Grants and Contracts Details
Description
Innate and acquired immune responses in the intestine must promote homeostasis in the presence of large
numbers of commensal microorganisms, while maintaining the capacity to defend the body against invasive
pathogens. The adult human intestinal tract is inhabited by 100 trillion microorganisms, 10 times more than the
number of human cells in the entire body. Commensal bacteria provide multiple benefits to the host, including
processing of essential nutrients, regulation of energy balance, protection against pathogens and maintenance
of epithelial integrity. However, inappropriate immune responses to colonic bacteria can lead to chronic
inflammatory bowel disease and life-threatening colitis. Host cells recognize microorganisms through pattern
recognition molecules including Toll-like receptors (TLRs), which bind microbial cell wall constituents, nucleic
acids and other byproducts. MyD88 is a cytoplasmic adaptor protein that transduces signals emanating from
most TLRs, as well as members of the IL-1R family. Recent studies have demonstrated that mice genetically
deficient in MyD88 expression are more sensitive to experimental colitis than are wild-type mice, suggesting a
key role for TLR and/or IL-1R signaling in regulation of intestinal inflammation. Our preliminary data
demonstrate that MyD88-deficient mice have severely depressed expression of the polymeric immunoglobulin
receptor (plgR), a key anti-inflammatory molecule that mediates epithelial transport of protective IgA
antibodies. Recent work by others has demonstrated that plgR-deficient mice are, like MyD88-deficient mice,
particularly sensitive to chemically-induced colitis. The goal of the proposed research is to generate novel
mouse models for studying epithelial-specific MyD88 signaling within the intact intestine. Specifically, we will
test the hypothesis that expression of MyD88 by epithelial cells is crucial for regulation of plgR gene
expression and protection against experimental colitis. We propose to generate novel chimeric and transgenic
mouse models in which MyD88 expression is restricted to epithelial cells or bone marrow-derived cells. We
will test the clinical and molecular responses of these mice to inflammatory stimuli in a model of experimental
colitis. These experiments should increase our knowledge of epithelial-specific MyD88 signaling, as well as
cross-talk between epithelial and immune cells, which is key to the identification of normal and dysregulated
responses to colonic bacteria.
Status | Finished |
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Effective start/end date | 9/30/07 → 8/31/10 |
Funding
- National Institute of Allergy and Infectious Diseases: $398,700.00
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