Scientific Abstract

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 genome wide association studies have shown that a specific polymorphism in the autophagy gene ATG16L1 increases susceptibility to ileal Crohn’s disease (CD). Autophagy is an evolutionarily conserved process by which cytoplasmic components are degraded to maintain cellular homeostasis. The autophagy pathway has been implicated in lymphocyte development, immune function, and in intracellular pathogen clearance, and thus, it has been suggested that ATG16L1’s potential role in autophagy-mediated pathogen response is critical to CD progression. However, the role of ATG16L1 in mammalian autophagy is unclear, and the human genetic studies do not address the mechanism by which mutation in ATG16L1 contributes to disease progression.

To address these concerns, we have established two mouse lines that contain distinct mutations within the mouse Atg16L1 locus. Remarkably, these mice demonstrate an abnormality in the ileum shared with patients with CD. Atg16L1 protein expression is severely reduced in these mice, and the induction of autophagy is abnormal. Importantly, intestinal tissue from both mouse lines displays abnormal histopathology. There is a severe defect in Paneth cells and the number of granules containing anti-microbial peptides, a feature that we are now finding in CD patients that have the ATG16L1 polymorphism. To date, there is no model organism that mimics this aspect of human CD. Moreover, this intestinal abnormality was completely cleared when the mice were re-derived in a separate barrier facility free of mouse pathogens suggesting that there is an infectious disease component to the pathology.

In this proposal, we describe three major objectives. First, we will determine the relevance of an autophagy defect to the intestinal pathology and CD. Second, we will identify the infectious disease component and determine the mechanism of the pathology. Finally, we will apply our observations to human tissues and thereby provide essential information on CD progression with the goal of developing novel therapeutic strategies.