Understanding changes to the molecular features of intestinal epithelial progenitors (IEPs) and their resident niche that occur in response to a variey of environmental and genetic insults will greatly enhance our knowledge of gut disease pathogenesis. For instance, what mechanisms result in the alteration of the normal controls for IEP proliferation during normal, physiologic wound healing? The goal of this application is to build on our findings that during colonic epithelial injury, the indigenous population of microbes in the gastro-intestinal tract activates macrophages through toll-like receptors (TLR) that in turn interact with colonic mesenchymal stem cells (cMSCs) that together interact with the overlying IEPs and stimulate proliferation and wound repair. cMSCs are important as they are a prominent source of prostaglandin-endoperoxide synthase 2 (Ptgs2). Two functional alleles of Ptgs2 were necessary for repair as wounds from Ptgs2-/- and Ptgs2+/- mice showed defects in the underlying muscularis propria and crypt regeneration. Ptgs2 mRNA was significantly induced in the wound bed at days two and four post-injury. Maximal Ptgs2 expression was observed in cMSCs. Therefore, we functionally screened mRNA binding proteins enriched in cMSCs for effects on Ptgs2 mRNA expression. We found the shRNA knockdown of Igf2bp1, a VICKZ mRNA binding protein and zip-code factor, led to a 5-fold decrease in Ptgs2 mRNA expression. We found that Igf2bp1 physically interacted with Ptgs2 mRNA, and Igf2bp1 expression was induced in cMSCs during repair with a time course similar to Ptgs2 induction. The goals of this proposal are to determine the mechanism of Igf2bp1 mRNA binding and the zip code function to Ptgs2. We will also determine the fate and role of cMSCs in colonic wound repair. This study will establish a basic for the role of Ptgs2 in cMSCs that could have implications for therapy of diseases such as inflammatory bowel disease that demonstrate poor healing.

Public Health Relevance

The goal of this project is to determine the role of mesenchymal stem cells in colonic injury. The findings from these studies should impact our understanding of the pathogenesis of human diseases such as inflammatory bowel disease where wound healing is abnormal. In the longer term, we propose that these studies will provide the basis to develop cell-based therapeutics (using mesenchymal stem cells) for these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK071619-07
Application #
8617834
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Carrington, Jill L
Project Start
2005-07-01
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
7
Fiscal Year
2014
Total Cost
$330,600
Indirect Cost
$113,100
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Song, Christina; Lee, Jacob S; Gilfillan, Susan et al. (2015) Unique and redundant functions of NKp46+ ILC3s in models of intestinal inflammation. J Exp Med 212:1869-82
Tinkum, Kelsey L; Stemler, Kristina M; White, Lynn S et al. (2015) Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival. Proc Natl Acad Sci U S A 112:E7148-54

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