2006 Fiscal Year Final Research Report Summary
Detection and regulation of hepatic diseases targeting TGF-β activation reaction.
| Project/Area Number |
16390215
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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 | RIKEN |
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Principal Investigator |
KOJIMA Soichi RIKEN, Mol Cell Pathol Res Unit, Unit Leader, 分子細胞病態学研究ユニット, 研究ユニットリーダー (10202061)
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| Co-Investigator(Kenkyū-buntansha) |
SAIO Masanao Gifu Univ., Dept Immunopathol, Associate Prof., 大学院・医学研究科免疫病理学, 助教授 (40242721)
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| Project Period (FY) |
2004 – 2006
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| Keywords | Fulminant hepatitis / TGF-β activation / Plasma kallikrein / Plasmin / Cutting edge recognizing antibody / Protease inhibitor / Hepatic stellate cells / Smad |
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| Research Abstract |
Transforming growth factor (TGF)-β, a 25 kD dimeric polypeptide playing a pivotal role in the pathogenesis of liver diseases, is produced as a high molecular weight latent form, and activated by plasmin (PLN) and plasma kallikrein (PLK) during pathogenesis of liver diseases. Blockage of the activation reaction with low molecular weight protease inhibitors prevented the development of the diseases in animal models. Based upon these findings, here, we found that
(1) PLN and PLK cleaved between K56-L57 and R58-L59 in LAP portion of human latent TGF-β1, respectively. We produced antibodies that specifically recognize the neo-epitopes formed by protease degradation, namely the cut ends of each cleavage site. The anti-R58 antibodies strongly stained liver sections from patients with fulminant hepatitis.
(2) The anti-L59 antibodies were successively used to establish ELISA to detect LAP degradation fragments in serum of mouse impaired liver regeneration model as well as rat CCl4 and bile duct ligation hepatic fibrosis models, showing a good correlation with serum transamidase levels and hepatic hydroxyproline levels.
(3) Decoy peptides containing the cleavage sites blocked the activation of TGF-β in the hepatic stellate cells and improved hepatic regeneration in the mouse model.
(4) In scleroderma TGF-β2 is the main isoform and MMP, but not PLN and PLK, appeared to be involved in its activation reaction.
(5) CXZ, which has been shown to suppress phosphorylation of Smad, successfully improved hepatic regeneration in the mouse model.
These results suggest that a PLN/PLK-dependent activation reaction occurs around hepatic stellate cells to produce active TGF-β, which may induce fibrosis and inhibit the proliferation of hepatocytes, thereby addressing a potential use for decoy peptides in hepatitis therapy. These results also suggest a potential usage of a LAP degradate as a novel biomarker for liver fibrosis.
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[Patent(Industrial Property Rights)] TGF-β活性化制御領域の切断面を認識する抗体2003
Inventor(s)
小嶋聡一, 近藤和嘉子, 堂前直
Industrial Property Rights Holder
小嶋聡一, 近藤和嘉子, 堂前直
Industrial Property Number
特願2003-313014, 国際特許PCT JP2004/013189, US優先権出願10/570606, EU EPC出願04772928.0, JP PCT出願特願2005-513729
Filing Date
20030904, 20040903
Description
「研究成果報告書概要(和文)」より
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[Patent(Industrial Property Rights)] TGF-β情報伝達経路阻害剤2003
Inventor(s)
小嶋聡一, 近藤和嘉子, 掛谷秀昭, 長田裕之, 坂本康治, 中田忠
Industrial Property Rights Holder
小嶋聡一, 近藤和嘉子, 掛谷秀昭, 長田裕之, 坂本康治, 中田忠
Industrial Property Number
特願2003-367654, 国際特許PCT A41801A, JP PCT出願特願2005-515065
Filing Date
20031028, 20041028
Description
「研究成果報告書概要(和文)」より
