Tissue factor (TF) driven disseminated intravascular coagulation is a hallmark of diverse systemic inflammatory response syndromes associated with bacterial sepsis and viral hemorrhagic fevers. In the previous funding period of this grant, we have used a mouse model of severe endotoxemia to define the roles of coagulation proteases and protease activated receptors (PARs) in regulating severe systemic inflammation leading to lethality. We identified the lymphatic system as the unexpected location for the coagulation-inflammation crosstalk and the dendritic cell (DC) as both the target of coagulation protease signaling and the origin for late stage dissemination of coagulation. We assigned pro-inflammatory roles to thrombin-PAR1 signaling and our preliminary data indicate that upstream TF-PAR2 signaling regulates systemic inflammation and improves survival. In this competing continuation application, we propose to address new questions in this research with the overall goal to further define the regulatory network that is controlled by DC TF signaling.
Aim 1 is to define cellular sources and locations of coagulation activation in progressive systemic inflammation. Here we address the novel concept that disseminated intravascular coagulation is initiated by activated DCs in the lymphatic system.
Aim 2 is to analyze the role of TF in regulating the function of interleukin 10-producing DCs and to define locations where TF signaling controls systemic inflammation.
Aim 3 is to characterize protective pathways downstream of TF-PAR2 signaling with particular emphasis on the role of interleukin 6 and potential collaborations of TF signaling with regulatory T cell networks. Together, these experiments promise to uncover currently incompletely defined pathways that switch DCs between inflammatory and suppressive activity and will advance our understanding of how TF signaling regulates innate immune responses.

Public Health Relevance

Elucidation of these regulatory pathways will have broad implications for new therapeutic approaches to interfere with deregulated innate immune response. Specifically, understanding the role of TF and coagulation signaling in the amplification and control of inflammation will advance the rational use of coagulation inhibitors and PAR antagonists for attenuation of systemic inflammatory response syndromes. In depth knowledge of these regulatory pathways of the coagulation cascade will enable therapeutic approaches that do not impair crucial protective mechanisms in various stages of the host response that copes with infectious organisms.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077753-06
Application #
7666104
Study Section
Special Emphasis Panel (ZRG1-HEME-D (03))
Program Officer
Kindzelski, Andrei L
Project Start
2004-06-16
Project End
2012-05-31
Budget Start
2009-08-01
Budget End
2010-05-31
Support Year
6
Fiscal Year
2009
Total Cost
$473,750
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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Wang, Jing; Chakrabarty, Sagarika; Bui, Quyen et al. (2015) Hematopoietic tissue factor-protease-activated receptor 2 signaling promotes hepatic inflammation and contributes to pathways of gluconeogenesis and steatosis in obese mice. Am J Pathol 185:524-35
Samad, Fahumiya; Ruf, Wolfram (2013) Inflammation, obesity, and thrombosis. Blood 122:3415-22
Reinhardt, Christoph; Bergentall, Mattias; Greiner, Thomas U et al. (2012) Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling. Nature 483:627-31
Rothmeier, Andrea S; Ruf, Wolfram (2012) Protease-activated receptor 2 signaling in inflammation. Semin Immunopathol 34:133-49
Ruf, W; Disse, J; Carneiro-Lobo, T C et al. (2011) Tissue factor and cell signalling in cancer progression and thrombosis. J Thromb Haemost 9 Suppl 1:306-15
Disse, Jennifer; Petersen, Helle Heibroch; Larsen, Katrine S et al. (2011) The endothelial protein C receptor supports tissue factor ternary coagulation initiation complex signaling through protease-activated receptors. J Biol Chem 286:5756-67
Disse, J; Ruf, W (2011) Endothelial protein C receptor is required for tissue factor ternary complex signaling in the mouse. J Thromb Haemost 9:2516-8

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