PI3K in LPS-induced coagulation and inflammation

PI3K 在 LPS 诱导的凝血和炎症中的作用

• 批准号: 7155143
• 负责人: James P Luyendyk
• 金额: $ 3.67万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2007-06-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7155143
• 关键词: androstane compound; biological signal transduction; blood coagulation; enzyme activity; enzyme linked immunosorbent assay; gene induction /repression; genetically modified animals; immunogenetics; immunopharmacology; inflammation; interleukin 10; interleukin 6; laboratory mouse; lipopolysaccharides; macrophage; phosphatidylinositol 3 kinase; postdoctoral investigator; septicemia; simvastatin

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.

描述（由申请人提供）：LPS诱导的凝结和炎症是细菌败血症发病机理的重要组成部分。在美国，败血症是非统治重症监护病房中死亡的主要原因。该提案的目的是确定PI3K-AKT信号通路在抑制LPS诱导的凝结和炎症中的作用。总体假设是PI3K-AKT途径对LPS诱导的凝结和炎症进行负调节。具体目标1将表征PI3K-AKT途径激活在LPS诱导的巨噬细胞产生的细胞因子和组织因子因子中的作用。我们将采用一种增加（PTEN - / - ）或减少（P85Alpha - / - ）PI3K-AKT途径激活的遗传方法。具体目标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PI3K抑制剂Wortmannin将阻止辛伐他汀在LPS处理的巨噬细胞和小鼠内毒素模型中的抗炎和抗凝作用。最终，该途径参与LPS诱导的炎症的表征可能允许开发可用于治疗脓毒症的新型策略。