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Elucidation of the pathophysiology of pulmonary fibrosis and development of new treatments by applying metabolome analysis

Research Project

Project/Area Number 18K08136
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53030:Respiratory medicine-related
Research InstitutionTohoku University

Principal Investigator

Ohkouchi Shinya  東北大学, 事業支援機構, 講師 (40375035)

Co-Investigator(Kenkyū-buntansha) 黒澤 一  東北大学, 事業支援機構, 教授 (60333788)
岡田 克典  東北大学, 加齢医学研究所, 教授 (90323104)
兼平 雅彦  東北大学, 大学病院, 助教 (90374941)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Keywords間葉系幹細胞 / Stanniocalcin-1 / 抗酸化作用 / 抗線維化作用 / 抗炎症作用 / 翻訳後修飾 / SOCS1 / SMAD7 / 脱共役呼吸 / 間質性肺炎 / 肺障害 / 治療 / 新型コロナウイルス感染症 / 吸入療法 / エピゲノム / メタボローム / 肺線維症
Outline of Final Research Achievements

Since the mesenchymal stem cell (MSC) -derived humoral factor Stanniocalcin-1 (STC1) regulates mitochondrial membrane potential, the effect of the addition or inhalation of STC1 on the central metabolic pathway were evaluated in cells and bleomycin inhalation mice model using comprehensive metabolomics analyses and specific measurements against each substance. We revealed STC1 affects the TCA, β-oxidation, methionine and glutathione pathway. These results explained the antioxidant effect of STC1 and suggested a relationship with post-translational modification (epigenetics). From additional experiments, we revealed that STC1 induced SOCS1 / SMAD7 demethylation and histone / SMAD7 acetylation. Furthermore, SOCS1 suppressed the JAK / STAT pathway and SMAD7 suppressed the TGFβ / SMAD pathway in cells and animal model. From the above, it was shown that STC1 may be used for the treatment of COVID19, autoimmune diseases, and fibrotic diseases.

Academic Significance and Societal Importance of the Research Achievements

STC1によるの難病治療への可能性を示したことが本研究成果の意義である。STC1経気道投与の特徴は、①細胞代謝と翻訳後修飾の相互関連に着目した新規作用機序、②生体物質であり、経気道投与が可能であることにより得られる高い安全性、③HEK293細胞を利用したリコンビナントタンパクとして、安価、簡便に得ることが可能であること、等である。用途として、①新型コロナウイルス感染症の感染予防薬・重症化予防及び治療、②JAK/STATが関連する関節リウマチ等の自己免疫疾患に対する治療、③TGFβ/SMADが関連する特発性肺線維症等の線維性疾患に対する治療などが考えられる。本研究に関して特許を出願中である。

Report

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

    (19 results)

All 2021 2020 2019 2018

All Journal Article (9 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 9 results,  Open Access: 6 results) Presentation (7 results) (of which Int'l Joint Research: 7 results) Book (2 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Targeting stanniocalcin‐1‐expressing tumor cells elicits efficient antitumor effects in a mouse model of human lung cancer2021

    • Author(s)
      Abe Kotaro、Kanehira Masahiko、Ohkouchi Shinya、Kumata Sakiko、Suzuki Yamato、Oishi Hisashi、Noda Masafumi、Sakurada Akira、Miyauchi Eisaku、Fujiwara Tohru、Harigae Hideo、Okada Yoshinori
    • Journal Title

      Cancer Medicine

      Volume: 10 Issue: 9 Pages: 3085-3100

    • DOI

      10.1002/cam4.3852

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Extraterrestrial hexamethylenetetramine in meteorites-a precursor of prebiotic chemistry in the inner solar system.2020

    • Author(s)
      Oba Y., Takano Y., Naraoka H., Furukawa Y., Glavin D. P., Dworkin J. P. and Tachibana S.
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 6243-6243

    • DOI

      10.1038/s41467-020-20038-x

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Validation of a new serum granulocyte?macrophage colony-stimulating factor autoantibody testing kit2020

    • Author(s)
      Nakata Koh, Tazawa Ryushi, Ohkouchi Shinya, Hirano Taizou, Kitamura Nobutaka
    • Journal Title

      ERJ Open Research

      Volume: 6 Issue: 1 Pages: 00259-2019

    • DOI

      10.1183/23120541.00259-2019

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Kobayashi K, Ohkouchi S, Sasahara Y, Ebina M, Nakata K, Saito R, Akiba M, Sado T, Oishi H, Watanabe T, Kurosawa H, Okada Y. Improvement of native pulmonary alveolar proteinosis after contralateral single living-donor lobar lung transplantation: A case report.2020

    • Author(s)
      Kobayashi K, Ohkouchi S, Sasahara Y, Ebina M, Nakata K, Saito R, Akiba M, Sado T, Oishi H, Watanabe T, Kurosawa H, Okada Y.
    • Journal Title

      Pediatr Transplant

      Volume: 24 Issue: 2

    • DOI

      10.1111/petr.13659

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhaled GM-CSF for Pulmonary Alveolar Proteinosis2019

    • Author(s)
      Tazawa R、Ueda T、Abe M、Tatsumi K、Eda R、Kondoh S、Morimoto K、Tanaka T、Yamaguchi E、Takahashi A、Oda M、Ishii H、Izumi S、Sugiyama H、Nakagawa A、Tomii K、Suzuki M、Konno S、Ohkouchi S、Tode N、Handa T、Hirai T、Inoue Y、Arai T、Asakawa K、Sakagami T、Hashimoto A、Tanaka T、Takada T、Mikami A、Kitamura N、Nakata K
    • Journal Title

      New England Journal of Medicine

      Volume: 381 Issue: 10 Pages: 923-932

    • DOI

      10.1056/nejmoa1816216

    • NAID

      120007087887

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Incidence of autoimmune pulmonary alveolar proteinosis estimated using Poisson distribution2019

    • Author(s)
      Kitamura Nobutaka、Ohkouchi Shinya、Tazawa Ryushi、Ishii Haruyuki、Takada Toshinori、Sakagami Takuro、Tanaka Takahiro、Nakata Koh
    • Journal Title

      ERJ Open Research

      Volume: 5 Issue: 1 Pages: 00190-2018

    • DOI

      10.1183/23120541.00190-2018

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Respiratory resistance among adults in a population-based cohort study in Northern Japan.2019

    • Author(s)
      Miura E, Tsuchiya N, Igarashi Y, Arakawa R, Nikkuni E, Tamai T, Tabata M, Ohkouchi S, Irokawa T, Ogawa H, Takai-Igarashi T, Suzuki Y, Kuriyama S, Tamiya G, Hozawa A, Yamamoto M, Kurosawa H.
    • Journal Title

      Respiratory Investigation

      Volume: 印刷中 Issue: 3 Pages: 30226-0

    • DOI

      10.1016/j.resinv.2018.12.008

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Peripheral alveolar nitric oxide concentration reflects alveolar inflammation in autoimmune pulmonary alveolar proteinosis.2018

    • Author(s)
      Hirano T, Ohkouchi S, Tode N, Kobayashi M, Ono M, Satoh T, Mitsuishi Y, Watanabe A, Tabata M, Irokawa T, Ogawa H, Sugiura H, Kikuchi T, Akasaka K, Tazawa R, Inoue Y, Nakata K, Kurosawa H, Ichinose M.
    • Journal Title

      ERJ open research

      Volume: 4 Issue: 1 Pages: 00071-2017

    • DOI

      10.1183/23120541.00071-2017

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Bone marrow mesenchymal stromal cells protect allograft lung transplants from acute rejection via the PD-L1/IL-17A axis2018

    • Author(s)
      Ishibashi Naoya、Watanabe Tatsuaki、Kanehira Masahiko、Watanabe Yui、Hoshikawa Yasushi、Notsuda Hirotsugu、Noda Masafumi、Sakurada Akira、Ohkouchi Shinya、Kondo Takashi、Okada Yoshinori
    • Journal Title

      Surgical Today

      Volume: 48 Issue: 7 Pages: 726-734

    • DOI

      10.1007/s00595-018-1643-x

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] tanniocalcin-1 (STC1) Affects SMAD7 Epigenetics, Increases Glutathione Synthesis and Ameliorate Bleomycin Fibrosis Through Regulating Integrated Metabolic Pathways2020

    • Author(s)
      Shinya Ohkouchi
    • Organizer
      米国胸部学会
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Stanniocalcin-1 (STC1) Affects SMAD7 Epigenetics, Increases Glutathione Synthesis And Ameliorate Bleomycin Fibrosis Through Regulating Integrated Metabolic Pathways2020

    • Author(s)
      Shinya Ohkouchi
    • Organizer
      米国胸部学会(ATS) 年次総会 2020 フィラデルフィア
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Comprehensive metabolome analysis reveals new mechanism of anti-fibrotic factor Stanniocalcin-1 (STC1) which modulate epigenetic regulation and oxidative stress2019

    • Author(s)
      Shinya Ohkouchi
    • Organizer
      アジア太平洋呼吸器学会(APSR) 年次総会 2019 ハノイ
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Comprehensive metabolome analysis reveals new mechanism of anti-fibrotic factor Stanniocalcin-1 (STC1) which modulate epigenetic regulation and oxidative stress2019

    • Author(s)
      Shinya Ohkouchi
    • Organizer
      米国胸部臨床学会
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] New Insights of the Pathology of Pulmonary Fibrosis Revealed by Metabolome Analysis2018

    • Author(s)
      Shinya Ohkouchi
    • Organizer
      米国胸部臨床学会
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] New Insights of the Pathology of Pulmonary Fibrosis Revealed by Metabolome Analysis2018

    • Author(s)
      Shinya Ohkouchi
    • Organizer
      太平洋アジア呼吸器学会
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Anti-fibrotic Factor Stanniocalcin1 (STC1) and Systemic Damage Response2018

    • Author(s)
      Shinya Ohkouchi
    • Organizer
      日本呼吸器学会
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Book] Disaster and Respiratory Diseases2019

    • Author(s)
      Ohkouchi Shinya, Yamauchi Kohei, Yamanda Shunsuke, Fujimoto Eisaku
    • Total Pages
      178
    • Publisher
      Springer
    • ISBN
      9789811325977
    • Related Report
      2019 Research-status Report
  • [Book] Disaster and Respiratory Disease2018

    • Author(s)
      Shinya Ohkouchi, Shinsuke Yamanda, Shu Hisata, Masao Tabata, Toshiya Irokawa, Hiromasa Ogawa, Hajime Kurosawa, Kohei Yamauchi, Keisaku Fujimoto
    • Total Pages
      178
    • Publisher
      Springer
    • ISBN
      9789811325977
    • Related Report
      2018 Research-status Report
  • [Patent(Industrial Property Rights)] コロナウイルス感染症の予防または治療剤2021

    • Inventor(s)
      大河内眞也
    • Industrial Property Rights Holder
      大河内眞也
    • Industrial Property Rights Type
      特許
    • Filing Date
      2021
    • Related Report
      2020 Annual Research Report

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Published: 2018-04-23   Modified: 2022-03-04  

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