The pro- and anti-coagulant pathways are linked to cell signaling through protease-activated receptors (PARs). The inflammatory TF-dependent signaling through PAR1 or PAR2 in vivo is poorly understood. The proposed studies are based on our recent finding that TF cytoplasmic domain deleted mice exhibit deregulated PAR signaling, but the TF cytoplasmic domain has no apparent function in regulating TF's procoagulant activity. The identified imbalance in TF signaling exhibited by TF cytoplasmic domain deleted mice provides novel opportunities to define the role of TF-dependent signaling to inflammatory responses associated with activation of coagulation.
Aim 1 is to characterize the enhanced inflammatory response of TF cytoplasmic domain deleted mice, to evaluate the inflammatory exacerbation in lung and kidney, and to determine whether the enhanced inflammatory response results in increased lethality in experimental endotoxemia.
Aim 2 is to define the contributions of PAR1 and PAR2 signaling to the enhanced inflammatory response in these mice, using genetic crosses with PAR1 or PAR2 deficient animals. The hypothesis is tested that the gain of function phenotype of TF cytoplasmic domain deleted mice is ablated by deletion of PAR1 or PAR2. These experiments will define the in vivo relevant PAR(s) downstream of TF-dependent signaling in inflammation.
Aim 3 is to employ the generated genetic mouse models for primary cell isolation to characterize the role of PAR1 and PAR2 downstream of TF in vitro, followed by validation in inflammatory models in vivo. By comparing the TF response with thrombin signaling, these experiments will elucidate the differences between TF and thrombin signaling in vascular cells. A long-term goal is to develop novel diagnostic approaches to distinguish between upstream and downstream coagulation signaling. Identification of such markers will facilitate the quantitation of coagulation signaling in vivo and thus advance clinical efforts to design therapeutic intervention in coagulant cell signaling pathways .

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077753-02
Application #
6908126
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Link, Rebecca P
Project Start
2004-06-16
Project End
2008-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
2
Fiscal Year
2005
Total Cost
$422,325
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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