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A critical role of Gas6-TAM signaling pathway in the pathology of HSCT-associated TMA

Research Project

Project/Area Number 18K08366
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionFukushima Medical University

Principal Investigator

Ogawa Kazuei  福島県立医科大学, 医学部, 教授 (40423800)

Co-Investigator(Kenkyū-buntansha) 大河原 浩  福島県立医科大学, 医学部, 准教授 (10381360)
池添 隆之  福島県立医科大学, 医学部, 教授 (80294833)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2020: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000)
Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsGas6 / Mer / 造血幹細胞移植 / 移植後TMA / GVHD / TMA / TA-TMA / HSCT / 同種造血幹細胞移植 / 血栓性微小血管障害症 / 急性移植片対宿主病 / TAM受容体
Outline of Final Research Achievements

Growth arrest-specific (Gas) 6 structurally belongs to the family of plasma vitamin K-dependent proteins working as a cofactor for activated protein C, and has growth factor-like properties through its interaction with receptor tyrosine kinases of the TAM family. Serum Gas6 levels were significantly increased in HSCT patients with transplant-associated thrombotic microangiopathy (TA-TMA), and Gas6 and a selective Mer tyrosine kinase (Mer) expression levels were upregulated in TA-TMA lesions of liver and kidney. In human umbilical vein endothelial cells (ECs),the exposure of sera isolated from patients with aute GVHD to ECs induced the downregulation of thrombomodulin, which were inhibited by UNC2250, a selective Mer tyrosine kinase inhibitor. In mouse HSCT models, we observed TA-TMA, which is characterized pathologically by thrombosis formation in the microvasculature of the liver and kidney. Of note, UNC2250 treatment suppressed TA-TMA in these mouse HSCT models.

Academic Significance and Societal Importance of the Research Achievements

本研究は移植後TMAの病態解明に寄与するとともに、 Gas6-Merシグナルが新たな治療標的候補や新規バイオマーカーとなることを示した。我々の研究成果は新たな創薬や検査法の開発に大きく貢献できる可能性を秘めている。我々の研究成果は新たな創薬や検査法の開発に大きく貢献できる可能性を秘めている。これらの研究結果は2018年10月日本血液学会総会(大阪)、2018年12月米国血液学会学術集会(サンディエゴ)にて発表した。研究成果は米国科学雑誌Blood Advancesに掲載された(Blood Adv.2019;3(14):2128-2143.)。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (5 results)

All 2019 2018

All Journal Article (1 results) Presentation (4 results)

  • [Journal Article] A critical role of the Gas6-Mer axis in endothelial dysfunction contributing to TA-TMA associated with GVHD2019

    • Author(s)
      Miki Furukawa, Xintao Wang, Hiroshi Ohkawara, Masahiko Fukatsu, Lobna Alkebsi, Hiroshi Takahashi, Kayo Harada-Shirado, Akiko Shichishima-Nakamura, Satoshi Kimura, Kazuei Ogawa, Takayuki Ikezoe
    • Journal Title

      Blood Advances

      Volume: 3(14) Pages: 2128-2143

    • Related Report
      2019 Research-status Report
  • [Presentation] ARDSの新規治療ターゲット:Gas6-Merシグナル2019

    • Author(s)
      第81回 日本血液学会学術集会 (2019.10.11-10.13, 東京) 古川未希, 王新涛, 大河原浩, 深津真彦, Alkebsi Lobna, 小川一英, 池添隆之.
    • Organizer
      第81回 日本血液学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] Gas6/Mer を目的とした新規ARDS治療法の開発2019

    • Author(s)
      深津真彦
    • Organizer
      日本血液学会東北地方会主催 血液学シンポジウム
    • Related Report
      2019 Research-status Report
  • [Presentation] GVHD及びTMAの病態におけるGas6-TAM受容体シグナルの関与2018

    • Author(s)
      古川未希 大河原浩 小川一英 池添隆之
    • Organizer
      2018年10月日本血液学会総会(大阪)
    • Related Report
      2018 Research-status Report
  • [Presentation] A Critical Role of Growth Arrest-Specific Gene 6-Mer Axis in the Pathogenesis of Endothelial Damage Contributing to Thrombotic Microangiopathy Associated with Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation2018

    • Author(s)
      古川未希 大河原浩 小川一英 池添隆之
    • Organizer
      2018年12月米国血液学会学術集会(サンディエゴ)
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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