| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2010: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2009: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
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| Research Abstract |
Hepatic fibrosis is a important step for progression from basic hepatic disease to hepatic cirrhosis and cancer. In this process, hepatic stellate cells (HSCs) were thought to play a central role. Recently it was reported that the expression level of NOX1, a novel catalytic subunit of NADPH oxidase, was increased in HSCs with its activation. The aim of this study was to clarify the role of NOX1 in the development of liver fibrosis using Noxl-deficient mice (NOX1 KO).
After bile duct ligation (BDL), increased expression of NOX1, elevation of ALT and AST levels, progression of hepatic fibrosis and increasing of activated HSC in liver tissue were observed in WT but not NOX1 KO. In primary cultured HSCs, its activation was not affected by NOX1 deficiency. However, cell proliferation was significantly attenuated in HSCs isolated from NOX1 KO. In these cells, significant increase of p27^<Kip1>, a cell cycle suppressor, significant reduction in phosphorylated forms of Akt and FOXO4 were confirmed. In addition, the level of oxidized inactivated form of phosphatase and tensine homolog (PETN), a negative regulator of PI3K/Akt pathway, was significantly decreased in HSCs of NOX1 KO. These results showed that NOX1 derived ROS aggravate hepatic fibrosis by oxidation of PTEN, which followed by Akt/FOXO4/p27^<Kip1> pathway dependent HSC proliferation.
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