DESCRIPTION (provided by applicant): The intestinal epithelium and gut-associated mucosal immune system must on the one (1) hand generate an inflammatory response to pathogenic bacteria while actively limiting inflammation to commensal organisms. Inflammatory bowel disease (IBD) develops in the genetically-susceptible host following a triggering event. The first gene to be identified as a disease-susceptibility gene in Crohn's disease is CARD15/NOD2, an intracellular pathogen-recognition receptor (PRR). Crohn's disease-associated polymorphisms in the CARD15/NOD2 gene result in a protein that is impaired in its ability to activate NF-kB in response to peptidoglycan. This data suggests that a defect in the innate immune response to commensal or pathogenic bacteria may culminate in chronic intestinal inflammation. Toll-like receptors (TLRs) are also PRRs. Binding of PAMPs to their respective TLRs results in NF-kB activation and clearance of bacteria. TLR4 is the receptor for lipopolysaccharide (LPS) present on Gram-negative bacteria. This application emanates from our surprising preliminary observation that mice with a null mutation in TLR4 (TLR4-/-) have increased clinical symptoms of colitis following administration of dextran sodium sulfate, a paucity of neutrophilic infiltration, and increased bacterial translocation. Similar results were observed in MyD88-/- mice suggesting this is the dominant pathway downstream of TLR4 accounting for this phenotype. Based on our preliminary data, we wish to test the hypothesis that signaling through TLR4 is required for the generation of an acute inflammatory response to intestinal injury and limiting the development of chronic intestinal inflammation. We will use the support from this R21 to generate robust animal models that establish the requirement for TLR4 in the initiation and perpetuation of intestinal inflammation.
|Effective start/end date||6/1/05 → 5/31/07|
- National Institutes of Health: $165,517.00
- National Institutes of Health: $169,500.00
Toll-Like Receptor 4
Inflammatory Bowel Diseases