PI3K in LPS-induced coagulation and inflammation

描述（由申请人提供）：lps诱导的凝血和炎症是细菌性败血症发病机制的重要组成部分。在美国，败血症是非冠状动脉重症监护病房死亡的主要原因。本提案的目的是确定PI3K-Akt信号通路在抑制LPS诱导的凝血和炎症中的作用。总体假设是PI3K-Akt通路负调控lps诱导的凝血和炎症。特异性Aim 1将描述PI3K-Akt通路激活在lps诱导的巨噬细胞产生细胞因子和组织因子中的作用。我们将采用增加（PTEN-/-）或减少（p85alpha-/-） PI3K-Akt通路激活的遗传方法。特异性目的2将评估辛伐他汀对lps诱导的凝血和炎症的抑制作用是否涉及PI3K-Akt信号的激活。我们假设wortmannin，一种PI3K抑制剂，会在lps处理的巨噬细胞和小鼠内毒素血症模型中阻断辛伐他汀的抗炎和抗凝作用。最终，表征这一途径在lps诱导炎症中的参与可能允许开发可用于治疗败血症的新策略。

DESCRIPTION (provided by applicant): 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.