A key problem in genetics is determining how common alleles contribute to human diseases that afflict but a few. Herein we address this by analyzing a unique new experimental model in which virus infection or treatment with dsRNA triggers Crohn's disease-like phenotypes in mice carrying a mutation in the Crohn's disease susceptibility-linked autophagy gene Atg16L1. Susceptibility to Crohn's disease, an inflammatory disease involving the ileum, is controlled in part by a T300A mutation in ATG16L1, a gene homologous to the essential yeast autophagy gene ATG16. We showed that murine Atg16L1 is an autophagy protein and found that mice that express low levels of Atg16L1 protein (hypomorphic, Atg16L1HM) have a striking abnormality of ileal epithelial Paneth cells including abnormal secretion of granules containing anti-microbial peptides1. Paneth cells regulate intestinal bacteria via secretion of granule contents. Crohn's disease patients homozygous for the T300A ATG16L1 mutation displayed the same Paneth cell abnormalities1. Thus we have developed a new mouse model relevant to the pathogenesis of an important human disease. The founding observation for this proposal is our discovery that Atg16L1HM mice rederived into our best barrier facility lack these Paneth cell abnormalities. Remarkably, infection with murine norovirus (MNV), murine cytomegalovirus (MCMV), or simply treatment with dsRNA triggers, only in Atg16L1HM mice, Crohn's disease-like Paneth cell granule abnormalities and also heightened susceptibility to intestinal inflammation and ileal atrophy/villus blunting in response to feeding dextran sodium sulfate (DSS). DSS is a commonly used trigger for intestinal pathology in mouse models of inflammatory bowel disease. These surprising observations set the stage for us to define pathogenetic mechanisms by which a common variant of a disease susceptibility gene (in this case Atg16L1) can interact with environmental factors (in this case virus infection/dsRNA and chemical damaging agents) to foster disease through the following Aims:
Aim 1. Test the hypothesis that Atg16L1 mutation in Paneth cells or macrophages generates infection/dsRNA-triggered Paneth cell defects and heightened susceptibility to DSS- induced pathology.
Aim 2. Define the mechanism(s) by which infection/dsRNA triggers Atg16L1-dependent Paneth cell defects and heightened susceptibility to DSS-induced pathology. 1. Cadwell,K. et al. A key role for autophagy and the autophagy gene Atg16L1 in mouse and human intestinal Paneth cells. Nature 456, 259-263 (2008).
A key problem in genetics is determining how diseases susceptibility alleles contribute to disease. Crohn's disease is a common inflammatory bowel disease that afflicts an increasing number of people in the developed world. Herein we define mechanisms related to Crohn's disease by analyzing a new experimental model in which virus infection or treatment with dsRNA triggers Crohn's disease-like phenotypes in mice carrying a mutation in the Crohn's disease susceptibility-linked autophagy gene Atg16L1.
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