Lay Summary

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 variation in the gene NOD2 is associated with susceptibility to CD.  NOD2 is thought to be part of a defense mechanism against certain bacteria involved in CD.  NOD2 mutation results in faulty recognition of bacteria.  Thus, defective sensing of bacteria in CD patients with mutant NOD2 may trigger inflammation in the gut.  However, many questions remain, including how NOD2 mutations contribute to CD.

Surprisingly, we find that NOD2 is expressed in Paneth cells, which are specialized intestinal cells located at the base of the cellular lining of the small intestine, a site frequently involved in disease.  Paneth cells secrete molecules against bacteria and appear to be involved in the defense against intestinal bacteria.  We propose to explore the hypothesis that NOD2 controls the antimicrobial function of Paneth cells and the bacteria normally present in the gut.  These studies may provide critical insight into the function NOD2 at intestinal sites and into the mechanism by which NOD2 mutations increase the susceptibility to CD.