• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

STUDIES ON THE PATHOPHYSIOLOGY OF THROMBOEMBOLIC DISEASES WITH SPECIAL REFERENCE TO THE UNDERLYING IMPAIRED BLOOD COAGULATION AND ITS REGULATION

Research Project

Project/Area Number 11470250
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field General surgery
Research InstitutionJichi Medical School

Principal Investigator

MATSUDA Michio  Jichi Medical School, Division of Cell and Molecular Medicine, Center for Molecular Medicine. Professor, 医学部, 教授 (50048980)

Co-Investigator(Kenkyū-buntansha) MIMURO Jun  Jichi Medical School, Division of Cell and Molecular Medicine, Center for Molecular Medicine. Instructor, 医学部, 講師 (10221607)
SUGO Teruko  Jichi Medical School, Division of Cell and Molecular Medicine, Center for Molecular Medicine. Instructor, 医学部, 講師 (60183844)
SAKATA Yoichi  Jichi Medical School, Division of Cell and Molecular Medicine, Center for Molecular Medicine. Associate Professor., 医学部, 助教授 (40129028)
MADOIWA Seiji  Jichi Medical School, Division of Cell and Molecular Medicine, Center for Molecular Medicine. Instructor, 医学部, 講師 (70296119)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥12,200,000 (Direct Cost: ¥12,200,000)
Fiscal Year 2000: ¥5,900,000 (Direct Cost: ¥5,900,000)
Fiscal Year 1999: ¥6,300,000 (Direct Cost: ¥6,300,000)
Keywordsfibrinogen / hereditary dysfibrinogen / structural alteration / thrombosis / bleeding tendency / fibrin ultra-structure / monoclonal antibody / anti-angiogenesis / 点変異 / 余剰糖鎖 / 血栓性素因 / 電顕学的分析 / フィブリンの超微細構造 / 抗フィブリノゲン・モノクロナル抗体
Research Abstract

1. Studies on the hereditary dysfibrinogens associated with thrombosis and/or bleeding In fibrinogen (Fbg) Osaka VI, a hereditary dysfibrinogen derived from a 36-year-old woman with a history of severe bleeding on two childbirths, we have identified an exchange of T to A in the stop codon (TAG) of the fibrinogen Bβ-chain gene leading to formation of a codon for Lys (AAG). Thus, 12 amino acid residues are translated to elongate the aberrant Bβ-chain and indeed, this extension has been confirmed by sequence analysis. There is a Cys residue next to the new carboxyl-terminus, which forms a disulfide bridge with its counterpart in another dysfibrinogen molecule. Thus, two types of end-linked Fbg-dimers exist in the patient's Fbg, i.e., a bilayer dimer end-linked at both ends and a longitudinally aligned dimer end-linked at either one of the two carboxyl-terminal ends. These dimers had been predicted by SDS-PAGE run under non-reducing conditions, where two molecular species, i.e., a normal s … More ized and a double-sized Fbg species had been visualized.
By transmission electron microscopy, the fibrin fibers appear extremely thin but the fibrin networks are highly branched and compact as compared with those of normal fibrin clots. We thus hypothesized that the abnormal branching may occur at the points in the double-stranded fibrin proitofibrils, where the abnormal dimeric molecules are incorporated. Furthermore, the Osaka VI fibrin clots are mechanically readily compressible leading to form very fragile fibrin clots. These fibrin clots may fail to exert their hemostatic function and thereby lead to easy bleeding (Blood 96(12) : 3779-3785, 2000). These findings seem to be comparable to those of Fbg Marburg associated with thrombosis besides bleeding after surgery. Namely, this dysfibringen also forms fine fibrin fibers and compact fibrin networks, but the fibrin fibers are highly resistant against plasmin, accounting for thromboembolic complications (Blood 91(9) : 3282-3288, 1999).
We have also studied the role of oligosacharides linked to Asn residue due to formation of a new glycosylation sequence of Asn-X-Thr/Ser in Fbgs Asahi and Lima (Ann NY Acad Sci, in press). Matsuda, the chief researcher, had chances to review these data at several international congresses and symposia (see the attached publication list).
2. Other studies
1) We have produced a monoclonal antibody, IF-123, that specifically recognizes elastase-digests of human fibrinogen/fibrin, and its epitope determination and clinical application have been successfully attempted (Blood 96(5) : 1721-1728, 2000).
2) A novel strategy for the tumor angiogenesis-targeted gene therapy has been established by generation of angiostatin from endogenous plasminogen by protease gene transsfer in mice (Cancer Gene Therapy 7(5) : 589-596, 2000). Less

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (65 results)

All Other

All Publications (65 results)

  • [Publications] Yang W: "Two-step spreading mode of human glioma cells on fibrin monomer : Interaction of aVb3 with the substratum followed by interaction of a5b1 with endogenous cellular fibronectin secreted in the extracellular matrix."Thromb Res. 93. 279-290 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mimuro J: "A new type of Ser substitution for g Arg-275 in fibrinogen Kamogawa I characterized by impaired fibrin assembly."Thromb Haemost. 81. 940-944 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Madoiwa S: "Developmental expression of plasminogen activator inhibitor-1 associated with thrombopoietin-dependent megakaryocytic differentiation."Blood. 94. 475-482 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nakamura M,: "Simultaneous core 2b1→6N-acetylglucosaminyltransferase up-regulation and sialyl-Lex expression during activation of human tonsillar B lymphocytes."FEBS Lett. 463. 125-128 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuda M: "Structure and function of fibrinogen : Insights from dysfibrinogens."Thromb Haemost. 82. 283-290 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] DiOrio JP: "Fibrinogen Marburg fibrin network structure."Microsc Microanal. 5. 1120-1121 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sugo T: "Fibrinogen Niigata : An abnormal fibrinogen with a Bb Asn-160 to Ser substitution associated with extra glycosylation at Bb Asn-158."Blood. 93. 279-290 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kikuchi J: "Induction of ubiquitin-conjugating enzyme by aggregated low density lipoprotein in human macrophages and its implications for"Arterioscler Thromb Basc Biol. 20. 128-134 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kohno I: "A monoclonal antibody specific to the granulocyte-derived elastase-fragment D species of human fibrinogen and fibrin : Its application to the measurement of granulocyte-derived elastase-digests in plasma."Blood. 95. 1721-1728 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuda KM: "A novel strategy for the tumor angiogenesis-targeted gene therapy : Generation of angiostatin from endogenous plasminogen by protease gene transfer."Cancer Gene Therapy. 7. 589-596 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuda M: "Structure and function of fibrinogen inferred from hereditary dysfibrinogens."Fibrinolysis & Proteolysis. 14. 187-197 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Furukawa Y: "Phosphorylation of Bcl-2 protein by CDC2 Kinase during G2/M phases and its role in cell cycle regulation."J Biol Chem. 275. 21661-21667 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuda M: "Structure and function of fibrinogen inferred from hereditary dysfibrinogens."Intern J Haematol. 72. 436-447 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sugo T: "End-linked homodimers in fibrinogen Osaka VI with a Bb-chain extension lead to fragile clot structure."Blood. 96. 3779-3785 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kikuchi J: "A simple semisolid subtraction method using carbodiimide-coated microplates."Mol Biotechnol. 15. 193-200 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Furukawa Y: "Lineage-specific regulation of cell cycle control gene expression during haematop oietic cell differentiation."Br J Haemat. 110. 663-673 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuda M: "Structur, function and physiological roles of human fibrinogen."The Japanese Journal of Obstetrical, Gynecologcal & Neonatal Hematology. 9(2). 1-10 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuda M: "Hereditary disorders of fibrinogen"Ann N Y Acad Sci,. (in press). (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yang W, Asakura S, Sakai T, Nakamura M, Fujimura K, Matsuda M: "Two-step spreading mode of human glioma cells on fibrin monomer : Interaction of α_vβ_3 with the substratum followed by interaction of α_5β_1 with endogenous cellular fibronectin secreted in the extracellular matrix."Thromb Res. 93. 279-290 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mimuro J, Kawata Y, Niwa K, Muramatsu S, Madoiwa S, Takano H, Sugo T, Sakata Y, Sugimoto T, Nose K, Matsuda M: "A new type of Ser substitution for γ Arg-275 in fibrinogen Kamogawa I characterized by impaired fibrin assembly."Thromb Haemost. 81. 940-944 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Madoiwa S, Komatsu N, Mimuro J, Kimura K, Matsuda M, Sakata Y: "Developmental expression of plasminogen activator inhibitor-1 associated with thrombopoietin-dependent megakaryocytic differentiation."Blood. 94. 475-482 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nakamura M, Ishida T, Kikuchi J, Furukawa Y, Matsuda M: "Simultaneous core 2β_1→6N-acetylgluc osaminyltransferase up-regulation and sialyl-Le^x expression during activation of human tonsillar B lymphocytes."FEBS Lett. 463. 125-128 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuda M, Sugo T, Yoshida N, Terukina S, Yamazumi K, Niwa K, Maekawa H : Structure and function of fibrinogen: "Insights from dysfibrinogens."Thromb Haemost. 82. 283-290 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] DiOrio JP, Mosesson MW, Hernandez I, Sugo T, Matsuda M: "Fibrinogen Marburg fibrin network structure."Microsc Microanal. 5. 1120-1121 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sugo T, Nakamikawa C, Takano H, Mimuro J, Yamaguchi S, Mosesson MW, Meh DA, DiOrio JP, Takahashi N, Takahashi H, Nagai K, Matsuda M: "Fibrinogen Niigata : An abnormal fibrinogen with a Bβ Asn-160 to Ser substitution associated with extra glycosylation at Bβ Asn-158."Blood. 94. 3806-3813 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kikuchi J, Furukawa Y, Kubo N, Tokura A, Hayashi N, Nakamura M, Matsuda M, Sakurabayashi I: "Induction of ubiquitin-conjugating enzyme by aggregated low density lipoprotein in human macrophages and its implications for atherosclerosis."Arterioscler Thromb Basc Biol. 20. 128-134 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kohno I, Inuzuka K, Itoh Y, Nakahara K, Eguchi Y, Sugo T, Soe G, Sakata Y, Murayama H, Matsuda M: "A monoclonal antibody specific to the granulocyte-derived elastase-fragment D species of human fibrinogen and fibrin : Its application to the measurement of granulocyte-derived elastase-digests in plasma."Blood. 95. 1721-1728 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuda KM, Madoiwa S, Hasumi Y, Kanazawa T, Saga Y, Kume A, Mano H, Ozawa K, Matsuda M: "A novel strategy for the tumor angiogenesis-targeted gene therapy : Generation of angiostatin from endogenous plasminogen by protease gene transfer."Cancer Gene Therapy. 7. 589-596 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuda M: "Structure and function of fibrinogen inferred from hereditary dysfibrinogens."Fibrinolysis & Proteolysis. 14. 187-197 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Furukawa Y, Iwase S, Kikuchi J, Terui Y, Nakamura M, Yamada H, Kano Y, Matsuda M: "Phosphorylation of Bcl-2 protein by CDC2 Kinase during G_2/M phases and its role in cell cycle regulation."J Biol Chem. 275. 21661-21667 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuda M: "Structure and function of fibrinogen inferred from hereditary dysfibrinogens."Intern J Haematol. 72. 436-447 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sugo T, Nakamikawa C, Yoshida N, Niwa K, Sameshima M, Mimuro J, Weisel J W, Nagita A, Matsuda M: "End-linked homodimers in fibrinogen Osaka VI with a Bβ-chain extension lead to fragile clot structure."Blood. 96. 3779-3785 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kikuchi J, Furukawa Y, Suzuki O, Hayashi N, Nakamura M, Morita M, Matsuda M: "A simple semisolid subtraction method using carbodiimide-coated microplates."Mol Biotechnol. 15. 193-200 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Furukawa Y, Kikuchi J, Nakamura M, Iwase S, Yamada H, Matsuda M: "Lineage-specific regulation of cell cycle control gene expression during haematopoietic cell differentiation."Br J Haemat. 110. 663-673 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuda M: "Structur, function and physiological roles of human fibrinogen."The Japanese Journal of Obstetrical, Gynecologcal & Neonatal Hematology. (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuda M, Sugo T: "Hereditary disorders of fibrinogen."Ann N Y Acad Sci. (in press.).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yang W: "Two-step spreading mode of human glioma cells on fibrin monomer : Interaction of aVb3 with the substratum followed by interaction of a5b1 with endogenous cellular fibronectin secreted in the extracellular matrix."Thromb Res. 93. 279-290 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Mimuro J: "A new type of Ser substitution for g Arg-275 in fibrinogen Kamogawa I characterized by impaired fibrin assembly."Thromb Haemost. 81. 940-944 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Madoiwa S: "Developmental expression of plasminogen activator inhibitor-1 associated with thrombopoietin-dependent megakaryocytic differentiation."Blood. 94. 475-482 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nakamura M,: "Simultaneous core 2b1→6N-acetylglucosaminyltransferase up-regulation and sialyl-Lex expression during activation of human tonsillar B lymphocytes."FEBS Lett. 463. 125-128 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Matsuda M: "Structure and function of fibrinogen : Insights from dysfibrinogens."Thromb Haemost. 82. 283-290 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] DiOrio JP: "Fibrinogen Marburg fibrin network structure."Microsc Microanal. 5. 1120-1121 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sugo T: "Fibrinogen Niigata : An abnormal fibrinogen with a Bb Asn-160 to Ser substitution associated with extra glycosylation at Bb Asn-158."Blood. 93. 279-290 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kikuchi J: "Induction of ubiquitin-conjugationg enzyme by aggregated low density lipoprotein in human macrophages and its implications for"Arterioscler Thromb Basc Biol. 20. 128-134 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kohno I: "A monoclonal antibody specific to the granulocyte-derived elastase-fragment D species of human fibrinogen and fibrin : Its application to the measurement of granulocyte-derived elastase-digests in plasma."Blood. 95. 1721-1728 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Matsuda KM: "A novel strategy for the tumor angiogenesis-targeted gene therapy : Generation of angiostatin from endogenous plasminogen by protease gene transfer."Cancer Gene Therapy. 7. 589-596 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Matsuda M: "Structure and function of fibrinogen inferred from hereditary dysfibrinogens."Fibrinolysis & Proteolysis. 14. 187-197 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Furukawa Y: "Phosphorylation of Bcl-2 protein by CDC2 Kinase during G2/M phases and its role in cell cycle regulation."J Biol Chem. 275. 21661-21667 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Matsuda M: "Structure and function of fibrinogen inferred from hereditary dysfibrinogens."Intern J Haematol. 72. 436-447 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sugo T: "End-linked homodimers in fibrinogen Osaka VI with a Bb-chain extension lead to fragile clot structure."Blood. 96. 3779-3785 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kikuchi J: "A simple semisolid subtraction method using carbodiimide-coated microplates."Mol Biotechnol. 15. 193-200 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Furukawa Y: "Lineage-specific regulation of cell cycle control gene expression during haematop oietic cell differentiation."Br J Haemat. 110. 663-673 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Matsuda M: "Structur, function and physiological roles of human fibrinogen."The Japanese Journal of Obstetrical, Gynecologcal & Neonatal Hematology. 9(2). 1-10 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Matsuda M: "Hereditary disorders of fibrinogen"Ann N Y Acad Sci. (in press). (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Wei Yang: "Two-step spreading mode of human glioma cells on fibrin monomer : Interaction of α_V β_3 with the substratum followed by interaction of α_5 β_1 with endogenous cellular fibronectin secreted in the extracellular matrix"Thromb Res. 93. 279-290 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Jun Mimuro: "A new type of Ser substitution for γ Arg-275 in fibrinogen Kamogawa I characterized by impaired fibrin assembly"Thromb Haemost. 81(6). 940-944 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Seiji Madoiwa: "Developmental expression of plasminogen activator inhibitor-1 associated with thrombopoietin-dependent megakaryocytic differentiation"Blood. 94(2). 475-482 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Mitsuru Nakamura: "Simultaneous core 2β_1 →6N-acetylglucosaminyltransferase up-regulation and sialyl-Le^X expression during activation of human tonsillar B lymphocytes"FEBS Lett. 463. 125-128 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Michio Matsuda: "Structure and function of fibrinogen : Insights from dysfibrinogens"Thomb Haemost. 82. 283-290 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] DiOrio JP: "Fibrinogen Marburg fibrin network structure"Microsc Microanal. 5. 1120-1121 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Teruko Sugo: "Fibrinogen Niigata : An abnormal fibrinogen with a Bβ Asn-160 to Ser substitution associated with extra glycosylation at BβAsn-158"Blood. 94. 3806-3813 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Jiro Kikuchi: "Induction of ubiquitin-conjugating ing enzyme by aggregated low density lipoprotein in human macrophages and its implications for atherosclerosis"Arterioscler Thromb Basc Biol. 20. 128-134 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Isao Kohno: "A monoclonal antibody specific to the granulocyte-derived elastase-fragment D species of human fibrinogen and fibrin : Its application to the measurement of granulocyte-derived elastase-digests in plasma"Blood. 95. (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kant M Matsuda: "A novel strategy for the tumor angiogenesis-targeted gene therapy : Generation of angiostatin from endogenous plasminogen by protease gene transfer"Cancer Gene Therapy, in press.

    • Related Report
      1999 Annual Research Report
  • [Publications] Michio Matsuda: "Structure and function of fibrinogen inferred from hereditary dysfibrinogens"Intern J Haematol, in press.

    • Related Report
      1999 Annual Research Report

URL: 

Published: 1999-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi