Activation of Toll-like receptor (TLR signaling) by conserved microbial molecular signatures promotes theinduction of both innate and adaptive immune responses. Such responses need to be kept under tightcontrol. 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 hyperinflammatoryresponses that characterize sepsis provide a paradigmatic example, as do the more localizedinappropriate inflammatory processes associated with arthritis. In addition to signaling the presence ofmicrobial 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 throughTLR4, the most robustly signaling of the TLRs.We recently discovered a novel endogenous inhibitor of TLR4 signaling in myeloid cells: the TLR4homolog RP105. The central hypothesis underlying these studies is that RP105 acts to mute injurioustissue inflammatory responses through modulation of TLR4 signaling driven by endogenous ligandsunmasked by tissue injury. The long-term goal of this research program is to define the molecularmechanisms that underlie dysregulation of tissue inflammatory responses in organ-specific autoimmunediseases such as the autoimmune arthritides. The studies in this proposal will employ genetic approachesto 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 #
2P30AR047363-06
Application #
7133613
Study Section
Special Emphasis Panel (ZAR1-EHB-D (O1))
Project Start
2006-03-01
Project End
2009-02-28
Budget Start
2006-03-01
Budget End
2007-06-30
Support Year
6
Fiscal Year
2006
Total Cost
$74,500
Indirect Cost
Name
Children's Hospital Med Ctr (Cincinnati)
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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