Intestinal mucosal wound resealing in inflammatory bowel disease

• Applicant: Dr. Markus Utech
• Subject Area: General and Visceral Surgery
• Term: from 2003 to 2005
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5422778

The gastrointestinal epithelium functions as an important barrier that separates luminal contents from underlying tissues. Disruption of the epithelial barrier in ischemic and inflammatory bowel diseases results in fluid/electrolyte loss and exposure of tissues to luminal antigens and pathogens. Superficial mucosal wounds rapidly reseal by epithelial cell migration, a process termed "restitution". During restitution, epithelial cells undergo significant changes in shape as they extrude cellular projections at the leading edge and migrate in a cohesive sheet to rapidly cover denuded surfaces. These cells communicate with the underlying matrix via focal cell matrix associations consisting of focal complexes (FACs) and ezrin/radixin/moesin complexes (ERMs). In such adhesive contacts, the actin cytoskeleton affiliates with transmembrane integrins via linker proteins that in turn provide the transient anchor required for forward cell movement. At a molecualr level these changes are achieved at least in part by actin-cytoskeletal restructuring and are modulated by attachment to the extracellular matrix via focal matrix contacts. Membrane targeting pathways of integrins in FACs/ERMs to sites of cell-matrix matrix adhesion and their recycling in endocytic pathways will be explored using morphologic, biochemical and molecular approaches. Restitution is in turn influenced by cytokines such as interferon g (IFN-g) and tumor necrosis factor a (TNF-a) released in the milieu of the damaged epithelium. Elevated expression of both these cytokines has been demonstrated in the mucosa of patients with active inflammatory bowel disease. My overall goal is to explore the dynamic re-organization of focal-cell matrix associations and analyze mechanisms by which these cytokines influence wound restitution.

• DFG Programme: Research Fellowships
• International Connection: USA
• Cooperation Partners: Professorin Dr. Asma Nusrat; Professor Charles Parkos, Ph.D.