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Creation of new therapeutic strategies for vascular malformations by targeting the ubiquitin E3 complex

Research Project

Project/Area Number 19K10030
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56070:Plastic and reconstructive surgery-related
Research InstitutionEhime University

Principal Investigator

Nakaoka Hiroki  愛媛大学, 医学部附属病院, 准教授 (30172266)

Co-Investigator(Kenkyū-buntansha) 東山 繁樹  愛媛大学, プロテオサイエンスセンター, 教授 (60202272)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords血管奇形 / 血管新生 / ユビキチンリガーゼ / ユビキチン / ケラチノサイト / ユビキチンE3リガーゼ / 血管腫 / 新規治療戦略
Outline of Research at the Start

血管奇形の新規薬物治療が可能になれば、患者利益、医療経済に貢献できるが、血管奇形の血管内皮細胞質的変化の分子基盤が未解明のため、特異的分子標的薬は未開発である。
本研究では血管奇形におけるCUL3型ユビキチンE3複合体軸の発現解析に基づいた血管奇形の分子標的薬のシーズ化合物の導出を目的とする。
各血管奇形組織で4つのCUL3複合体軸の発現を解析し、血管奇形由来血管内皮細胞の培養系でCUL3複合体軸の発現抑制時の血管機能を細胞レベルで解析する。アルファスクリーンシステムでCUL3複合体の形成阻害剤を検索し、4つのCUL3複合体依存的な血管機能制御の分子基盤を分子標的薬の開発標的として導出する。

Outline of Final Research Achievements

The dysregulation of angiogenesis, new vascular vessel formation, causes some vascular malformations. The disease leads to not only the decrease of patients’ quality of life but also the critical health issues such as heart failure. To date, pharmaceutics for vascular malformations is not well established because of the lack of molecular mechanisms underlying the formation of malformations. In this study, we found that a BTBP for the cullin-3/RING ubiquitin ligase complex highly expressed in endothelial cells of vascular malformations. We also screened compounds which inhibit the BTBP function using the AlphaScreen system. As a result, a set of compounds were identified as an inhibitor of the cullin-3/BTBP interaction.

Academic Significance and Societal Importance of the Research Achievements

血管奇形は異常/過剰な血管新生が原因となる疾患と考えられている。外見・容姿・機能面への影響に加え、重篤化すると心不全などの病態を引き起こすものも見られる。本研究で見出した血管奇形で発現するユビキチンリガーゼに対する阻害剤は今後新たな血管奇形の治療薬のシーズとして期待される。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (5 results)

All 2021 2020

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (2 results) (of which Invited: 1 results)

  • [Journal Article] Japanese Clinical Practice Guidelines for Vascular Anomalies 20172020

    • Author(s)
      Mimura Hidefumi、Akita Sadanori、Fujino Akihiro、Jinnin Masatoshi、Ozaki Mine、Osuga Keigo、Nakaoka Hiroki、et.al
    • Journal Title

      The Journal of Dermatology

      Volume: 47 Issue: 5

    • DOI

      10.1111/1346-8138.15189

    • NAID

      50014510455

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Japanese clinical practice guidelines for vascular anomalies 20172020

    • Author(s)
      Mimura Hidefumi、Akita Sadanori、Fujino Akihiro、Jinnin Masatoshi、Ozaki Mine、Osuga Keigo、Nakaoka Hiroki、et.al
    • Journal Title

      Japanese Journal of Radiology

      Volume: 38 Issue: 4 Pages: 287-342

    • DOI

      10.1007/s11604-019-00885-5

    • NAID

      50014510455

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Japanese clinical practice guidelines for vascular anomalies 20172020

    • Author(s)
      Mimura Hidefumi、Akita Sadanori、Fujino Akihiro、Jinnin Masatoshi、Ozaki Mine、Osuga Keigo、Nakaoka Hiroki、et.al
    • Journal Title

      Pediatrics International

      Volume: 62 Issue: 3 Pages: 260-307

    • DOI

      10.1111/ped.14077

    • NAID

      50014510455

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 脈管腫・脈管奇形の分類と治療2021

    • Author(s)
      中岡啓喜
    • Organizer
      日本皮膚科学会 愛媛地方会 第72回学術大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 乳児血管腫の治療 -患者家族に寄り添う診療を目指してー2021

    • Author(s)
      中岡啓喜
    • Organizer
      第36回北日本形成外科学会
    • Related Report
      2021 Annual Research Report
    • Invited

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Published: 2019-04-18   Modified: 2023-01-30  

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