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炎症性Th17細胞においてRORγtが認識するリポクオリティ分子機構の解明

Publicly Offered Research

Project AreaQuality of lipids in biological systems
Project/Area Number 16H01352
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionChiba University

Principal Investigator

遠藤 裕介  千葉大学, 大学院医学研究院, 特任講師 (80612192)

Project Period (FY) 2016-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
Fiscal Year 2017: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2016: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
KeywordsRORγt / ACC1 / 脂質代謝 / Th17細胞 / リピドミクス解析 / ゲノム編集 / 脂質 / 細胞内代謝 / 免疫学 / 病態医化学 / リポクオリティ / RORyt / 炎症性免疫疾患
Outline of Annual Research Achievements

本研究は、Th17細胞のマスター転写因子であるRORγtの脂質リガンドを同定し、Th17細胞分化における脂質代謝の役割を正確に理解することで、脂質・RORγtを標的とした新たな創薬ターゲット・診断ツールの構築を目的とする。平成29年度の一連の研究で、以下に示す3つの新知見を見出した。
1.RORγt脂質リガンドによるマウス病態モデル解析:ACC1の選択的阻害剤TOFAをマウスに投与することにより、Th17細胞依存的な自己免疫疾患マウスモデル EAE及びTh17誘導性の喘息病態が抑制されるか検討したところ、予想どおりEAE病態の劇的な改善が認められた。また、TOFAによるEAE病態の改善は肥満病態状況下においても同様に認められた。
2.RORγtの内在性リガンドとなる脂質代謝物の同定:これまでの研究実績により、RORγtの内在性リガンドとなりうる候補脂質代謝物は絞り込まれた。脂質代謝酵素の発現を基に、ACC1よりもさらに下流の酵素をゲノム編集技術により遺伝子欠損スクリーニングを行い、RORγtの機能を低下させる経路および、脂質代謝物を選別した。このスクリーニング手法を用いて酵素Xを欠損させたところ、RORγtの転写活性能および、Th17細胞分化能が著しく低下することが示された。
3.脂質代謝酵素X欠損マウスの解析:2の結果を基に、脂質代謝酵素X欠損マウスについて解析を行った。Cas9システムを用いた酵素Xの結果と同様に、酵素X欠損マウス由来のCD4 T細胞をTh17細胞分化条件下で培養したところ、Th17細胞分化能の低下が認められた。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (13 results)

All 2017 2016 Other

All Journal Article (5 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 5 results,  Open Access: 5 results,  Acknowledgement Compliant: 2 results) Presentation (6 results) (of which Int'l Joint Research: 4 results,  Invited: 2 results) Book (1 results) Remarks (1 results)

  • [Journal Article] Epigenetic regulation of T-helper cell differentiation, memory, and plasticity in allergic asthma2017

    • Author(s)
      Tumes Damon J.、Papadopoulos Magdalene、Endo Yusuke、Onodera Atsushi、Hirahara Kiyoshi、Nakayama Toshinori
    • Journal Title

      Immunol. Rev

      Volume: 278 Issue: 1 Pages: 8-19

    • DOI

      10.1111/imr.12560

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The obesity-related pathology and Th17 cells.2017

    • Author(s)
      Endo, Y., Yokote, K., and Nakayama, T.
    • Journal Title

      Cell. Mol. Life Sci.

      Volume: 74 Issue: 7 Pages: 1231-1245

    • DOI

      10.1007/s00018-016-2399-3

    • NAID

      40021094104

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Th2 cells in health and disease.2016

    • Author(s)
      Nakayama T, Hirahara K, Onodera A, Endo Y, Hosokawa H, Shinoda K, Tumes DJ, Okamoto Y.
    • Journal Title

      Annu Rev Immunol.

      Volume: 35 Issue: 1 Pages: 53-84

    • DOI

      10.1146/annurev-immunol-051116-052350

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Akt1-mediated Gata3 phosphorylation controls the repression of IFNγ in memory-type Th2 cells.2016

    • Author(s)
      Hosokawa H, Tanaka T, Endo Y, Kato M, Shinoda K, Suzuki A, Motohashi S, Matsumoto M, Nakayama K, Nakayama T.
    • Journal Title

      Nat Commun.

      Volume: - Issue: 1 Pages: 11289-11289

    • DOI

      10.1038/ncomms11289

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells.2016

    • Author(s)
      Angela, M.,* Endo, Y.,* Asou, H. K., Yamamoto, T., Tumes, D. J., Tokuyama, H., Yokote, K., and Nakayama, T.
    • Journal Title

      Nat. Commun.

      Volume: 7 Issue: 1 Pages: 13683-13683

    • DOI

      10.1038/ncomms13683

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] Elucidation of the role of fatty acid metabolism in Th17 cell differentiation under obese conditions.2017

    • Author(s)
      Endo, Y., and Nakayama, T.
    • Organizer
      7th International Workshop of Kyoto T Cell Conference,
    • Place of Presentation
      京都大学医学部・芝蘭会館(京都府京都市)
    • Year and Date
      2017-03-17
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Th2 (Tpath2) cells in airway inflammation.2017

    • Author(s)
      Nakayama, T., Endo, Y., Shinoda, K., and Hirahara, K.
    • Organizer
      7th International Workshop of Kyoto T Cell Conference
    • Place of Presentation
      京都大学医学部・芝蘭会館(京都府京都市)
    • Year and Date
      2017-03-16
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Elucidation of the role of fatty acid metabolism in Th cell differentiation under obese conditions.2017

    • Author(s)
      Endo, Y.
    • Organizer
      AAI Annual Meeting Immunology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Elucidation of the role of fatty acid metabolism in Th cell differentiation under obese conditions.2017

    • Author(s)
      Endo, Y.
    • Organizer
      Leibniz-AMED Workshop on Chronic Inflammation, Infection and Healthy Aging
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Fatty acid metabolic reprogramming via mTOR-mediated induction of PPARγ directs early activation of T cells.2016

    • Author(s)
      Endo, Y., Yamamoto, T., Tumes, D. J., and Nakayama, T.
    • Organizer
      第45回日本免疫学会総会・学術集会
    • Place of Presentation
      沖縄コンベンションセンター(沖縄県宜野湾市)
    • Year and Date
      2016-12-07
    • Related Report
      2016 Annual Research Report
  • [Presentation] Obesity drives Th17 cell differentiation by inducing the carboxylase ACC1 and fatty acid biosynthesis.2016

    • Author(s)
      Endo, Y., and Nakayama, T.
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-12-01
    • Related Report
      2016 Annual Research Report
  • [Book] Chronic Inflammation Mechanisms and Regulation2016

    • Author(s)
      Endo, Y., Hirahara, K., Shinoda, K., Iinuma, T., Yamamoto, H., Motohashi, S., Okamoto, Y., and Nakayama, T.
    • Total Pages
      701
    • Publisher
      SPRINGER NATURE
    • Related Report
      2016 Annual Research Report
  • [Remarks] 千葉大学大学院医学研究院免疫発生学

    • URL

      http://www.m.chiba-u.ac.jp/class/meneki/

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report

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Published: 2016-04-26   Modified: 2018-12-17  

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