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 patients to the development of colorectal cancer. Although the precise etiology of CD and UC remains unclear, aberrant immune responses against commensal microbiota are widely thought to underlie the pathogenesis of IBD. Multiple receptors of the Toll- like receptors (TLR), Nod-like receptors (NLRs) and cytosolic DNA sensors families are expressed on epithelial and immune cells in the gastrointestinal tract and have been implicated in IBD and colorectal cancer. Research studies by our lab and others have shown an important role for NLRs and cytosolic DNA sensors in the prevention of tumorigenesis. Type I interferon signaling can be activated by one or more these receptors. Importantly, single nucleotide polymorphisms (SNPs) in the genes encoding NLRs, cytosolic DNA sensors and molecules of the interferon-signaling pathway are linked to susceptibility to colorectal cancer. However, the downstream effector mechanisms governed by type I interferons that mediate this protection are not well understood. In this proposal, we show that interferon regulatory factor 1 (IRF1), which is induced in response to type I interferon signaling, is critical for preventing destructive inflammatory immune responses and associated tumorigenesis in the intestine. The major goal of this proposal is to mechanistically define the cellular and molecular basis underlying regulation of colitis and colorectal tumorigenesis by IRF1. The proposed studies will generate new therapeutic options for these devastating inflammatory diseases.

Public Health Relevance

The innate immune family members are associated with high risk for developing Crohn's disease and colorectal cancer. Nonetheless, the role of distinct signaling pathways mediated by innate immune receptors in the development of inflammation and colorectal tumorigenesis has not been unraveled. The proposed studies will contribute to our insight into the key molecular mechanisms by which innate signaling pathways and IRF1 participate in IBD and colorectal tumorigenesis and create new therapeutic options for devastating inflammatory diseases.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Daschner, Phillip J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
St. Jude Children's Research Hospital
United States
Zip Code
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