Scientific Abstract

Proposal No.   IBD-0003R
Principal Investigator:  Geoffrey W. Krissansen, Ph.D.
Applicant Organization:  University of Auckland (New Zealand)
Project Title:  Pattern recognition receptors as potential susceptibility loci for Crohn's disease
Period of Award:  November 1, 2002 – March 31, 2005

Crohn’s disease (CD) is a chronic inflammatory bowel disease affecting approximately one in 1000 people in western countries.  The immune system attacks the digestive tract, causing inflammation, fibrostenotic lesions, fistula formation, and sometimes perforation of tissues.  The prevailing theory is that the immune system’s response to bacteria in genetically susceptible individuals becomes dysregulated.

Recent research identified a gene that was mutated in ~15% of Crohn’s patients.  The gene mapped to a CD susceptibility locus on chromosome 16, and encoded the NOD2 protein.  NOD2 is an intracellular protein expressed in monocytes, which helps the innate immune system recognize and respond to bacterial lipopolysaccharide (LPS).  It transduces signals that activate proinflammatory genes.  Mutated NOD2 is less responsive to bacterial LPS, but displays slightly higher constitutive activity, suggesting the innate immune response in Crohn’s patients is impaired.  NOD2 is but one of several “pattern recognition receptors” (PRRs) that link the innate immune response to microbial products.

Here, we aim to determine:  a) whether other PRR genes are CD susceptibility loci, b) how NOD2 mutation affects the functions of monocytes, and c) whether over-expressed wild-type NOD2 can restore NOD2 function to Crohn’s patients’ monocytes.