Activation of Toll-like receptor (TLR signaling) by conserved microbial molecular signatures promotes the induction of both innate and adaptive immune responses. Such responses need to be kept under tight control. Immune responses that are delayed or of insufficient vigor can lead to a failure to control infection. On the other hand, excessive or inappropriate inflammation can be harmful or even fatal. The hyperinflammatory responses that characterize sepsis provide a paradigmatic example, as do the more localized inappropriate inflammatory processes associated with arthritis. In addition to signaling the presence of microbial products, the TLR pathway is also involved in signaling the presence of altered or damaged self. A variety of molecular patterns generated during tissue inflammation have been shown to signal through TLR4, the most robustly signaling of the TLRs. We recently discovered a novel endogenous inhibitor of TLR4 signaling in myeloid cells: the TLR4 homolog RP105. The central hypothesis underlying these studies is that RP105 acts to mute injurious tissue inflammatory responses through modulation of TLR4 signaling driven by endogenous ligands unmasked by tissue injury. The long-term goal of this research program is to define the molecular mechanisms that underlie dysregulation of tissue inflammatory responses in organ-specific autoimmune diseases such as the autoimmune arthritides. The studies in this proposal will employ genetic approaches to define the role of RP105 (and TLR4) in two well-defined mouse models of microbial productindependent, localized, inflammatory tissue injury: (1) sterile inflammation induced by oil of turpentine;and (2) antibody-induced arthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Center Core Grants (P30)
Project #
5P30AR047363-10
Application #
8098915
Study Section
Special Emphasis Panel (ZAR1)
Project Start
2010-07-01
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
10
Fiscal Year
2010
Total Cost
$85,625
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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