The current submission of the Program Project Grant (PPG), """"""""Cellular Decisions of Differentiation in the Gl Tract"""""""" integrates the efforts of three investigators (two basic science and one clinical) from three Departments at the University of Michigan. The central goals of the proposed studies generally remain the same as the prior two cycles: (a) To understand how gastric epithelial cells develop and maintain their identity by expressing or responding to developmental signaling pathways activated by the peptide morphogen sonic hedgehog (Shh) or the transmembrane signaling receptor Notch (b) To investigate how the patterns of cellular differentiation in the gastric corpus, gastric antrum and intestine use these signaling pathways to maintain homeostasis or respond to environmental stress, e.g., chronic inflammation. Subproject #1 entitled """"""""Modulation of myeloid cell phenotype by hedgehog signals"""""""" will expand upon the intial translational observation that the Hedgehog target gene Glil expressed in myeloid cells modulates the epithelial response to inflammation. Subproject #2 entitled """"""""Role of Hedgehog signaling in chronic gastritis and metaplasia"""""""" will examine the role of chronic inflammation, specifically proinflammatory cytokines in mediating changes in patterns of cellular differentiation, e.g., metaplasia in the gastric corpus and hyperplasia in the antrum. Subproject #3 entitled """"""""Notch Regulation of Gastric Epithelial Cell Homeostasis and Tumorigenesis"""""""" will explore the effect of the Notch pathway on Lgr5+ stem cells in the antrum and its possible interaction with the Hedgehog pathway. The PPG will support one service core (Cell Biology Core) to efficiently, process, analyze and coordinate tissue samples and flow cytometric analysis between the three projects. In summary, the PPG will use a variety of different mouse models and cell or molecular -based approaches to understand how gastric and intestinal cells maintain their homeostasis, but then modify their cellular patterns of differentiation in response to chronic inflammation ultimately directing the cll towards a pro-proliferative phenotype.

Public Health Relevance

The PPG brings together both basic and translational concepts to dissect the use developmental pathways, e.g.. Hedgehog and Notch signaling to execute cellular decisions for homeostasis versus pathologic responses to environmental stressors, e.g., bacterial infection, inflammation, chemical injury, which can segue to neoplastic transformation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK062041-12
Application #
8710162
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (M3))
Program Officer
Carrington, Jill L
Project Start
2002-07-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
12
Fiscal Year
2014
Total Cost
$1,385,553
Indirect Cost
$486,852
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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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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