The idiopathic inflammatory bowel diseases (IBD) which includes Crohn's disease and ulcerative colitis are chronic disorders of the gastrointestinal tract of unknown etiology with a combined prevalence of about 150-200 cases per 100,000 in western countries. Although the etiology of IBD is unknown, a large body of evidence suggest that these diseases are multifactorial and likely caused by an abnormal inflammatory response directed against luminal and/or enteric microflora in a genetically susceptible host. However, the genetic basis for this abnormal inflammatory response to enteric bacteria is unknown. Genome-wide searches for IBD-susceptibility genes have resulted in the identification of several loci harboring potential predisposing genes for Crohn's disease. Of these, linkage to the pericentromeric region of chromosome 16 (IBD1 locus) has been replicated by several independent studies to confer susceptibility to disease. We have identified Nod2, a gene that encodes a protein with homology to plant disease resistance gene products, that is located in the peak region of linkage disequilibrium on chromosome 16. We have found that a frameshift mutation and genetic variants of Nod2 are highly associated with susceptibility to Crohn's disease by genetic analysis in multi-case disease families and case-control studies. Nod2 is expressed in monocytes and activates NF- kappaB. Significantly, wild- type Nod2 confers responsiveness to bacterial lipopolysaccharides and this activity is deficient in mutant-Nod2 associated with Crohn's disease. These observations suggest a link between an innate immunity pathway controlled : byNod2 and susceptibility to Crohn's disesase. Our overall hypothesis is that Nod2 recognizes lipopolysaccharidesin the cytosol and activates a NF-kappaB signaling pathway in the host cell that protects the host against entericbacteria. Our preliminary results suggest a model in which deficiency in the Nod2 pathway leads to an abnormal T cell-mediated response to enteric bacteria and tissue destruction. We propose three Specific Aims to explore our hypothesis: (i) Determine the sequence of Nod2 that mediates functional activity and - -recognition of bacterial LPS. The analyses will include study of Nod2 variants associated with Crohn's disease and systematic mutagenesis of Nod2; (ii) Determine the structure of LPS recognized by Nod2 and (iii) Characterize mice deficient in Nod2 to determine its role in the response to luminal and pathogenic enteric bacteria. The proposed studies should improve our understanding of the role of Nod2 in innate immunity and provide-important insight into the link between genetic variation in Nod2 and susceptibility to Crohn's disease. The studies may lead to novel therapeutic approaches for Crohn's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061707-05
Application #
7009624
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Karp, Robert W
Project Start
2002-04-08
Project End
2007-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
5
Fiscal Year
2006
Total Cost
$294,903
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Núñez, Gabriel; Sakamoto, Kei; Soares, Miguel P (2018) Innate Nutritional Immunity. J Immunol 201:11-18
Werner, Jessica L; Escolero, Sylvia G; Hewlett, Jeff T et al. (2017) Induction of Pulmonary Granuloma Formation by Propionibacterium acnes Is Regulated by MyD88 and Nox2. Am J Respir Cell Mol Biol 56:121-130
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Kim, Donghyun; Zeng, Melody Y; Núñez, Gabriel (2017) The interplay between host immune cells and gut microbiota in chronic inflammatory diseases. Exp Mol Med 49:e339
Kim, Donghyun; Seo, Sang-Uk; Zeng, Melody Y et al. (2017) Mesenchymal Cell-Specific MyD88 Signaling Promotes Systemic Dissemination of Salmonella Typhimurium via Inflammatory Monocytes. J Immunol 199:1362-1371
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Kim, Donghyun; Kim, Yun-Gi; Seo, Sang-Uk et al. (2016) Nod2-mediated recognition of the microbiota is critical for mucosal adjuvant activity of cholera toxin. Nat Med 22:524-30
Caruso, Roberta; Núñez, Gabriel (2016) Innate Immunity: ER Stress Recruits NOD1 and NOD2 for Delivery of Inflammation. Curr Biol 26:R508-R511
Burberry, Aaron; Zeng, Melody Y; Ding, Lei et al. (2014) Infection mobilizes hematopoietic stem cells through cooperative NOD-like receptor and Toll-like receptor signaling. Cell Host Microbe 15:779-91

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