Regulation of intestinal barrier by Junctional Adhesion Molecule-A (JAM-A) during homeostasis and inflammation

• Applicant: Dr. Kevin Börner
• Subject Area: General and Visceral Surgery
• Term: from 2020 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 455209265

The intestinal epithelial barrier (IEB) plays a vital role in protecting from luminal antigens while allowing for paracellular transport and absorption of nutrients. Intestinal mucosal injury leads to an exacerbated local immune response, which in turn results in inflammation, tissue damage and barrier breakdown, all of which are conditions associated with chronic inflammatory gastrointestinal pathologies such as inflammatory bowel disease (IBD). Efficient mucosal repair is thus critical to re-establish barrier and uphold intestinal function. Studies have identified the tight junction protein Junctional Adhesion Molecule-A (JAM-A) as a regulator of intestinal homeostasis. Loss of JAM-A has been demonstrated to increase intestinal permeability, decrease neutrophil recruitment to the gut and impair intestinal epithelial cell migration. Despite its clear involvement in intestinal homeostasis - a state greatly perturbed in IBD - nothing is known about the role of JAM-A in epithelial wound healing. In this project we will investigate how epithelial JAM-A regulates intestinal mucosal wound repair and homeostasis. For this, complementary in vitro and in vivo work will be conducted using model intestinal epithelial cell lines (SK-CO15, T84), primary murine epithelial cells (colonoids), and mouse strains with a total knockout or inducible, epithelial-specific loss of JAM-A. Wound closure, neutrophil recruitment and epithelial migration will be analyzed to further characterize the function of epithelial JAM-A in mucosal repair. Preliminary work for this proposal suggests that JAM-A deficiency in intestinal epithelial cells impairs wound closure in vivo. Understanding the mechanisms by which epithelial JAM-A modulates mucosal wound healing and intestinal barrier properties will provide important insights into the pathophysiology of chronic intestinal inflammatory conditions such as IBD.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Charles Parkos, Ph.D.