Scientific Abstract

Proposal No.   IBD-0091R
Principal Investigator:  Gabriel Nuñez, M.D.
Applicant Organization:  University of Michigan (Ann Arbor, U.S.A.)
Project Title:  Role of Nod2 in the control of Paneth cell function and intestinal microflora 
Period of Award:  May 1, 2004 - May 31, 2006

Crohn’s disease (CD) is a chronic and debilitating disease affecting more than 500,000 individuals in the United States and millions worldwide.  Both environmental (particularly intestinal bacteria) and genetic factors are known to play a critical role in the development of CD.

Recent studies have revealed that genetic variation in NOD2 is associated with susceptibility to CD.  NOD2 is an intracellular protein that recognizes muramyl dipeptide (MDP), a conserved motif in peptidoglycan (PGN), and activates a host defense pathway against bacteria.  Homozygosity or compound heterozygosity for NOD2 mutations increases the risk 20-40-fold, while heterozygosity leads to minimal increase in risk, indicating that loss of NOD2 function is important for disease development.  Consistent with the genetic observations, all three CD-associated NOD2 mutations result in proteins that are deficient in inducing NF-κB activation in response to bacterial components including PGN and MDP.  The ability of NOD2 to activate NF-κB in response to bacteria suggests that defective sensing of intestinal bacteria somehow promotes susceptibility to disease.  However, many questions remain, including how NOD2 mutations contribute to CD and why NOD2 mutations are associated with ileal disease.

Surprisingly, we find that NOD2 is expressed in Paneth cells, which are specialized intestinal cells located at the base of the crypts of Liberkühn in the small intestine.  Paneth cells secrete antimicrobial peptides and have been implicated in the host defense against pathogenic bacteria and maintenance of the resident microbiota in the gut.  We propose to explore the hypothesis that NOD2 controls the antimicrobial function of Paneth cells and the maintenance of the resident intestinal microflora.  These studies may provide critical insight into the function NOD2 at intestinal sites and into the mechanism by which NOD2 mutations are associated with ileal inflammation in CD.