Analysis of mechanism by which a Wnt/beta-catenin/CBP signaling inhibitor ameliomates NASH-induced liver fibrosis
Project/Area Number |
17K15584
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Research Category |
Grant-in-Aid for Young Scientists (B)
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Allocation Type | Multi-year Fund |
Research Field |
General pharmacology
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Research Institution | Tokyo Metropolitan Institute of Medical Science |
Principal Investigator |
YAMAJI Kenzaburo 公益財団法人東京都医学総合研究所, ゲノム医科学研究分野, 研究員 (40508628)
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Project Period (FY) |
2017-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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Keywords | 非アルコール性脂肪肝炎 / 肝線維化 / β-カテニン/CBPシグナル阻害剤 / 脱線維化 / NASH / Wnt/β-カテニン/CBPシグナル阻害剤 / 脱線維化作用 / PRI-724 / 非アルコール性脂肪肝炎 (NASH) / wnt/beta-カテニン/CBP |
Outline of Final Research Achievements |
NASH is a progressive fibrotic disease, which increasing the risk of developing hepatocellular carcinoma, however, there are still no efficient therapeutic strategy. In the present study, we examined efficacy of PRI-724 treatment to NASH-related liver fibrosis and characterized the mechanism of PRI-724 efficacy. By daily administering PRI-724 in NASH-induced liver fibrosis mice, normalization of hepatic architecture and decrease of collagen fibrils were observed after administration of PRI-724. Hepatic expressions of αSMA, type I and type III collagens, liver fibrosis markers, were significantly decreased. Moreover, expression of matrix metalloproteinase Mmp8 and Mmp9 in the liver were significantly increased. PRI-724 increased MMP-9 production in liver neutrophils and macrophages, therefore, MMP-9 is possibly contributing the improve of liver fibrosis. In conclusion, PRI-724, a selective Wnt/β-catenin/CBP inhibitor, shows therapeutic effect for NASH-related liver fibrosis/cirrhosis.
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Academic Significance and Societal Importance of the Research Achievements |
NASHを含めて肝硬変や肝不全に対しては、肝移植以外にいまだ有用な根治的治療法はない。しかし、肝移植にはドナー不足や患者負担などの大きな問題がある。米国では肝移植が必要な疾患の第一位はNASHであり、大きな問題になっている。PRI-724はB型およびC型肝炎ウイルスに起因する肝硬変患者を対象として開発が進んでいる薬剤であるが、本研究ではNASHに起因する肝硬変に対してもPRI-724は治療薬となりうる可能性を示す結果が得られた。
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Report
(4 results)
Research Products
(9 results)
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[Journal Article] Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model2017
Author(s)
Yuko Tokunaga, Yosuke Osawa, Takahiro Ohtsuki, Yukiko Hayashi, Kenzaburo Yamaji, Daisuke Yamane, Mitsuko Hara, Keisuke Munekata, Kyoko Tsukiyama-Kohara, Tsunekazu Hishima, Soichi Kojima, Kiminori Kimura, and *Michinori Kohara
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Journal Title
Scientific Reports
Volume: 7
Issue: 1
Pages: 325-325
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Presentation] A CBP/β-catenin signaling inhibitor, PRI-724, improves NASH-induced liver fibrosis and disorder2019
Author(s)
Kenzaburo Yamaji, Yuko Tokunaga, Daisuke Yamane, Bouchra Kitab, Yosuke Osawa, Kiminori Kimura, Chise Tateno, Yoichiro Hirose, Kyoko Tsukiyama-Kohara, Michinori Kohara
Organizer
米国肝臓学会 (AASLD) 2019
Related Report
Int'l Joint Research
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[Presentation] PRI-724, a selective inhibitor of Wnt/β-catenin/CBP signaling, ameliomates NASH-induced liver fibrosis2018
Author(s)
Kenzaburo Yamaji, Yuko Tokunaga, Takahiro Ohtsuki, Yosuke Osawa, Kiminori Kimura, Go Sugawara, Yuji Ishida, Chise Tateno, Yoichiro Hirose, Yukiko Hayashi, Tsunekazu Hishima, Michinori Kohara
Organizer
AASLD The Liver Meeting 2018
Related Report
Int'l Joint Research
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