Crohn disease (CD) is a complex disease involving both genetic and environmental factors. We propose that a specific form of CD can be defined based on Paneth cell function. Of the 150 susceptibility alleles that are associated with this disease, we have previously identified two genes with coding mutations that are associated with abnormal Paneth cell function. These genes are NOD2 and ATG16L1, which have previously been proposed to be functionally linked in other cell types. Our previous work studying the role of Atg16L1 in mouse and mutations in ATG16L1 in CD patients has shown that Paneth cells are targeted by loss of function of this gene and that specific microbes could trigger this defect. We have developed new tools to evaluate the role of environmental triggers including the ability to robustly culture primary intestinal epithelial cells from endoscopic biopsies. The data generated the current proposal and we now propose to utilize the substantial resources of the NIDDK IBD Genetics Research Consortium. In three aims, we will 1) Define a pathway(s) driven by additional CD susceptibility alleles that drive Paneth cell malfunction, 2) Determine the environmental trigger of ATG16L1 T300A and 3) Determine if Paneth cell phenotypes are durable or require constant stimulation. If successful, this project should define a subtype of Crohn's disease and provide biomarkers in the stool and tissue and eventually novel therapeutic targets.

Public Health Relevance

The goal of this project is to determine a novel subtype of Crohn's disease based on the effects of genetics and microbial factors on Paneth cells. The findings from these studies should impact our understanding of the pathogenesis of inflammatory bowel disease. In the longer term, we propose that these studies will provide the basis to define a subtype of Crohn disease and will allow the development of novel therapeutics that target Paneth cell function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56DK095820-01A1
Application #
9131861
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (O4))
Program Officer
Karp, Robert W
Project Start
2015-09-15
Project End
2016-08-31
Budget Start
2015-09-15
Budget End
2016-08-31
Support Year
1
Fiscal Year
2015
Total Cost
$412,500
Indirect Cost
$78,750
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Šimurina, Mirna; de Haan, Noortje; Vu?kovi?, Frano et al. (2018) Glycosylation of Immunoglobulin G Associates With Clinical Features of Inflammatory Bowel Diseases. Gastroenterology 154:1320-1333.e10
Liu, Ta-Chiang; Naito, Takeo; Liu, Zhenqiu et al. (2017) LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn's disease patients. JCI Insight 2:e91917
Liu, Ta-Chiang; Stappenbeck, Thaddeus S (2016) Genetics and Pathogenesis of Inflammatory Bowel Disease. Annu Rev Pathol 11:127-48