Role of Plakoglobin on Intestinal Mucosal Healing and Epithelial Barrier Regulation in Inflammatory Bowel Disease

• Applicants: Dr. Matthias Kelm; Professor Dr. Nicolas Schlegel
• Subject Area: General and Visceral Surgery
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 497335951

Inflammatory Bowel Diseases (IBD) display a complex pathogenesis that is poorly understood. To date, therapies focus on the modulation of the aberrant immune response in IBD which is associated with high rates of side effects and a limited clinical response in a majority of patients. Since restoration of the intestinal epithelial barrier (IEB) and mucosal healing is an important therapeutic aim in IBD treatment, specific approaches to target the intestinal epithelium are needed. Previous search pointed to the relevance of the desmosomal proteins Desmoglein-2 (Dsg2) and Desmocollin-2 (Dsc2) on barrier stabilization and wound healing in the gut and especially in IBD patients by largely undefined mechanisms. Preliminary work for this proposal suggests that the desmosomal plaque protein plakoglobin is a critical regulator for desomosomal integrity: in intestinal specimens and organoids generated from patients with IBD plakoglobin was significantly reduced. In vitro, siRNA-induced downregulation of plakoglobin in cell cultures of intestinal epithelial cells resulted in a loss of Dsg2 at cell borders, reduced intercellular adhesion and changes of intestinal epithelial wound healing. Based on this, we hypothesize that the loss of Plakoglobin is critically involved in the regulation of intestinal barrier function and mucosal healing. On a mechanistic level, Plakoglobin might act as a scaffold protein to facilitate signaling pathways important for cell motility, intestinal barrier function and mucosal healing which may play a relevant role for the onset and perpetuation of intestinal barrier function in IBD. The aim of this proposal is to comprehensively evaluate the role of intestinal plakoglobin in vivo following intestinal epithelial selective inducible knockout of Plakoglobin in mice (VilCreERT2 JUP-/-). This mouse strain has been generated in preparation for this project. In addition, murine enteroids, human enteroids from IBD patients and intestinal epithelial cell lines will serve to elucidate the mechanisms underlying plakoglobin-dependent barrier regulation and mucosal healing. On a long-term perspective, this will add novel insights into specific mechanisms and potential novel therapeutic targets to reconstitute mucosal homeostasis in patients with IBD.

• DFG Programme: Research Grants