Abstract
Inflammation-induced gastrointestinal diseases, such as inflammatory bowel diseases (IBD) and Helicobacter-induced gastric pathologies (in particular cancer), are major contributors to health problems worldwide. There is emerging evidence that a loss of the gastrointestinal mucosal barrier integrity is a significant contributor to the pathophysiology of these disorders. Inappropriate overexpression of transmembrane mucins can affect the gastrointestinal mucosal barrier. Of particular interest is the transmembrane MUC13. This mucin, which is predominantly expressed in the intestines and only at a very low level in the stomach, has been shown to be significantly upregulated in the inflamed stomach and more specifically in adenocarcinoma and early events of the carcinogenesis process. Aberrant expression of MUC13 has also been seen in inflamed colonic mucosal biopsies from IBD patients. These findings clearly show the importance of the pro-inflammatory activity of MUC13 signalling during the gastric disease process and in IBD and necessitates further research.
Therefore, this project firstly (work package 1(WP1)) aims to determine the role of gastrointestinal MUC13 signaling during inflammation. In particular, the role of MUC13 in epithelial cell apoptosis as well as the signal transducers regulating its expression will be identified using cell and mice models of gastric disease and IBD.
The inappropriate overexpression of transmembrane mucins can affect the mucosal barrier integrity by disrupting cell polarity and cell-cell interactions resulting in loss of tight junctions. Tight junctions regulate cell polarity and their formation is dependent on the PAR3-PAR6-aPKC (PAR) complex. Dysfunction of the PAR complex can be mediated by a receptor tyrosine kinase, belonging to the ErbB family, which can be activated by transmembrane mucins. Additionally, the vasointestinal peptide (VIP) has been implicated in tight junction regulation and mucin expression and seems to be affected upon inflammation. The second aim of this project (WP2) is thus to investigate whether aberrant MUC13 expression has an effect on the integrity of the gastrointestinal mucosal barrier by participating in receptor tyrosine kinase activation and thereby contributing to the disruption of the PAR complex and VIP signaling. For this purpose, immunoprecipitation, microscopic and transfection assays and in vivo models will be used.
Finally (WP3), MUC13 expression and the key molecules in MUC13-induced gastrointestinal mucosal barrier disruption will be validated in a translational set-up using biopsies from patients with gastric disease and IBD. This might result in new strategies to treat these disorders and/or in the identification of new diagnostic biomarkers.
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