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Development of novel therapeutic strategies targeting cellular metabolism in autoimmune diseases

Research Project

Project/Area Number 18K08387
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54020:Connective tissue disease and allergy-related
Research InstitutionKobe University

Principal Investigator

Saegusa Jun  神戸大学, 医学研究科, 准教授 (20514970)

Co-Investigator(Kenkyū-buntansha) 森信 暁雄  神戸大学, 医学研究科, 准教授 (10294216)
河野 誠司  神戸大学, 医学部附属病院, 特命教授 (20351512)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords関節リウマチ / グルタミン代謝 / オートファジー / クロロキン / マウス関節炎モデル / 代謝 / グルタミノリシス / ラパマイシン / 自己免疫疾患 / 全身性自己免疫疾患
Outline of Final Research Achievements

The glutamine metabolism inhibitor 6-diazo-5-oxo-L-norleucin (DON) and the mTOR inhibitor rapamycin suppressed T cell proliferation. In addition, the combined use of both showed a significantly stronger growth inhibitory effect than the case of a single agent. DON and rapamycin suppressed Th17 cell differentiation. DON suppressed the differentiation of bone marrow cells into dendritic cells and macrophages and promoted the differentiation into bone marrow-derived inhibitory cells (MDSC).
Furthermore, the effect of both drugs on suppressing mouse arthritis was examined. We demonstrated that combined treatment with rapamycin and DON additively ameliorated the arthritis in SKG mice, possibly by suppressing CD4+ T cell proliferation and Th17 differentiation.

Academic Significance and Societal Importance of the Research Achievements

関節リウマチの病態には細胞内代謝異常が関わっており、グルタミン代謝阻害薬とmTOR阻害薬の併用療法は関節リウマチの新規治療法になり得ると考えられた。

Report

(2 results)
  • 2021 Final Research Report ( PDF )
  • 2018 Research-status Report
  • Research Products

    (9 results)

All 2019 2018

All Journal Article (6 results) (of which Peer Reviewed: 5 results,  Open Access: 6 results) Presentation (3 results) (of which Int'l Joint Research: 3 results)

  • [Journal Article] Additive effects of inhibiting both mTOR and glutamine metabolism on the arthritis in SKG mice2019

    • Author(s)
      Ueda Yo、Saegusa Jun、Okano Takaichi、Sendo Sho、Yamada Hirotaka、Nishimura Keisuke、Morinobu Akio
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 6374-6374

    • DOI

      10.1038/s41598-019-42932-1

    • NAID

      120006624233

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Immunometabolism in rheumatoid arthritis2018

    • Author(s)
      Okano Takaichi、Saegusa Jun、Takahashi Soshi、Ueda Yo、Morinobu Akio
    • Journal Title

      Immunological Medicine

      Volume: 41 Issue: 3 Pages: 89-97

    • DOI

      10.1080/25785826.2018.1531186

    • NAID

      120006840208

    • Related Report
      2018 Research-status Report
    • Open Access
  • [Journal Article] Myeloid-derived suppressor cells in non-neoplastic inflamed organs2018

    • Author(s)
      Sendo Sho、Saegusa Jun、Morinobu Akio
    • Journal Title

      Inflammation and Regeneration

      Volume: 38 Issue: 1

    • DOI

      10.1186/s41232-018-0076-7

    • NAID

      120006539277

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] MicroRNA-124 inhibits TNF-α- and IL-6-induced osteoclastogenesis2018

    • Author(s)
      Ohnuma Kenichiro、Kasagi Shimpei、Uto Kenichi、Noguchi Yoriko、Nakamachi Yuji、Saegusa Jun、Kawano Seiji
    • Journal Title

      Rheumatology International

      Volume: 39 Issue: 4 Pages: 689-695

    • DOI

      10.1007/s00296-018-4218-7

    • NAID

      120006629301

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] S100A12 facilitates osteoclast differentiation from human monocytes2018

    • Author(s)
      Nishida Miwa、Saegusa Jun、Tanaka Shino、Morinobu Akio
    • Journal Title

      PLOS ONE

      Volume: 13 Issue: 9 Pages: e0204140-e0204140

    • DOI

      10.1371/journal.pone.0204140

    • NAID

      120006529678

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cardiac Dysfunction in Duchenne Muscular Dystrophy Is Less Frequent in Patients With Mutations in the Dystrophin Dp116 Coding Region Than in Other Regions2018

    • Author(s)
      Yamamoto Tetsushi、Awano Hiroyuki、Zhang Zhujun、Sakuma Mio、Kitaaki Shoko、Matsumoto Masaaki、Nagai Masashi、Sato Itsuko、Imanishi Takamitsu、Hayashi Nobuhide、Matsuo Masafumi、Iijima Kazumoto、Saegusa Jun
    • Journal Title

      Circulation: Genomic and Precision Medicine

      Volume: 11 Issue: 1

    • DOI

      10.1161/circgen.117.001782

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Combined inhibition of mechanistic target of rapamycin and glutamine metabolism inhibits CD4 T cell proliferation and Th17 differentiation, facilitates the expansion of myeloid-derived suppressor cells, and synergistically ameliorates arthritis in SKG mice.2018

    • Author(s)
      Ueda Y, Saegusa J, Okano T, Sendo S, Yamada H, Akashi K, Onishi A, Morinobu A
    • Organizer
      American College of Rheumatology 82nd Annual Scientific Meeting
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Tofacitinib facilitates the expansion of myeloid-derived suppressor cells and ameliorates interstitial lung disease in SKG mice.2018

    • Author(s)
      Sendo S, Saegusa J, Ichise Y, Yamada H, Naka I, Ueda Y, Okano T, Morinobu A
    • Organizer
      American College of Rheumatology 82nd Annual Scientific Meeting
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Combination therapy of rapamycin and a glutamine antagonist facilitates the expansion of myeloid-derived suppressor cells and ameliorates arthritis in SKG mice.2018

    • Author(s)
      Ueda Y, Saegusa J, Okano T, Sendo S, Yamada H, Ichise Y, Naka I, Takahashi S, Akashi K, Onishi A, Morinobu A
    • Organizer
      The 19th Annual European Congress of Rheumatology - EULAR
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research

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Published: 2018-04-23   Modified: 2025-03-27  

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