The gastrointestinal epithelium plays a central role in maintaining and coordinating mucosal homeostasis and immunity. Intestinal epithelial barrier compromise in mucosal wounds is seen in many pathologic states that encompass inflammatory bowel diseases, ischemia, mechanical injury and surgical procedures. Coordinated epithelial cell migration and proliferation required for wound closure is a complex process that is not well understood. Our overarching hypothesis is that epithelial and immune cell mediators in the intestinal mucosa coordinate epithelial repair responses. Thus, the proposed studies will identify and characterize mechanisms by which lipid and protein mediators in the intestinal mucosa promote wound repair. Knowledge gained from these studies in the short term will provide a better understanding of basic mechanisms by which inflammatory cell and epithelial mediators control intestinal epithelial homeostasis and mucosal wound repair. In the long term these studies will aid in the development of new therapeutic strategies aimed at promoting intestinal mucosal wound repair.

Public Health Relevance

The lining of the gastrointestinal tract plays an important role in immune defense, which can be significantly compromised by conditions such as inflammatory bowel diseases, ischemia, mechanical injury and surgical procedures. This grant will address mechanisms by which the mucosal lining heals after such damage. Knowledge gained from these studies in the short term will provide a better understanding of basic mechanisms by which wound healing is controlled, and in the long term, these studies will aid in the development of new therapeutic strategies aimed at promoting mucosal wound repair.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055679-18
Application #
9119597
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Greenwel, Patricia
Project Start
1998-08-01
Project End
2018-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
18
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Flemming, Sven; Luissint, Anny-Claude; Nusrat, Asma et al. (2018) Analysis of leukocyte transepithelial migration using an in vivo murine colonic loop model. JCI Insight 3:
Hinrichs, Benjamin H; Matthews, Jason D; Siuda, Dorothée et al. (2018) Serum Amyloid A1 Is an Epithelial Prorestitutive Factor. Am J Pathol 188:937-949
Quiros, Miguel; Nishio, Hikaru; Neumann, Philipp A et al. (2017) Macrophage-derived IL-10 mediates mucosal repair by epithelial WISP-1 signaling. J Clin Invest 127:3510-3520
Garcia-Hernandez, Vicky; Quiros, Miguel; Nusrat, Asma (2017) Intestinal epithelial claudins: expression and regulation in homeostasis and inflammation. Ann N Y Acad Sci 1397:66-79
Harusato, A; Abo, H; Ngo, V L et al. (2017) IL-36? signaling controls the induced regulatory T cell-Th9 cell balance via NF?B activation and STAT transcription factors. Mucosal Immunol 10:1455-1467
Cruz-Acuña, Ricardo; Quirós, Miguel; Farkas, Attila E et al. (2017) Synthetic hydrogels for human intestinal organoid generation and colonic wound repair. Nat Cell Biol 19:1326-1335
Sumagin, R; Brazil, J C; Nava, P et al. (2016) Neutrophil interactions with epithelial-expressed ICAM-1 enhances intestinal mucosal wound healing. Mucosal Immunol 9:1151-62
Luissint, Anny-Claude; Parkos, Charles A; Nusrat, Asma (2016) Inflammation and the Intestinal Barrier: Leukocyte-Epithelial Cell Interactions, Cell Junction Remodeling, and Mucosal Repair. Gastroenterology 151:616-32
Kudelka, Matthew R; Hinrichs, Benjamin H; Darby, Trevor et al. (2016) Cosmc is an X-linked inflammatory bowel disease risk gene that spatially regulates gut microbiota and contributes to sex-specific risk. Proc Natl Acad Sci U S A 113:14787-14792
Matthews, Jason D; Sumagin, Ronen; Hinrichs, Benjamin et al. (2016) Redox control of Cas phosphorylation requires Abl kinase in regulation of intestinal epithelial cell spreading and migration. Am J Physiol Gastrointest Liver Physiol 311:G458-65

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