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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
2P01DK062041-11
Application #
8607418
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (M3))
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
11
Fiscal Year
2013
Total Cost
$428,964
Indirect Cost
$153,103
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Ding, Lin; El Zaatari, Mohamad; Merchant, Juanita L (2016) Recapitulating Human Gastric Cancer Pathogenesis: Experimental Models of Gastric Cancer. Adv Exp Med Biol 908:441-78
Gifford, Gail B; Demitrack, Elise S; Keeley, Theresa M et al. (2016) Notch1 and Notch2 receptors regulate mouse and human gastric antral epithelial cell homoeostasis. Gut :
Ding, Lin; Hayes, Michael M; Photenhauer, Amanda et al. (2016) Schlafen 4-expressing myeloid-derived suppressor cells are induced during murine gastric metaplasia. J Clin Invest 126:2867-80
Syu, Li-Jyun; Zhao, Xinyi; Zhang, Yaqing et al. (2016) Invasive mouse gastric adenocarcinomas arising from Lgr5+ stem cells are dependent on crosstalk between the Hedgehog/GLI2 and mTOR pathways. Oncotarget 7:10255-70
Companioni Nápoles, Osmel; Tsao, Amy C; Sanz-Anquela, José Miguel et al. (2016) SCHLAFEN 5 expression correlates with intestinal metaplasia that progresses to gastric cancer. J Gastroenterol :
Demitrack, Elise S; Samuelson, Linda C (2016) Notch regulation of gastrointestinal stem cells. J Physiol 594:4791-803
Gurdziel, Katherine; Vogt, Kyle R; Walton, Katherine D et al. (2016) Transcriptome of the inner circular smooth muscle of the developing mouse intestine: Evidence for regulation of visceral smooth muscle genes by the hedgehog target gene, cJun. Dev Dyn 245:614-26
Gurdziel, Katherine; Vogt, Kyle R; Schneider, Gary et al. (2016) Computational prediction and experimental validation of novel Hedgehog-responsive enhancers linked to genes of the Hedgehog pathway. BMC Dev Biol 16:4
Demitrack, Elise S; Gifford, Gail B; Keeley, Theresa M et al. (2015) Notch signaling regulates gastric antral LGR5 stem cell function. EMBO J 34:2522-36
Gurdziel, Katherine; Lorberbaum, David S; Udager, Aaron M et al. (2015) Identification and Validation of Novel Hedgehog-Responsive Enhancers Predicted by Computational Analysis of Ci/Gli Binding Site Density. PLoS One 10:e0145225

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