191-204
Waghray, Meghna; Zavros, Yana; Saqui-Salces, Milena et al. (2010) Interleukin-1beta promotes gastric atrophy through suppression of Sonic Hedgehog. Gastroenterology 138:562-72, 572.e1-2
El-Zaatari, Mohamad; Zavros, Yana; Tessier, Art et al. (2010) Intracellular calcium release and protein kinase C activation stimulate sonic hedgehog gene expression during gastric acid secretion. Gastroenterology 139:2061-2071.e2

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