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Exploration of candidate compounds that overcome infectious disease by inducing TRAF6 degradation

Research Project

Project/Area Number 16K08352
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Environmental and hygienic pharmacy
Research InstitutionMusashino University

Principal Investigator

Muroi Masashi  武蔵野大学, 薬学部, 教授 (70311389)

Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords感染症疾患 / Toll-like receptor / 炎症性疾患 / エンドトキシン / 感染症 / Toll-like erceptor / 自然免疫 / TRAF6 / IRAK-1 / 炎症性メディエーター / 微生物・感染症学
Outline of Final Research Achievements

I previously found that IRAK-1, a kinase involved in Toll-like receptor signaling, induced degradation of TRAF6, an indispensable molecule for Toll-like receptor signaling. This study explored a minimal structural region of IRAK-1 for the degradation, which may applicable to the treatment of infectious diseases through inhibition of exacerbated production of inflammatory mediators.
Among 712 amino acids of IRAK-1, I found that only Death Domain(D: amino acid 1-102)and C1 (amino acid 523-618) or C2 (amino acid 619-712) were required for the degradation of TRAF6. C1 and C2 contain three potential TRAF6-binding sequences, each of which consists of five amino acids, and I also found that expression of these sequence structures in cells induced degradation of TRAF6.
These results provide a possibility for obtaining a therapeutic drug, which inhibits exacerbated production of inflammatory mediators, for infectious diseases, and shed light on the treatment of unovercome infectious diseases.

Academic Significance and Societal Importance of the Research Achievements

細菌感染症疾患は、米国内だけでもこれによる死者が年間に数十万人にも達すると推定されている臨床上の重大な問題であるにもかかわらず、現在、効果的な治療法がなく、有効な治療薬の開発が切に望まれている。本研究では感染症疾患につながる炎症性メディエーター産生に関与するTRAF6を効果的に分解するペプチドを見出した。このペプチド構造を擬態する低分子化学物質が得られれば細菌感染症疾患治療薬の開発に多大に貢献するものである。また、TRAF6蛋白質の機能抑制は骨新生を促すことも報告されており、TRAF6の分解を誘導する薬物は、骨粗鬆症、関節リウマチなどの運動器疾患の治療薬の開発にもつながるものと期待できる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (15 results)

All 2019 2018 2017 2016

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 1 results) Presentation (11 results) (of which Invited: 1 results) Book (1 results)

  • [Journal Article] IRF1 supports DNA binding of STAT1 by promoting its phosphorylation2018

    • Author(s)
      Zenke Kosuke、Muroi Masashi、Tanamoto Ken-ichi
    • Journal Title

      Immunology and Cell Biology

      Volume: 96 Issue: 10 Pages: 1095-1103

    • DOI

      10.1111/imcb.12185

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Time dependent distinct roles of Toll-like receptor 4 in a house-dust-mite-induced asthma mouse model2018

    • Author(s)
      Ishii T, Niikura Y, Kurata K, Muroi M, Tanamoto K, Nagase T, Sakaguchi M, Yamashita N
    • Journal Title

      Scandinavian Journal of Immunology

      Volume: 87 Issue: 3 Pages: 1-7

    • DOI

      10.1111/sji.12641

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] AKT1 distinctively suppresses MyD88-depenedent and TRIF-dependent Toll-like receptor signaling in a kinase activity-independent manner2018

    • Author(s)
      Zenke Kosuke、Muroi Masashi、Tanamoto Ken-ichi
    • Journal Title

      Cellular Signalling

      Volume: 43 Pages: 32-39

    • DOI

      10.1016/j.cellsig.2017.12.002

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed
  • [Presentation] 一酸化窒素合成酵素(iNOS)の転写と発現におけるNF-κB1(p50/p105)の役割2019

    • Author(s)
      善家 孝介、竹居 芳恵 、津田 知希、相馬 柊子、室井 正志、棚元 憲一
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] STAT1の活性化にはN末側アミノ酸も必要である2019

    • Author(s)
      室井 正志、善家 孝介、棚元 憲一
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] STAT1により誘導されるIRF1はSTAT1を活性化する2019

    • Author(s)
      室井正志、善家孝介、棚元憲一
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Research-status Report
  • [Presentation] AKT1はキナーゼ活性に依存せずTLR4シグナリング活性化を抑制する2019

    • Author(s)
      善家孝介、室井正志、棚元憲一
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Research-status Report
  • [Presentation] AKT1はキナーゼ活性に依存せずTLR4シグナリング活性化を抑制する2018

    • Author(s)
      善家孝介、室井正志、棚元憲一
    • Organizer
      日本薬学会第138年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] STAT1により誘導されるIRF1はSTAT1を活性化する2018

    • Author(s)
      室井正志、善家孝介、棚元憲一
    • Organizer
      日本薬学会第138年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] AKT1によるToll-like receptorシグナリングの調節2018

    • Author(s)
      室井正志、善家孝介、棚元憲一
    • Organizer
      第100回日本細菌学会関東支部総会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] Role of the C-terminal region of STAT1 on its binding to the GAS element.2017

    • Author(s)
      Muroi M., Zenke K., Tsuchiya K., and Tanamoto K.
    • Organizer
      第90回日本細菌学会総会
    • Place of Presentation
      仙台国際センター
    • Year and Date
      2017-03-19
    • Related Report
      2016 Research-status Report
  • [Presentation] Suppression of Toll-like receptor signaling by kinase-dead AKT1.2017

    • Author(s)
      Zenke K., Muroi M., Ido T., Tanobe R., Ihashi Y., and Tanamoto K.
    • Organizer
      第90回日本細菌学会総会
    • Place of Presentation
      仙台国際センター
    • Year and Date
      2017-03-19
    • Related Report
      2016 Research-status Report
  • [Presentation] STAT1における二量体化とGASへの結合に必要なアミノ酸配列2017

    • Author(s)
      室井正志、善家孝介、土屋光平、棚元憲一
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台国際センター
    • Related Report
      2016 Research-status Report
  • [Presentation] Toll-like receptorシグナリングに対する非活性型AKT1の抑制作用2017

    • Author(s)
      善家孝介、室井正志、井戸貴彬、田野邊竜平、井橋佑太、棚元憲一
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台国際センター
    • Related Report
      2016 Research-status Report
  • [Book] エンドトキシン・自然免疫研究「TRAF6を介したシグナル伝達とシグナル抑制に必要なIRAK-1の構造領域」2016

    • Author(s)
      室井正志、棚元憲一
    • Total Pages
      3
    • Publisher
      医学図書出版
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2022-12-28  

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