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.
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