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The role of TGF-b family signaling in regulation of vascular integrity

Research Project

Project/Area Number 17K08794
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Experimental pathology
Research InstitutionTokyo University of Pharmacy and Life Science

Principal Investigator

Itoh Fumiko  東京薬科大学, 生命科学部, 准教授 (70502582)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
KeywordsTGF-β / 血管新生 / BMP / がん / 難治性血管疾患 / TGF-βファミリー / ミオスタチン / 低酸素 / 脱ユビキチン化酵素 / 血管退縮 / 退縮 / リンパ管新生 / Smad4 / BMP / 血管 / 貧血 / 造血幹細胞
Outline of Final Research Achievements

TGF-b signaling is involved in the normal vascular development and maintenance. Contrary to the well-documented to the action of TGF-b signaling in developmental angiogenesis, it was not clear how TGF-b BMP signaling regulate vascular system. To address this issue, Smad4 conditional knockout (CKO) mice to delete the all TGF-b superfamily, or Smad1/Smad5 CKO mice to destroy BMP signaling, were crossed with VE-Cad-icreER mice in which Cre recombinase is induced in blood and lymphatic endothelial cells by tamoxifen (Tx). I have found that BMP signaling but not TGF-b signaling is important for maintenance vascular integrity because deletion of BMP signaling in endothelial cells resulted in the death of these mice. Interestingly, these mice can be used as model mice for intractable vascular disease.

Academic Significance and Societal Importance of the Research Achievements

TGF-βファミリーシグナルの異常は、がんの悪性化や難治性血管疾患と関連している。本研究により作成された遺伝子改変マウスは、TGF-βファミリーシグナルが原因と考えられている難治性血管疾患のモデルマウスとして有益であることが示された。今後これらのマウスの解析から、疾患の発症メカに図鵜や治療法の開発に繋がると期待される。
TGF-βファミリーシグナルの阻害薬として、ペプチド製剤が有効であることが示されたほか、新規抗がん剤の治療標的として脱ユビキチン化酵素素材剤を同定することができた。特異的なTGF-βシグナル阻害剤は様々な疾患に応用できると考えられる。

Report

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

    (22 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (4 results) Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 1 results) Presentation (14 results) (of which Int'l Joint Research: 6 results,  Invited: 3 results) Book (1 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] KU leuben(ベルギー)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Iveland University(アイスランド)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] KU Leuven(ベルギー)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] KU Leuven/Department Cardiovascular Sciences(Belgium)

    • Related Report
      2017 Research-status Report
  • [Journal Article] The evolutionarily conserved deubiquitinase UBH1/UCH-L1 augments DAF7/TGF-β signaling, inhibits dauer larva formation, and enhances lung tumorigenesis.2020

    • Author(s)
      Nagata A, Itoh F, Sasho A, Sugita K, Suzuki R, Hinata H, Shimoda Y, Suzuki E, Maemoto Y, Inagawa T, Fujikawa Y, Ikeda E, Fujii C, Inoue H.
    • Journal Title

      J. Biol. Chem

      Volume: in press Issue: 27 Pages: 9105-9120

    • DOI

      10.1074/jbc.ra119.011222

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] PDZK1-interacting protein 1 (PDZK1IP1) traps Smad4 protein and suppresses transforming growth factor-β (TGF-β) signaling2019

    • Author(s)
      Ikeno S, Nakano N, Sano K, Minowa T, Sato W, Akatsu R, Sakata N, Hanagata N, Fujii M, Itoh F, Itoh S.
    • Journal Title

      J Biol Chem.

      Volume: 294 Issue: 13 Pages: 4966-4980

    • DOI

      10.1074/jbc.ra118.004153

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Presentation] Hypoxia enhances the expression level of UCH-L1 and potentiate TGF-β/Smad signaling.2019

    • Author(s)
      Itoh F,.
    • Organizer
      TGF-β Signaling Meeting, 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Hypoxia potentiates TGF-β signaling by induction of deubiquitinase UCH-L1.2019

    • Author(s)
      Itoh F, Nagata A, Furuta C, Hinata H, Sasho A, Itoh S & Inoue H.
    • Organizer
      FASEB Science Research Conferences; TGF-β superfamily conference,
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 脱ユビキチン化酵素 UCH-L1 は 低酸素条件下でTGF-β シグナルを増強する.2019

    • Author(s)
      永田麻未, 佐粧彩海, 鈴木理子, 鈴木映里, 下田裕太, 藤川雄太, 伊東史子, 井上英史
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ミオスタチン前駆体由来のミオスタチン阻害最小ペプチドはがん悪液質を改善する2019

    • Author(s)
      伊東史子、伊東進.
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] BMPシグナルはリンパ管の機能維持に必須である2019

    • Author(s)
      伊東 史子、稲川 俊彦、斎藤 裕紀 、石橋 美穂、久保田 義顕、伊東 進
    • Organizer
      第43回日本リンパ学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Endothelial TGF-β signaling inhibit tumor angiogenesis and metastasis2018

    • Author(s)
      Itoh F, Takagi T, Saito Y, Miyamoto T, Inagawa T, Nakano Y, Sano K, Fruttiger M, Itoh S
    • Organizer
      20th International Vascular Biology Meeting
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 内皮細胞のTGF-βファミリーシグナルは生命維持に必須である2018

    • Author(s)
      伊東 史子
    • Organizer
      第42回日本リンパ学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] ユビキチン C 末端加水分解酵素 UCH-L1 は Smad2 を介して TGF-β シグナルを正に制御する2018

    • Author(s)
      永田 麻未, 佐粧 彩海, 鈴木 理子, 鈴木 映里, 下田 裕太, 藤川 雄太, 渡部 琢也, 伊東 史子, 井上 英史
    • Organizer
      第91回 日本生化学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] Rndothelial TGF-b/BMP signaling is essential for maintaining vascular function2018

    • Author(s)
      Fumiko Itoh
    • Organizer
      12th International BMP conference
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Endothelial specific depletion of BMP-Smad signaling affects vascular function2018

    • Author(s)
      Ishibashi M, Inagawa T, SaitoY, WatanabeT, Kubota T, Itoh S, Zwijsen A, Itoh F.
    • Organizer
      12th International BMP conference
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] BMPシグナルによるリンパ管の機能維持2018

    • Author(s)
      伊東 史子、稲川 俊彦、石橋 美穂、斎藤 裕紀 、久保田 義顕、伊東 進
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] epletion of endothelial TGF-b signaling induces both tumor angiogenesis and metastasis.2017

    • Author(s)
      Fumiko Itoh
    • Organizer
      ASEB Science research conference.
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 13.伊東史子.血管・リンパ管内皮細胞におけるTGF-βファミリーシグナルの重要性.2017

    • Author(s)
      伊東史子
    • Organizer
      日本分子生物学会年会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 腫瘍転移におけるTGF-βファミリーシグナルの役割2017

    • Author(s)
      伊東史子
    • Organizer
      日本リンパ学会総会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Book] 基礎講義 遺伝子工学Ⅱ2018

    • Author(s)
      深見 希代子、山岸 明彦
    • Total Pages
      192
    • Publisher
      東京化学同人
    • ISBN
      9784807909513
    • Related Report
      2018 Research-status Report
  • [Patent(Industrial Property Rights)] マイオスタチン阻害ペプチド2017

    • Inventor(s)
      林 良雄、伊東 史子
    • Industrial Property Rights Holder
      林 良雄、伊東 史子
    • Industrial Property Rights Type
      特許
    • Filing Date
      2017
    • Acquisition Date
      2017
    • Related Report
      2017 Research-status Report

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

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