The Program Project Grant (PPG), """""""" Cellular Decisions of Differentiation in the GI Tract"""""""" integrates the efforts of four investigators (two basic science and two clinical) from three Departments of the University of Michigan Medical School. The central goals of the work proposed in the PPG are: (a) To understand how epithelial cells in the upper gastrointestinal tract acquire their identity, both with respect to tissue identity (gastric vs. small intestine) and lineage identity (enteroendocrine cell vs. enterocyte or goblet cell) during ontogeny; (b) To investigate how the patterns of cellular differentiation in the acidsecreting epithelium of the stomach are normally controlled through specific intracellular pathways and how these pathways are altered by pathological insults (such insults can cause an alteration in identity of the gastric epithelium, such that it acquires a small intestinal phenoytpe). Subproject #1 examines the cis and trans factors that control identity in the intestinal epithelial cell, from a tissue-specific standpoint (stomach versus intestine), a regional standpoint (duodenum vs. distal intestine) and a differentiation standpoint (crypt vs. tip). In addition, in conjunction with Subprojects #2 and #4, the question of how gene regulation changes when stomach cells acquire intestinal identity (intestinal metaplasia) after pathological insult will be examined. Subproject #2 will trace the development of the enteroendocrine cell lineage within the intestine using cholecystokinin (CCK) as an early marker for this cell compartment. This work will utilize regulatory transgenes generated in Subproject #1. Subproject #3 will focus on how endogenous growth factors present in the stomach control the pattern of differentiation of the parietal cell. Subproject #4 examines the pathways through which the gastric epithelium responds to inflammation and/or bacterial overgrowth in the stomach through the generation of intestinal metaplasia, an alteration in gastric cell identity; the role of the pathways identified in Subproject #3 will be examined. Two Cores will assist the PPG investigators in the performance of Cell Biology techniques (Core A) and with Administration of the program (Core B). Both Cores will enhance the already strong interaction between these four investigators across Departmental lines. Overall, this PPG application will further our understanding of how cells make decisions of identity and differentiation in the stomach and intestine of the GI tract and will provide clues as to how this identity may be altered in pathological states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK062041-03
Application #
6778219
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (M1))
Program Officer
May, Michael K
Project Start
2002-09-15
Project End
2007-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
3
Fiscal Year
2004
Total Cost
$1,262,419
Indirect Cost
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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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
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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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