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.
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.
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