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 are crucial for mucosal wound closure, yet many aspects of this complex process are not well understood. Mucosal reparative events are orchestrated by the epithelium itself as well as by a spatiotemporal interplay of epithelial-immune cell cross-talk. Select inflammatory cytokines initiate synthesis of mediators that not only serve to influence the inflammatory cascade but also dismantle it and promote repair. The overarching hypothesis is that temporal recruitment and activation of immune cells into injured sites influence epithelial signaling to promote repair. Thus, the proposed studies will identify and characterize mechanisms by which immune cell derived mediators influence and regulate intestinal epithelial 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 #
5R01DK055679-21
Application #
9868994
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Greenwel, Patricia
Project Start
1998-08-01
Project End
2024-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
21
Fiscal Year
2020
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
Lili, Loukia N; Farkas, Attila E; Gerner-Smidt, Christian et al. (2016) Claudin-based barrier differentiation in the colonic epithelial crypt niche involves Hopx/Klf4 and Tcf7l2/Hnf4-? cascades. Tissue Barriers 4:e1214038
Alam, Ashfaqul; Leoni, Giovanna; Quiros, Miguel et al. (2016) The microenvironment of injured murine gut elicits a local pro-restitutive microbiota. Nat Microbiol 1:15021
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

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