Abstract

LPS-induced coagulation and inflammation are important components of the pathogenesis of bacterial sepsis. In the United States, sepsis is the leading cause of death in non-coronary intensive care units. The objective of this proposal is to determine the role of the PI3K-Akt signaling pathway in suppressing LPS- induced coagulation and inflammation. The overall hypothesis is that the PI3K-Akt pathway negatively regulates LPS-induced coagulation and inflammation.
Specific Aim 1 will characterize the role of PI3K-Akt pathway activation in LPS-induced cytokine and tissue factor production by macrophages. We will employ a genetic approach that either increases (PTEN-/-) or decreases (p85alpha-/-) PI3K-Akt pathway activation.
Specific Aim 2 will evaluate whether the inhibitory effect of simvastatin on LPS-induced coagulation and inflammation involves activation of PI3K-Akt signaling. We hypothesize that wortmannin, a PI3K inhibitor, will block the anti-inflammatory and anticoagulant effects of simvastatin in LPS-treated macrophages and in a mouse endotoxemia model. Ultimately, characterization of the involvement of this pathway in LPS-induced inflammation may allow for development of novel strategies that can be used to treat sepsis. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HL085983-01
Application #
7155143
Study Section
Special Emphasis Panel (ZRG1-F10-H (20))
Program Officer
Meadows, Tawanna
Project Start
2006-09-01
Project End
2007-06-04
Budget Start
2006-09-01
Budget End
2007-06-04
Support Year
1
Fiscal Year
2006
Total Cost
$36,664
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Luyendyk, James P; Schabbauer, Gernot A; Tencati, Michael et al. (2008) Genetic analysis of the role of the PI3K-Akt pathway in lipopolysaccharide-induced cytokine and tissue factor gene expression in monocytes/macrophages. J Immunol 180:4218-26
Kidd, Linda B; Schabbauer, Gernot A; Luyendyk, James P et al. (2008) Insulin activation of the phosphatidylinositol 3-kinase/protein kinase B (Akt) pathway reduces lipopolysaccharide-induced inflammation in mice. J Pharmacol Exp Ther 326:348-53
Ganey, Patricia E; Luyendyk, James P; Newport, Sandra W et al. (2007) Role of the coagulation system in acetaminophen-induced hepatotoxicity in mice. Hepatology 46:1177-86
Luyendyk, James P; Piper, J Daniel; Tencati, Michael et al. (2007) A novel class of antioxidants inhibit LPS induction of tissue factor by selective inhibition of the activation of ASK1 and MAP kinases. Arterioscler Thromb Vasc Biol 27:1857-63