Mechanism and therapeutic application of a novel integrin blocking mAb that inhibit liver fibrosis in mice
| Project/Area Number |
17H04161
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | Hiroshima University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
茶山 一彰 広島大学, 医系科学研究科(医), 教授 (00211376)
西道 教尚 広島大学, 保健管理センター, 研究員 (00583486)
仙谷 和弘 広島大学, 医系科学研究科(医), 講師 (30508164)
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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 |
¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000)
Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2017: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
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| Keywords | インテグリン / 肝線維症 / TGFβ / 筋線維芽細胞 / YAP-1 / インテグリンα8β1 / YAP1 / 線維化 / 肝臓 / 肝線維化 / 抗体医薬 / Integrin α8β1 / α-SMA / Fibrosis / TGF-β |
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| Outline of Final Research Achievements |
The integrin family, matrix receptors, is an appealing therapeutic target proteins. Excessive matrix deposition is substantial pathology in tissue fibrosis. Integrin α8β1 is a messenchymal integrin that functions as a receptor for matrx proteins including nephronectin. Its participation in development of fibrosis has been unknown mainly due to a lack of a specific inhibitor, inparticular a neutralization monoclonal antibody. After we successfully generated the blocking mAb, we have demonstrated that the inhibition ammeliorates fibrosis in mouse liver fibrosis models.
In the present investigation, we have shown, as functional evidence, its TGF-β activation capacity and myofibroblast differentiation promotion.In addition, tissue stiffness-induced expression and accumulated expressionin fibroblasts strongly support the profibrotic propety of α8β1.
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| Academic Significance and Societal Importance of the Research Achievements |
実際現在幾つかのインテグリン阻害剤が臨床試験に入っている。しかし、個々のインテグリンの阻害剤作製は容易ではなく、現在まで一部のインテグリンで抗線維化作用が確かめられているだけである。α8β1も例外ではなく、線維芽細胞での明瞭な発現にも拘わらず、線維化への関与は不明であった。
我々の作製したインテグリンα8β1阻害抗体は、抗線維化効果を示すと同時に、その機序や発現機構から、線維化の機序と抑制に対する多くの示唆を与えた。また、同時にこの阻害抗体自体が、抗体医薬としての大きなポテンシャルを有する。何故なら、ニワトリを宿主として作製されたため、マウスだけでなくヒト分子にも同様の阻害効果を示す。
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Report
(4 results)
Research Products
(12 results)
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[Journal Article] The Crosstalk Between TGF-β and Periostin Can Be Targeted for Pulmonary Fibrosis.2020
Author(s)
Nanri Y, Nunomura S, Terasaki Y, Yoshihara T, Hirano Y, Yokosaki Y, Yamaguchi Y, Feghali- Bostwick C, Ajito K, Murakami S, Conway SJ, Izuhara K.
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Journal Title
Am J Respir Cell Mol Biol
Volume: 62
Issue: 2
Pages: 204-216
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Expansion of hedgehog activation disrupts stromal identity and induces emphysema.2018
Author(s)
Chaoqun Wang, Nabora Soledad Reyes de Mochel, Stephanie Christenson, Monica Cassandras, Rebecca Moon, Alexis Brumwell, Lauren Byrnes, Alfred Li, Yasuyuki Yokosaki, Peiying Shan, Julie Sneddon, David Jablons, Patty J. Lee, Michael A. Matthay, Harold Chapman, Tien Peng.
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Journal Title
J Clin Invest
Volume: 128
Issue: 10
Pages: 4343-4358
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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