Title |
Innate signaling pathways in colitis and colorectal tumorigenesis
|
Institution |
ST. JUDE CHILDREN'S RESEARCH HOSPITAL, MEMPHIS, TN
|
Principal Investigator |
KANNEGANTI, THIRUMALA-DEVI
|
NCI Program Director |
Daschner
|
Cancer Activity |
Cancer Etiology
|
Division |
DCB
|
Funded Amount |
$426,313
|
Project Dates |
07/09/2012 - 04/30/2022
|
Fiscal Year |
2018
|
Project Type |
Grant
|
Research Topics w/ Percent Relevance |
Cancer Types w/ Percent Relevance |
Cancer (100.0%)
Autoimmune Diseases (100.0%)
Digestive Diseases (100.0%)
Inflammatory Bowel Disease (100.0%)
|
Colon/Rectum (100.0%)
|
Research Type |
Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors
|
Abstract |
? DESCRIPTION (provided by applicant): 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. " |