ROLE OF FXR IN LPS-INDUCED INFLAMMATION AND COAGULATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该项目的长期目标是确定法尼醇X受体(FXR)在炎症和凝血中的作用。法尼醇X受体(FXR)是一种配体激活的核受体，已被证明调节包括胆汁酸、脂肪和葡萄糖代谢在内的多种生物学过程。在核受体水平上的药物干预可能会为胆汁淤积性肝病、糖尿病和脓毒症等炎症性疾病带来有希望的新疗法。我们假设，FXR在小鼠体内的激活通过激活巨噬细胞中的抗炎信号通路来减少炎症和凝血。FXR已被证明可以调节肝脏中PI3K-Akt通路的激活和胰岛素敏感性。我们的研究表明，巨噬细胞中PI3K-Akt通路的激活抑制了炎症和凝血。我们目前的项目将确定FXR在脂多糖(LPS)诱导的炎症和凝血反应中的调节作用。这项拟议的研究将利用从FXR缺陷小鼠分离的巨噬细胞和急性脂多糖诱导的体内炎症模型。这些研究将为调节脂质和葡萄糖代谢的途径在急性炎症和凝血中的作用提供重要的见解。这些实验的结果可能导致新的药理学方法来改善胰岛素敏感性，并限制败血症、淤胆性肝病和代谢综合征的炎症和凝血。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long term goal of this project is to determine the role of the farnesoid X receptor (FXR) in inflammation and coagulation. The farnesoid X receptor (FXR) is a ligand activated nuclear receptor that has been shown to regulate diverse biological processes including bile acid, lipid and glucose metabolism. Pharmacologic intervention at the level of this nuclear receptor may lead to promising new treatments for inflammatory diseases including cholestatic liver disease, diabetes and sepsis. We hypothesize that the activation of FXR in mice reduces inflammation and coagulation by activation of anti-inflammatory signaling pathways in macrophages. FXR has been shown to modulate activation of the PI3K-Akt pathway and insulin sensitivity in the liver. Our studies indicate that activation of the PI3K-Akt pathway in macrophages inhibits inflammation and coagulation. Our current project will determine the role of FXR in the modulation of lipopolysaccharide (LPS)-induced inflammation and coagulation. The proposed studies will utilize macrophages isolated from FXR-deficient mice and in vivo models of acute LPS-induced inflammation. These studies will provide important insight into the role of pathways regulating lipid and glucose metabolism in acute inflammation and coagulation. The results of these experiments may lead to novel pharmacologic approaches to improve insulin sensitivity and limit inflammation and coagulation in sepsis, cholestatic liver disease and the metabolic syndrome.