ROLE OF FXR IN LPS-INDUCED INFLAMMATION AND COAGULATION

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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，已被证明可调节多种生物过程，包括胆汁酸、脂质和葡萄糖代谢。在这种核受体水平的药物干预可能会导致有希望的新的治疗炎症性疾病，包括胆汁淤积性肝病，糖尿病和败血症。我们假设小鼠中FXR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。已显示FXR调节肝脏中PI 3 K-Akt通路的活化和胰岛素敏感性。我们的研究表明，巨噬细胞中PI 3 K-Akt通路的激活抑制炎症和凝血。我们目前的项目将确定FXR在脂多糖（LPS）诱导的炎症和凝血调节中的作用。拟议的研究将利用从FXR缺陷小鼠和急性LPS诱导的炎症的体内模型中分离的巨噬细胞。这些研究将提供重要的洞察力的作用，调节脂质和葡萄糖代谢的途径在急性炎症和凝血。这些实验的结果可能会导致新的药理学方法，以提高胰岛素敏感性和限制炎症和凝血败血症，胆汁淤积性肝病和代谢综合征。

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.