Epithelial-mesenchymal interactions are required during ontogeny for gut morphogenesis and serve a critical role in epithelial carcinogenesis. Epimorphin is a mesenchymal/myofibroblast protein with homology to the syntaxin family of secretory vesicle docking proteins. We generated Epimorphin-/- (Epi-/-) mice, which are viable yet have increased small bowel length, mucosal surface area, crypt cell proliferation and crypt fission. Epi-/- mice were partially protected from acute colitis induced by dextran sodium sulfate. Our data suggest that the gut phenotype of the Epi-/- mouse derives from effects on bone morphogenetic protein (Bmp), wnt-?- catenin and Hedgehog (Hh) signaling pathways. This is consistent with our observation that aged Epi-/- mice have a significantly increased incidence of small bowel adenomatous polyps, and occasionally develop invasive cancer. The hypotheses are 1. Epimorphin is a stromal inhibitor of epithelial proliferation in the gut, which acts by directly regulating synthesis and/or secretion of Bmps and other myofibroblast growth factors. 2. Epimorphin protects against polyp formation by modulating crypt cell proliferation and fission. 3. Epimorphin deletion predisposes to intestinal polyposis and carcinogenesis by reducing secretion of stromal Bmp and other growth factors, thus modulating wnt-?-catenin and Hh signaling pathways. 4. Epimorphin deletion enhances colonic epithelial repair by increasing crypt cell proliferation after acute injury. 5. Long term loss of epimorphin will enhance tumor formation in an injury/chronic inflammation cancer model.
The Specific Aims are: 1. Determine how epimorphin deletion leads to enhanced crypt cell proliferation and small intestinal polyp formation. 2. Clarify mechanisms by which myofibroblast epimorphin inhibits epithelial proliferation, using myofibroblast-epithelial co-cultures. 3. Determine mechanisms by which epimorphin deletion ameliorates injury induced by DSS, and whether this enhances carcinogenesis associated with DSS-induced injury/inflammation. Significance: we have a unique model of small bowel polyp formation and carcinogenesis, produced by deletion of a single myofibroblast gene. The Epi-/- mouse model has suggested a novel paradigm for the regulation of crypt cell proliferation, crypt fission, and small bowel polyp formation and has provided us with the tools to define the role of myofibroblasts and their secretory products in gut epithelial homeostasis, carcinogenesis and in epithelial injury and repair processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061216-10
Application #
7787117
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
Carrington, Jill L
Project Start
2001-09-30
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
10
Fiscal Year
2010
Total Cost
$302,314
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Shaker, Anisa; Gargus, Matthew; Fink, Julie et al. (2014) Epimorphin(-/-) mice are protected, in part, from acute colitis via decreased interleukin 6 signaling. Transl Res 164:70-83
van den Brink, Gijs R; Rubin, Deborah C (2013) Foxf2: a mesenchymal regulator of intestinal adenoma development. Gastroenterology 144:873-6
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Shaker, Anisa; Binkley, Jana; Darwech, Isra et al. (2013) Stromal cells participate in the murine esophageal mucosal injury response. Am J Physiol Gastrointest Liver Physiol 304:G662-72
Shaker, Anisa; Swietlicki, Elzbieta A; Wang, Lihua et al. (2010) Epimorphin deletion protects mice from inflammation-induced colon carcinogenesis and alters stem cell niche myofibroblast secretion. J Clin Invest 120:2081-93
Shaker, Anisa; Rubin, Deborah C (2010) Intestinal stem cells and epithelial-mesenchymal interactions in the crypt and stem cell niche. Transl Res 156:180-7
Yu, Cong; Jiang, Shujun; Lu, Jianyun et al. (2010) Deletion of Tis7 protects mice from high-fat diet-induced weight gain and blunts the intestinal adaptive response postresection. J Nutr 140:1907-14
Wang, Lihua; Tang, Yuzhu; Rubin, Deborah C et al. (2007) Chronically administered retinoic acid has trophic effects in the rat small intestine and promotes adaptation in a resection model of short bowel syndrome. Am J Physiol Gastrointest Liver Physiol 292:G1559-69
Rubin, Deborah C (2007) Intestinal morphogenesis. Curr Opin Gastroenterol 23:111-4

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