Lay Summary

Proposal No. IBD-0220
Principal Investigator:  Jean-Luc Desseyn, Ph.D.
Applicant Organization:  INSERM (Institut National de la Santé et de la Recherche Médicale) (Lille, France)
Project Title:  Protective action of a cysteine-rice mucin domain on the intestinal mucosa in experimental colitis
Period of Award:  February 1, 2008 – March 31, 2010

The mucus layer covers the digestive epithelium and performs many functions that collectively protect the epithelial cells lining the gut. Mucins are the primary constituents of this gel layer and are responsible for the viscous and elastic gel-like properties. These mucins are large size, high carbohydrate complex molecules that form long polymeric structures via their N- and C-termini domains. Their central parts carrying extended O-glycosylated chains are interrupted by naked CYS domains highly conserved through evolution that are believed to be involved in hydrophobic interactions. These hydrophobic domains on adjacent molecules act as the crosslinks of the gel and are likely responsible, in part, for its rheological properties.

Ulcerative colitis (UC) and Crohn's disease are the two most important inflammatory bowel diseases (IBD) and are thought to result from an inappropriate response of the mucosal immune system. The mucus layer is compromised in IBD and a thinner colonic mucus layer has been observed in UC patients and it is believed that the aberrant response of the host is facilitated by this defect.

The objective of this proposed research is to study the efficiency of the mucin CYS domain to counterbalance the decrease of the mucus barrier in IBD animal models. We will create a mouse transgenic line that will secrete into the colonic lumen a string of 12 CYS domains that should greatly reinforce the mucus layer. We will use two complementary mouse models to test the protective effect of the CYS domain in IBD.