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Detection and regulation of hepatic diseases targeting TGF-β activation reaction.

Research Project

Project/Area Number 16390215
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionRIKEN

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)

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)
古谷 裕  独立行政法人理化学研究所, 分子細胞病態学研究ユニット, 協力研究員 (80392108)
奥野 正隆  国立大学法人岐阜大学, 医学部消化器病態学第一内科, 助教授 (10204140)
Project Period (FY) 2004 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥14,100,000 (Direct Cost: ¥14,100,000)
Fiscal Year 2006: ¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2005: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 2004: ¥5,200,000 (Direct Cost: ¥5,200,000)
KeywordsFulminant hepatitis / TGF-β activation / Plasma kallikrein / Plasmin / Cutting edge recognizing antibody / Protease inhibitor / Hepatic stellate cells / Smad
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.

Report

(4 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • Research Products

    (53 results)

All 2007 2006 2005 2004 2003 Other

All Journal Article (40 results) Book (7 results) Patent(Industrial Property Rights) (6 results)

  • [Journal Article] A guide to murine fibrinolytic factor structure, function, assays, and genetic alterations : A Review.2007

    • Author(s)
      Matsuo, O. et al.
    • Journal Title

      J. Thromb. Haemost. 5(4)

      Pages: 680-689

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Synergistic growth inhibition by acyclic retinoid and vitamin K2 in human hepatocellular carcinoma cells.2007

    • Author(s)
      Kanamori, T. et al.
    • Journal Title

      Cancer Sci. 98 (3)

      Pages: 431-437

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] 17 β-estradiol induces IL-1α gene expression in rheumatoid fibroblast-like synovial cells through estrogen receptorα (ERα)and augmentation of transcriptional activity of Sp1 by dissociating histone deacetylase 2 (HDAC 2) from ERα.2007

    • Author(s)
      Itoh, Y. et al.
    • Journal Title

      J. Immunol. 178 (5)

      Pages: 3059-3066

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] A guide to murine fibrinolytic factor structure, function, assays, and genetic alterations : A Review.2007

    • Author(s)
      Matsuo O. et al.
    • Journal Title

      J. Thromb. Haemost. 5(4)

      Pages: 680-689

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] synergistic growth inhibition by acyclic retinoid and vitamin K2 in human hepatocellular carcinoma cells.2007

    • Author(s)
      Kanamori T. et al.
    • Journal Title

      Cancer Sci. 98(3)

      Pages: 431-437

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] 17β-estradiol induces IL-1α gene expression in rheumatoid fibroblast-like synovial cells through estrogen receptor (ERα) and augmentation of transcriptional activity of Sp1 by dissociating histone deacetylase 2 (HDAC 2) from ERα.2007

    • Author(s)
      Itoh Y.
    • Journal Title

      J. Immunol. 178(5)

      Pages: 3059-3066

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] A guide to murine fibrinolytic factor structure, function, assays, and genetic alterations: A Review.2007

    • Author(s)
      Matsuo, O., et. al.
    • Journal Title

      J Thromb and Haemost. (In press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Synergistic growth inhibition by acyclic retinoid and vitamin K2 in human hepatocellular carcinoma cells.2007

    • Author(s)
      Kanamori, T., et. al.
    • Journal Title

      Cancer Sci. 98(3)

      Pages: 431-437

    • Related Report
      2006 Annual Research Report
  • [Journal Article] 17 β-estradiol induces IL-1 α gene expression in rheumatoid fibroblast-like synovial cells through estrogen receptor α (ERα) and augmentation of transcriptional activity of Sp1 by dissociating histone deacetylase 2 (HDAC2) from ERα2007

    • Author(s)
      Itoh, Y., et. al.
    • Journal Title

      J Immunol. 178(5)

      Pages: 3059-3066

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Change erythocytes into thrombolytic agents.2006

    • Author(s)
      Kojima, S.
    • Journal Title

      Blood 108 (6)

      Pages: 1789-1790

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Zonal differences in gallium-67 uptakes between perivenous versus periportal regions of rat liver following carbon tetrachloride treatment.2006

    • Author(s)
      Abe, S.et al.
    • Journal Title

      Hepatol Res. 36 (2)

      Pages: 78-85

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Change erythocytes into thrombolytic agents.2006

    • Author(s)
      Kojima S.
    • Journal Title

      Blood 108(6)

      Pages: 1789-1790

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Zonal differences in gallium-67 uptakes between perivenous versus periportal regions of rat liver following carbon tetrachloride treatment.2006

    • Author(s)
      Abe S.et al.
    • Journal Title

      Hepatol. Res. 36(2)

      Pages: 78-85

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Change erythocytes into thrombolytic agents.2006

    • Author(s)
      Kojima, S., et. al.
    • Journal Title

      Blood 108(6)

      Pages: 1789-1790

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Zonal differences in gallium-67 uptakes between perivenous versus periportal regions of rat liver following carbon tetrachloride treatment.2006

    • Author(s)
      Abe, S., et. al.
    • Journal Title

      Hepatol Res. 36(2)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Acyclic retinoid in the chemoprevention of hepatocellular carcionoma.2005

    • Author(s)
      Kojima.S.et al.
    • Journal Title

      Int. J. Oncol. 24(4)

      Pages: 797-805

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Te involvement of polyamines as substrates of transglutaminase in zonal different hepatocyte proliferation after partial hepatectomy.2005

    • Author(s)
      Ohtake.Y.et al.
    • Journal Title

      Biol. Pharm. Bull. 28(2)

      Pages: 349-352

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Prevention of rat hepatocarcinogenesis by acyclic retinoid is accompanied by reduction in emergence of both TGF-β-expressing oval-like cells and activated hepatic stellate cells.2005

    • Author(s)
      Sano, T. et al.
    • Journal Title

      Nutrition and Cancer 51(2)

      Pages: 197-206

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Identification, evolution, and regulation of expression of guinea pig trappin with an unusually long transglutaminase substrate domain.2005

    • Author(s)
      Furutani, Y. et al.
    • Journal Title

      J. Biol. Chem. 280(21)

      Pages: 20204-20215

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] シコニン類縁体β-HIVSによるがんの増殖・転移および血管新生の抑制2005

    • Author(s)
      小見悠介, 他
    • Journal Title

      日本血管止血学会誌 16(4)

      Pages: 393-396

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary 2005 Annual Research Report
  • [Journal Article] Prevention of rat hepatocarcinogenesis by acyclic retinoid is accompanied by reduction in emergence of both TGF-β-expressing oval-like cells and activated hepatic stellate cells2005

    • Author(s)
      Sono T.et al.
    • Journal Title

      Nutrition and Cancer 51(2)

      Pages: 197-206

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Identification, evolution, and regulation of expression of guinea pig trappin with an unusually long transglutaminase substrate domain.2005

    • Author(s)
      Furutani Y. et al.
    • Journal Title

      J.Biol.Chem. 280(21)

      Pages: 20204-20215

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] β-HIVS, a derivative of shikonin, suppresses cancer cell growth, angiogenesis, and metastasis in vivo.2005

    • Author(s)
      Komi Y.et al.
    • Journal Title

      Jpn. J. Thromb. Hemost. 16(4)

      Pages: 393-396

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] The involvement of polyamines as substrates of transglutaminase in zonal different hepatocyte proliferation after partial hepatectomy.2005

    • Author(s)
      Ohtake.Y.et al.
    • Journal Title

      Biol.Pharm.Bull. 28(2)

      Pages: 349-352

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Prevention of rat hepatocarcinogenesis by acyclic retinoid is accompanied by reduction in emergence of both TGF-α-expressing oval-like cells and activated hepatic stellate cells.2005

    • Author(s)
      Sano, T. et al.
    • Journal Title

      Nutrition and Cancer 51(2)

      Pages: 197-206

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Identification, evolution, and regulation of expression of guinea pig trappin with an unusually long transglutaminase substrate domain.2005

    • Author(s)
      Furutani, Y. et al.
    • Journal Title

      J.Biol.Chem. 280(21)

      Pages: 20204-20215

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Te involvement of polyamines as substrates of transglutaminase in zonal different hepatocyte proliferation after partial hepatectomy.2005

    • Author(s)
      Ohtake.Y.et al.
    • Journal Title

      Biol.Pharm.Bull. 28(2)

      Pages: 349-352

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Retinoids in Cancer Chemoprevention.2004

    • Author(s)
      Okuno, M. et al.
    • Journal Title

      Current Cancer Drug Target. 4(3)

      Pages: 285-298

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary 2004 Annual Research Report
  • [Journal Article] Retinoic acid controls blood vessel formation by modulating endothelial and mural cell interaction via transcriptional regulation of angiopoietin-2 in vascular progenitor cells.2004

    • Author(s)
      Suzuki, Y. et al.
    • Journal Title

      Blood 104(1)

      Pages: 166-170

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary 2004 Annual Research Report
  • [Journal Article] The RING finger protein, RNF8, interacts with retinoid X receptorα and enhances its transcription-stimulating activity.2004

    • Author(s)
      Takano, Y. et al.
    • Journal Title

      J. Bioi Chem. 279(18)

      Pages: 18926-18934

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Androgen-dependent expression, gene structure, and molecularevolution of guinea pig caltrin II, a WAP motif protein.2004

    • Author(s)
      Furutani, Y. et al.
    • Journal Title

      Biol. Reprod. 71(5)

      Pages: 1583-1590

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Retinoids in cancer chemoprevention2004

    • Author(s)
      Okuno M. et al.
    • Journal Title

      Current Cancer Drug Target 4(3)

      Pages: 285-298

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Retinoic acid controls blood vessel formation by modulating endothelial and mural cell interaction via transcriptional regulation of angiopoientin-2 in vascular progenitor cells2004

    • Author(s)
      Suzuki Y. et al.
    • Journal Title

      Blood 104(1)

      Pages: 166-170

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] The RING finger protein, RNF8, interacts with retinoid X receptora and enhances its transcription-stimulating activity.2004

    • Author(s)
      Takano Y. et al.
    • Journal Title

      J. Biol. Chem 279(18)

      Pages: 18926-18934

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Androgen-dependent expression. gene structure, and molecularevolution of guinea pig caltrin II, a WAP motif protein.2004

    • Author(s)
      Furutani Y. et al.
    • Journal Title

      Biol. Reprod. 71(5)

      Pages: 1583-1590

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] The RING finger protein, RNF8, interacts with retinoid X receptor α and enhances its transcription-stimulating activity.2004

    • Author(s)
      Takano, Y. et al.
    • Journal Title

      J.Biol.Chem. 279(18)

      Pages: 18926-18934

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Androgen-dependent expression, gene structure, and molecularevolution of guinea pig caltrin II, a WAP motif protein.2004

    • Author(s)
      Furutani, Y. et al.
    • Journal Title

      Biol.Reprod. 71(5)

      Pages: 1583-1590

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Acyclic retinoid in the chemoprevention of hepatocellular carcionoma.2004

    • Author(s)
      Kojima.S.et al.
    • Journal Title

      Int.J.Oncol 24(4)

      Pages: 797-805

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Acyclic retinoid in the chemoprevention of hepatocellular carcionoma.

    • Author(s)
      Kojima S. et al.
    • Journal Title

      Biol. Pharm. Bull. 28(2)

      Pages: 349-352

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Murine platelet, coagulation, and fibrinolytic parameters : A Review.

    • Author(s)
      Jirouskova, M. et al.
    • Journal Title

      J Thromb and Haemost. (In press)

    • Related Report
      2005 Annual Research Report
  • [Book] Vitamins and the liver (A and D) : The Textbook of Hepatology.2007

    • Author(s)
      Okuno, M. et al.
    • Publisher
      Oxford, Blackwell Publishing. (In press)
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Book] Basic science to clinical practice(Section 2.3.11, Vitamins and the liver (A and D)., in The Textbook of Hepatology)2007

    • Author(s)
      Okuno M. et al.
    • Publisher
      Oxford, Blackwell Publishing(in press)
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Book] Vitamins and the liver (A and D): Textbook of Hepatology. Dufour2007

    • Author(s)
      Okuno, M., et. al.
    • Publisher
      Oxford, Blackwell Publishing. (In press)
    • Related Report
      2006 Annual Research Report
  • [Book] Vitamins and the liver (A and D): Textbook of Hepatology. Dufour2006

    • Author(s)
      Okuno, M. et al.
    • Publisher
      Oxford, Blackwell Publishing.(In press)
    • Related Report
      2005 Annual Research Report
  • [Book] uPAの基礎と臨床、線溶系と増殖因子『図説血栓止血血管学』(瀬白帝ほか編)2005

    • Author(s)
      小嶋聡一, 他
    • Total Pages
      834
    • Publisher
      中外医学社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Book] Hemostasis, and vascular sciences(Basic science and clinical practice of uPA, Fibrinolysis and growth factores, in Thrombosis)2005

    • Author(s)
      Kojima S. et al.
    • Publisher
      Chuugai igakusya
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Book] uPAの基礎と臨床、線溶系と増殖因子『図説血栓止血血管学』(一瀬白帝ほか編)2005

    • Author(s)
      小嶋聡一, 他
    • Total Pages
      834
    • Publisher
      中外医学社
    • Related Report
      2005 Annual Research Report
  • [Patent(Industrial Property Rights)] TGF-β活性化反応阻害物質2007

    • Inventor(s)
      小嶋聡一, 寺岡龍太郎
    • Industrial Property Rights Holder
      小嶋聡一, 寺岡龍太郎
    • Industrial Property Number
      2007-058222
    • Filing Date
      2007-03-08
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Patent(Industrial Property Rights)] TGF-β活性化反応阻害物質2007

    • Inventor(s)
      小嶋聡一、寺岡龍太郎
    • Industrial Property Rights Holder
      小嶋聡一、寺岡龍太郎
    • Industrial Property Number
      2007-058222
    • Filing Date
      2007-03-08
    • Related Report
      2006 Annual Research Report
  • [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
      2003-313014
    • Filing Date
      2003
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [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
      2003-367654
    • Filing Date
      2003
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Patent(Industrial Property Rights)] TGF-β活性化制御領域の切断面を認識する抗体

    • 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
      2003-313014
    • Related Report
      2005 Annual Research Report
  • [Patent(Industrial Property Rights)] TGF-β情報伝達経路阻害剤

    • 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
      理化学研究所
    • Industrial Property Number
      2003-367654
    • Related Report
      2005 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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