Crohn's disease (CD) is a multifactorial disease thought to be caused by an abnormal inflammatory response directed against enteric bacteria in genetically susceptible individuals. More than 70 genes have been shown to regulate the susceptibility to CD. Genetic variation in the Nod2 gene is, of all genetic loci identified, the mot strongly associated with risk for developing CD. Nod2 is an intracellular pattern recognition receptor that is activated by muramyl dipeptide (MDP), a conserved motif in peptidoglycan, and upon activation induces inflammatory and anti-microbial molecules. Notably, CD-associated Nod2 variants display impaired recognition of MDP. The loss-of-function of Nod2 mutations and the requirement of homozygocity for Nod2 mutations to confer CD susceptibility suggest that defective intestinal immunity promotes disease. Nod2 mutations are associated with ileal, but not colonic, disease suggesting that Nod2 plays a critical role in the regulation of ileal immunity Nod2 is highly expressed in Paneth cells, a specialized cell population located in the crypts that produces anti-microbial peptides. In addition to their host defense role, Paneth cells regulate the intestinal microbiota through the luminal release of anti-microbial peptides. It has been suggested that in the presence of loss-of-function CD-associated Nod2 mutations, specific pathogenic bacteria and/or commensals with potential to induce pathology, or "pathosymbionts", accumulate leading to inappropriate inflammation. However, the ability of CD-associated Nod2 mutations to regulate host defense to enteric bacteria or commensals remains to be investigated. Using mice that harbor the common CD-associated Nod22939iCstop mutation, we propose to test the hypotheses including that Nod22939iCstop impairs Paneth cell function and the clearance of pathogenic bacteria and/or pathobionts leading to inappropriate increase of intestinal inflammation. In addition, we propose to use mutant mice harboring floxed Nod2 alleles to determine the cell- intrinsic role of Nod2 in the regulation of inflammatory responses and host defense against enteric pathogens. The proposed studies should lead to novel insight into the role of Nod2 and CD-associated Nod2 mutations in enteric inflammation and host defense.

Public Health Relevance

Crohn's disease (CD) is a common and debilitating inflammatory disease of the gastrointestinal tract caused by an inappropriate mucosal immune response to enteric bacteria in genetically susceptible individuals. A major CD susceptibility gene is Nod2. Three major Nod2 mutations, L1007fsinsC, R702W and G908R have been found to be associated with CD. However, the mechanisms by which mutant Nod2 confer increased susceptibility to CD remain poorly understood. In this grant application, we proposed studies to understand the role of CD-associated mutant and wild-type Nod2 in intestinal immunity and inflammatory disease.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK061707-12
Application #
8703076
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Carrington, Jill L
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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