Inflammatory bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC) constitute a major health problem in developed countries. Moreover, IBD predisposes to the development of colorectal cancer. Although the precise etiology of CD and UC remains unclear, aberrant immune responses against commensal microflora are widely thought to underlie IBD. Multiple receptors of the extracellular interleukin (IL) receptor and Toll-like receptor (TLR) families are expressed on epithelial and immune cells in the gastro-intestinal tract and have been implicated in IBD. More recently, single nucleotide polymorphisms (SNPs) in the genes encoding the NOD-like receptor (NLR) family members Nod2 and Nlrp3 were linked to CD susceptibility. Peptidoglycan fragments from bacteria activate Nod2, which triggers recruitment of the adaptor protein Rip2 resulting in K63- linked ubiquitylation and activation of NF-?B and MAP kinase signaling cascades. Our studies show that both Nod2 and Rip2 are critical regulators preventing destructive inflammatory immune responses in the intestinal inflammation and colorectal tumorigenesis. However, although Rip2 is downstream of Nod2 in activating NF-kB pathway, surprisingly, our findings indicate previously undefined and divergent roles for Nod2 and Rip2. Altogether, the major goals of this proposal are to mechanistically define the molecular basis underlying regulation of intestinal immune response to colitis-associated colorectal tumorigenesis by Nod2 and Rip2 signaling. The proposed studies give insight into the key overlapping and non-overlapping molecular mechanisms by which NLR/Nod2/Rip2 participate in IBD and colorectal tumorigenesis and create new therapeutic options for devastating inflammatory diseases.

Public Health Relevance

Innate immune system has been suggested to mediate the development of intestinal inflammation and carcinogenesis. Nonetheless, the role of distinct innate immune signaling pathways in the development of inflammation and colorectal tumorigenesis is yet to be unraveled. The proposed studies will contribute to our insight into the key molecular mechanisms by which Nod2 and Rip2 participate in IBD and colorectal tumorigenesis and create new therapeutic options for devastating inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA163507-03
Application #
8658700
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Daschner, Phillip J
Project Start
2012-07-09
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
City
Memphis
State
TN
Country
United States
Zip Code
38105
Kesavardhana, Sannula; Kanneganti, Thirumala-Devi (2017) Mechanisms governing inflammasome activation, assembly and pyroptosis induction. Int Immunol 29:201-210
Qi, X; Gurung, P; Malireddi, R K S et al. (2017) Critical role of caspase-8-mediated IL-1 signaling in promoting Th2 responses during asthma pathogenesis. Mucosal Immunol 10:128-138
Man, Si Ming; Place, David E; Kuriakose, Teneema et al. (2017) Interferon-inducible guanylate-binding proteins at the interface of cell-autonomous immunity and inflammasome activation. J Leukoc Biol 101:143-150
Lupfer, Christopher R; Stokes, Kate L; Kuriakose, Teneema et al. (2017) Deficiency of the NOD-Like Receptor NLRC5 Results in Decreased CD8+ T Cell Function and Impaired Viral Clearance. J Virol 91:
Sharma, Deepika; Kanneganti, Thirumala-Devi (2017) Inflammatory cell death in intestinal pathologies. Immunol Rev 280:57-73
Zhu, Qifan; Kanneganti, Thirumala-Devi (2017) Cutting Edge: Distinct Regulatory Mechanisms Control Proinflammatory Cytokines IL-18 and IL-1?. J Immunol 198:4210-4215
Gurung, Prajwal; Fan, Gaofeng; Lukens, John R et al. (2017) Tyrosine Kinase SYK Licenses MyD88 Adaptor Protein to Instigate IL-1?-Mediated Inflammatory Disease. Immunity 46:635-648
Gresnigt, Mark S; Jaeger, Martin; Subbarao Malireddi, R K et al. (2017) The Absence of NOD1 Enhances Killing of Aspergillus fumigatus Through Modulation of Dectin-1 Expression. Front Immunol 8:1777
Sharma, Deepika; Sharma, Bhesh Raj; Vogel, Peter et al. (2017) IL-1? and Caspase-1 Drive Autoinflammatory Disease Independently of IL-1? or Caspase-8 in a Mouse Model of Familial Mediterranean Fever. Am J Pathol 187:236-244
Man, Si Ming; Karki, Rajendra; Kanneganti, Thirumala-Devi (2017) Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev 277:61-75

Showing the most recent 10 out of 63 publications