Lay Summary

Proposal No.   IBD-0052
Principal Investigator:  Koichi Kobayashi, M.D., Ph.D.
Applicant Organization:  Yale University (New Haven, Connecticut, U.S.A.)
Project Title:  A role of innate immunity in the pathogenesis of inflammatory bowel disease
Period of Award:  January 1, 2003 – February 28, 2005

Inflammatory bowel disease (IBD) affects approximately 0.5 % of the general population in most developed countries.  Although some advances have been made in understanding these diseases, we still do not know how IBD is caused.

It has been proposed that the inflammatory response to bacteria in the gut causes the diseases. For example, treatment with antibiotics may relieve the symptoms of IBD patients.  In mouse models of IBD, disease develops infrequently under bacteria-free conditions.

Recent findings have revealed that cell surface receptors called Toll-like receptors (TLRs) detect bacterial pathogens.  This detection leads to activation of immune cells.  One possible mechanism of IBD pathogenesis is that enhanced TLR activation causes the disease.  We will test this hypothesis using mice with increased TLR signaling and other mice with decreased TLR signaling.

Another major recent finding in IBD is the discovery of the NOD2 gene mutation in some Crohn’s disease patients.  NOD2 is postulated to function as part of a bacterial recognition system. Two possibilities exist as to how NOD2 mutation causes IBD; NOD2 may function independently from the TLR system or NOD2 may function dependently on the TLR system.  We generated mice that lack the NOD2 gene.  By comparing NOD2 deficient mice and NOD2 deficient mice with decreased TLR signaling, we will attempt to resolve this issue.

These studies use several mutant mouse models of IBD generated in our laboratory.  The information collected from this study will contribute to our understanding of IBD pathogenesis and in the long term could pave the way for novel treatments through intervention in the TLR and NOD2 systems.