The gastrointestinal epithelium functions as a dynamic permeability barrier that separates luminal contents from underlying tissue compartments and is vital in maintaining mucosal homeostasis. Pathologic processes such as inflammatory bowel disease and ischemia induce epithelial injury and mucosal wounds that result in barrier disruption. In response to injury, intestinal epithelial cells (IECs) migrate as a cohesive sheet to rapidly cover denuded surfaces, close wounds and re-establish the critical epithelia barrier in a process termed restitution. Epithelial cell migration is critically dependent on actin cytoskeletal restructuring, directional polarization of cells into the wound and dynamic focal cell-matrix adhesion turnover. The long term goals of this proposal are to define mechanisms by which the intestinal epithelium migrates in response to injury and inflammation to efficiently reseal mucosal barrier defects. We recently determined that a multifunctional membrane associated and actin binding protein, Annexin 2 (AnxA2) and a secreted regulator of Wnt signaling, Dickkopf-1 (Dkk-1), play critical roles in controlling IEC migration and restitution. Thus our aims in this proposal are to define the mechanisms by which AnxA2 and Dkk-1 regulate IEC motility and wound closure. These studies will not only advance our understanding of AnxA2 and Dkk-1 function in the intestine, but will also aid in the development of new therapeutic strategies aimed at facilitating mucosal barrier recovery.

Public Health Relevance

The gastrointestinal epithelium functions as an important barrier that separates luminal contents from underlying tissue compartments. Disruption of the epithelial barrier in inflammatory bowel diseases and ischemia result in fluid &electrolyte loss and exposure of tissues to luminal antigens and pathogens. To rapidly reseal such wounds, epithelial cells migrate in a process termed restitution. Our studies are aimed at understanding mechanisms by which the intestinal epithelium migrates to rapidly cover denuded surfaces and reseal wounds. We recently determined that two proteins, annexin-2 and Dickkopf-1 control intestinal epithelial cell migration and wound recovery. The proposed studies will analyze the mechanisms by which these proteins regulate intestinal epithelial wound recovery. These investigations will not only define the mechanisms by which these proteins regulate wound resealing, but will also provide new ideas to identify therapeutic agents aimed at promoting intestinal epithelial wound closure and mucosal barrier recovery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055679-14
Application #
8210982
Study Section
Special Emphasis Panel (ZRG1-DIG-C (02))
Program Officer
Carrington, Jill L
Project Start
1998-08-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
14
Fiscal Year
2012
Total Cost
$330,417
Indirect Cost
$117,245
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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
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:
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
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
Gómez-Suárez, M; Gutiérrez-Martínez, I Z; Hernández-Trejo, J A et al. (2016) 14-3-3 Proteins regulate Akt Thr308 phosphorylation in intestinal epithelial cells. Cell Death Differ 23:1060-72

Showing the most recent 10 out of 67 publications