| Project/Area Number |
22590714
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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 | Akita University |
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Principal Investigator |
MIURA Koichi 秋田大学, 医学部, 講師 (90375238)
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| Project Period (FY) |
2010 – 2012
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| Project Status |
Completed (Fiscal Year 2012)
|
| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2012: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2010: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 肝臓学 / 非アルコール性脂肪性肝炎 / Toll-like receptor / 炎症性サイトカイン / ケモカイン |
|---|
| Research Abstract |
Nonalcoholic steatohepatitis (NASH) is a hepatic manifestation of metabolic syndrome. Currently, no effective treatment for NASH is available due to its complex mechanism. We hypothesized that altered immune response by TLR ligands causes excess lipid accumulation and inflammation in the liver. Thus, we used gene-modified mice including TLR2 KO, TLR4 KO, and TLR9 KO mice to determine the role of TLRs in CDAA-induced NASH. We also examined mice deficiency in CCR2, a chemokine receptor for MCP-1. Compared to WT mice, TLR2 KO, TLR4 KO, and TLR9 KO mice showed less steatosis, inflammation and fibrosis. Several pro-inflammatory cytokines including IL-1. were decreased in these gene-modified mice. IL-1R KO mice demonstrated lesser grades of NASH. Infiltration of inflammatory cells including macrophages was attenuated in these KO mice. A part of infiltrated macrophages were derived from bone marrow and showed inflammatory phenotype. CCR2 KO mice showed less inflammation and fibrosis. By preventing macrophage recruitment using CCR2 inhibitor, NASH was ameliorated. These results demonstrate that TLR ligands and its target macrophages play key roles in the development of NASH. Pro-inflammatory cytokines released from macrophages contribute to inflammation and promote to the progression of NASH. We will extend these experiments to develop novel immunologic therapy for NASH. To date, seven papers on NASH were accepted to scientific journals.
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