Lay Summary

Proposal No. IBD-0246

Principal Investigator: Herbert W. Virgin, M.D., Ph.D.

Applicant Organization: Washington University (St. Louis, Missouri, U.S.A.)

Project Title: In vivo function of Crohn’s disease susceptibility gene ATG16L1 in intestinal inflammation

Period of Award: September 1, 2008 – February 28, 2011

 

Recently, several groups have discovered that individuals carrying a mutation in the gene ATG16L1 are at an increased risk in developing Crohn’s disease. In yeast, a gene that is similar to mammalian ATG16L1 is involved in autophagy, a process by which cells regulate their inner environment through recycling of cellular components. Interestingly, autophagy has been shown to be important in helping our immune system control pathogens such as viruses and bacteria. Since bacteria living in our intestines are thought to trigger Crohn’s disease, some researchers believe that people who have a mutation in ATG16L1 have an autophagy defect which makes it difficult to control the bacteria. However, the role of ATG16L1 in mammalian autophagy has not been carefully examined, and there remain many questions on how pathogens in our intestines contribute to Crohn’s disease.

 

To address these problems, we have created mice that contain mutations in the ATG16L1 gene. Remarkably, these mice develop abnormalities in the same part of the intestine as patients with Crohn’s disease who have the ATG16L1 mutation. Specifically, there is a striking defect in Paneth cells, cells that pump antimicrobial factors into the small intestine. In addition, we are finding that autophagy is defective in these mice providing evidence that ATG16L1 is an autophagy gene in mammals and not just yeast. These exciting observations raise very important questions. Why does a mutation in ATG16L1 lead to an intestinal Paneth cell defect? Are pathogens responsible for this abnormality? What role, if any, does autophagy play in keeping our intestines safe? By answering these questions, we will provide essential information on Crohn’s disease progression with the goal of developing novel therapeutic strategies.