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Mechanisms of fibrin polymerization based on analysis for dysfunctional fibrinogen variants

Research Project

Project/Area Number 17K09009
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Laboratory medicine
Research InstitutionShinshu University

Principal Investigator

Okumura Nobuo  信州大学, 学術研究院保健学系, 教授 (60252110)

Co-Investigator(Kenkyū-buntansha) 平 千明  信州大学, 学術研究院保健学系, 助教 (40779310)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywordsフィブリノゲン / フィブリン重合反応 / aホール / Ca結合部位 / D:D結合能部位 / A:a結合 / B:b結合 / トロンビン / フィブリノゲン機能異常症 / 血栓症 / 出血 / IgA-λ型Mタンパク / 血液凝固 / 蛋白質機能異常 / 遺伝子変異 / 臨床検査
Outline of Final Research Achievements

We analyzed the IgA-λ type M-protein influenced fibrin polymerization. Some of patient's fibrinogen bound to M-protein causes the alteration of fibrin clot formation. We identified the thrombogenic homozygous dysfibrinogememia (BβA68T) and analyzed the fibrin polymerization. The variant's polymerization was improved at the conditions closed to in vivo. Therefore this patient needs to prevent thrombosis but not bleeding complications.Recombinant γΔN319D320 and γD318Y fibrinogen were found to be completely no polymerization by thrombin. The reason was suggested that marked changes in the tertiary structure of the γ-module of variants influenced the the location and/or orientation of the adjacent β-module, which led to impaired “B-b” interactions.

Academic Significance and Societal Importance of the Research Achievements

フィブリノゲン(Fbg)機能異常症の原因は先天性と後天性に大別される.M蛋白の存在は後天性異常の原因として高頻度である.今回の研究ではその詳細機序を明らかにした.
先天性異常では、血栓症例と出血症例に大別される.血栓形成性BβAla68ThrホモFbgのFbn転換は生理的条件下では正常に近く出血の危険性は低いと推測した.一方,Fbn転換が欠如し出血の危険があるγΔN319D320の機能解析の結果,残念ながら製剤輸注以外適切な治療薬がないことが明らかになった。
以上,Fbgの機能異常症の原因と症状は患者ごとに違いが大きく,今後も丁寧な診断と詳細な解析が患者QOL改善に役立つと考える.

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (25 results)

All 2020 2019 2018 2017

All Journal Article (10 results) (of which Peer Reviewed: 10 results,  Open Access: 4 results) Presentation (15 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] The heterozygous variant fibrinogen, γA289V (Kanazawa III), was confirmed as hypodysfibrinogenemia by plasma and recombinant fibrinogens2020

    • Author(s)
      Kaido T, Yoda M, KamijoT, Taira C, Higuchi Y, Okumura N.
    • Journal Title

      Int J Lab Hematol

      Volume: 42 Issue: 2 Pages: 190-197

    • DOI

      10.1111/ijlh.13152

    • NAID

      120007099524

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Acquired dysfibrinogenemia: monoclonal λ-type IgA binding to fibrinogen caused lower functional plasma fibrinogen level and abnormal clot formation2020

    • Author(s)
      Arai S, Kamijo T, Takezawa Y, Sugano M, Nakazawa H, Yanagisawa R, Uehara T, Honda T, Okumura N.
    • Journal Title

      Int J Hematol

      Volume: 111 Issue: 1 Pages: 96-104

    • DOI

      10.1007/s12185-020-02874-1

    • NAID

      120007180894

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] γD318Y fibrinogen shows no fibrin polymerization due to defective “A-a” and “B-b” interactions, whereas that of γK321E fibrinogen is nearly normal2019

    • Author(s)
      KamijoT, Mukai S, Taira C, Higuchi Y, Okumura N.
    • Journal Title

      Thromb Res

      Volume: 182 Pages: 150-158

    • DOI

      10.1016/j.thromres.2019.08.017

    • NAID

      120007180893

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ファクターオートフィブリノーゲンの基礎的性能評価とフィブリノーゲン異常症例における測定値の検討2018

    • Author(s)
      永田和宏,新井慎平,向井早紀,竹澤由夏,菅野光俊,本田孝行,奥村伸生.
    • Journal Title

      医学検査

      Volume: 67 Pages: 7-12

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Hereditary Fibrinogen Aα-Chain Amyloidosis in Asia: Clinical and Molecular Characteristics2018

    • Author(s)
      Yazaki M、Yoshinaga T、Sekijima Y、Kametani F、Okumura N
    • Journal Title

      Int J Mol Sci

      Volume: 19 Issue: 1 Pages: 320-320

    • DOI

      10.3390/ijms19010320

    • NAID

      120007099523

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fibrin monomers derived from thrombogenic dysfibrinogenemia, Naples-type variant (BβAla68Thr), showed almost entirely normal polymerization2018

    • Author(s)
      Kamijo T, Nagata K, Taira C, Higuchi Y, Arai S, Okumura N.
    • Journal Title

      Thromb Res

      Volume: 172 Pages: 1-3

    • DOI

      10.1016/j.thromres.2018.10.004

    • NAID

      120007099533

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] フィブリノゲン蓄積病を呈する異常フィブリノゲン産生細胞の線維状封入体形成と小胞体ストレス応答2018

    • Author(s)
      上條途夢,大久保奈緒,平千明,樋口由美子,新井慎平,奥村伸生
    • Journal Title

      臨床病理

      Volume: 66 Pages: 1058-1064

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] DVTを発症した先天性フィブリノゲン異常症患者Fibrinogen Matsumoto I のFDP-E分画異常高値の精査2018

    • Author(s)
      新井慎平,中越りつこ,倉田淳一,川崎健治,菅野光俊,上原剛,本田孝行,奥村伸生
    • Journal Title

      検査血液

      Volume: 19 Pages: 306-313

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] A novel mutation in the fibrinogen Bβ chain (c.490G>A; End of Exon 3) causes a splicing abnormality and ultimately leads to congenital hypofibrinogenemia2017

    • Author(s)
      Taira C, Matsuda K, Arai S, Sugano M, Uehara T, Okumura N.
    • Journal Title

      Int. J. Mol. Sci.

      Volume: 18 Issue: 11 Pages: 2470-2470

    • DOI

      10.3390/ijms18112470

    • NAID

      120007099522

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A novel frameshift mutation in the fibrinogen γC terminal region, FGG c.1169_1170 del AT, leading to hypofibrinogenemia2017

    • Author(s)
      Nagata K, Arai S, Taira C, Sugano M, Honda T, Okumura N.
    • Journal Title

      Thromb Res

      Volume: 159 Pages: 82-85

    • DOI

      10.1016/j.thromres.2017.10.002

    • NAID

      120007099532

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] FGG c.112+62_65 del AATAとFGG c.1299+4 del Aのコンパウンドヘテロ型フィブリノゲン異常症Tsukuba Iの解析2019

    • Author(s)
      向井早紀,新井慎平,竹澤由夏,菅野光俊,本田孝行,奥村伸生
    • Organizer
      第20回日本検査血液学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] PT-derived法と凝固反応曲線変化量dHによるフィブリノゲン異常症検出法の検討2019

    • Author(s)
      新井慎平,上條途夢,篠原 翔,新井信夫,菅野光俊,柳沢 龍,上原 剛,本田孝行,奥村伸生
    • Organizer
      第20回日本検査血液学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] γG287~G292領域のアミノ酸置換(特にγA289V KanazawaIII)によるフィブリノゲン合成と分泌に対する影響する2019

    • Author(s)
      海藤貴大,依田将大,上條途夢,平 千明,奥村伸生
    • Organizer
      第59回日本臨床化学会年次学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Residues in the fibrinogen γD-module are essential for fibrinogen secretion and fibrin polymerization using hole ‘a’ or hole ‘b’.2019

    • Author(s)
      Kamijo T, Mukai S, Taira C, Higuchi Y, Okumura N
    • Organizer
      The 57th Congress of the Korean Association of Medical Technologists and International Conference
    • Related Report
      2019 Annual Research Report
  • [Presentation] フィブリンに全く転換できないリコンビナントフィブリノゲンγD318Yの機能解析2019

    • Author(s)
      上條途夢,依田将大,海藤貴大,平 千明,奥村伸生
    • Organizer
      第66回日本臨床検査医学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 無フィブリノゲン血症を疑い遺伝子検査を実施した重度DIC患者の1例2019

    • Author(s)
      依田将大,海藤貴大,上條途夢,平 千明,塚田唯子,奥村伸生
    • Organizer
      第66回日本臨床検査医学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 27年間で認められた長野県内のフィブリノゲン異常症17家系27症例の解析2019

    • Author(s)
      上條途夢,海藤貴大,依田将大,平 千明,樋口由美子,新井慎平,竹澤由夏,奥村伸生
    • Organizer
      第44回長野県臨床検査学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 変異型フィブリノゲンBβ44Arg->Cysがフィブリノゲン重合反応に与える影響の検討2019

    • Author(s)
      海藤貴大,依田将大,上條途夢,平 千明,樋口由美子,新井慎平,竹澤由夏,奥村伸生
    • Organizer
      第44回長野県臨床検査学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] FGA1238bp欠失を有する無フィブリノゲン血症2例のハプロタイプ解析2018

    • Author(s)
      平 千明,上條途夢,菅野光俊,奥村伸生
    • Organizer
      第58回日本臨床化学会年次学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] フィブリノゲン蓄積病を呈するフィブリノゲン低下症型フィブリノゲン産生細胞の小胞体ストレスの研究2018

    • Author(s)
      上條途夢,大久保奈緒,平 千明,奥村伸生
    • Organizer
      第58回日本臨床化学会年次学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 血栓形成性異常フィブリノゲン(Shizuoka)のトロンビンによる凝固関連機能の解析2018

    • Author(s)
      上條途夢,平 千明,樋口由美子,新井慎平,奥村伸生
    • Organizer
      第65回日本臨床検査医学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 自動分析装置による測定でフィブリノゲン活性値の偽低値と異常凝固波形を示したIgA Mタンパク症例の解析2018

    • Author(s)
      新井慎平,上條途夢,竹澤由夏,川崎健治,菅野光俊,本田孝行,奥村伸生
    • Organizer
      第65回日本臨床検査医学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Production and biochemical analysis of mutated fibrinogen Aα produced by CHO cells with D523AGTC in FGA Japan original mutation.2018

    • Author(s)
      Yoshinaga T, Yazaki M, Sekijima Y, Kametani F, Okumura N
    • Organizer
      The XVI International Symposium on Amyloidosis
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Analysis of acquired dysfibrinogenemia caused by IgA monoclonal gammopathy with anaphylactoid purpura2017

    • Author(s)
      Arai S, Takezawa Y, Mukai S, Nakagoshi R, Miyazaki A, Ishimine N, Kawasaki K, Taira C, Sugano M, Honda T, Okumura N
    • Organizer
      29 th World Congress of World Association of Societies of Pathology and Laboratory Medicine
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 新規遺伝子変異を有する先天性フィブリノゲン低下症の分子生物学的解析2017

    • Author(s)
      平 千明,菅野光俊,奥村伸生
    • Organizer
      第57回日本臨床化学会年次学術集会
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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