Lay Summary

Proposal No.  IBD-0132R
Principal Investigator:  Jean-Pierre Hugot, M.D., Ph.D.
Applicant Organization:  Naturalia et Biologia (Paris, France)
Project Title:  Identification and genetic analysis of the genes coding for CARD15 interacting proteins
Period of Award:  February 1, 2005 – October 31, 2006

Inflammatory bowel diseases (IBD) are complex genetic disorders resulting from the interaction between genes and environmental factors.  Just a few of these predisposing factors have been characterized today.  From the genetic point of view, CARD15/NOD2 is the best known IBD susceptibility gene.  This gene plays a role in Crohn’s disease (CD) where it explains about 20% of the genetic predisposition to the disease.  It is thus expected that additional genes are involved in the susceptibility to IBD.  Some of them have been located throughout the genome, but they remain to be identified.  In order to find new IBD genes, we logically postulate that at least some of them have a functional relationship with CARD15/NOD2.

The CARD15/NOD2 protein defines a specific pathway by which bacterial components are able to induce an inflammation in its host.  CARD15/NOD2 mutations associated with CD are characterized by a defect of this pathway:  bacteria are not able to induce a response by the innate immunity system.  Considering that IBD is characterized by a chronic inflammation, there is an apparent paradox that requires further studies.  However, little is known today on the CARD15/NOD2 pathway.  Therefore, defining the proteins that interact with CARD15/NOD2 in vivo will clearly represent a big step forward to shed light on CARD15/NOD2 function and IBD mechanism.

To answer these two questions, we have developed a yeast two hybrid (Y2H) procedure.  By employing this method, we have identified 14 new proteins interacting with CARD15/NOD2.  Our aim now is to further study their function in relation to CARD15/NOD2 and to test their coding genes as new candidate for IBD predisposition.

We will develop a combined approach including functional and genetic experiments.  The functional studies will help to define the effect of the newly identified protein on the normal and mutated CARD15/NOD2 proteins.  The genetic studies will take advantage of an already recruited cohort of more than 1000 European families.  Altogether these studies will test the hypothesis that at least some of the genes coding for the CARD15/NOD2 interacting proteins are involved in the genetic predisposition to IBD.

This work will thus help to improve our understanding of the genetic predisposition to IBD and disease mechanisms.  It will contribute to both diagnostic and therapeutic development in IBD.