| Project/Area Number |
12670498
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Kyushu University |
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Principal Investigator |
NAKAMUTA Makoto Kyushu University Hospital Assistant Professor, 医学部附属病院, 助手 (00294918)
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| Co-Investigator(Kenkyū-buntansha) |
ENJOJI Munechika Kyushu University Hospital Assistant Professor, 医学部附属病院, 助手 (20253411)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2002: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2001: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2000: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Keywords | MCP1 / 7ND / Hepatic fibrosis / Liver cirrhosis / chemokine / cytokine / gene therapy / hepatic stellate cell / 変異型MCP-1 / 肝繊維化 / サイトカイン / CCR2 / コラーゲン |
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| Research Abstract |
Background: Monocyte Chemoattractant Protein-1 (MCP-1) has been implicated in the process of hepatic inflammation, recruiting monocytes and lymphocytes during liver injury. MCP-1 also activates directly hepatic stellate cells, which play a major role in hepatic fibrosis. However, it remains unclear whether blockage of MCP-1 signaling could prevent hepatic fibrosis in vivo.
Methods: We evaluated a strategy for anti-MCP-1 gene therapy against hepatic fibrosis by transfecting an amino-terminal deletion mutant, lacking the amino-terminal codons 2 to 8 of the human MCP-1 gene and designated 7ND, into skeletal muscle in a rat experimental model of dimethylnitrosamine (DMN) induced fibrosis.
Results: Anti-MCP-1 gene therapy decreased significantly the occurrence of DMN-induced hepatic fibrosis evaluated by computed image analysis and by measurement of hydroxyproline contents of the liver, accompanied by a reduction in the expressions of α-smooth muscle actin. This treatment also caused a significant decrease in hepatic tissue levels of interleukin- (IL-) 12 (Th1 cytokine) and an increase in those of IL-10 (Th2 cytokine), indicating a change in the TH1/Th2 cytokine balance in the liver.
Conclusions: Blockade of MCP-1 after intramuscular transfer of the 7ND gene suppressed hepatic fibrosis, and this strategy may be a useful and feasible gene therapy against hepatic fibrosis.
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