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Analysis of lipid factors driving post-lysosomal signaling.

Planned Research

Project AreaPost-lysosome: Understanding of Higher-order Biological Processes initiated by the site of degradation
Project/Area Number 21H05146
Research Category

Grant-in-Aid for Transformative Research Areas (B)

Allocation TypeSingle-year Grants
Review Section Transformative Research Areas, Section (III)
Research InstitutionThe University of Tokyo

Principal Investigator

Nishimura Taki  東京大学, 大学院医学系研究科(医学部), 特任講師 (70552991)

Co-Investigator(Kenkyū-buntansha) 大場 陽介  慶應義塾大学, 薬学部(芝共立), 講師 (90968603)
永沼 達郎  北海道大学, 薬学研究院, 助教 (60779619)
Project Period (FY) 2021-08-23 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥33,150,000 (Direct Cost: ¥25,500,000、Indirect Cost: ¥7,650,000)
Fiscal Year 2023: ¥11,310,000 (Direct Cost: ¥8,700,000、Indirect Cost: ¥2,610,000)
Fiscal Year 2022: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
Fiscal Year 2021: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
Keywordsポストリソソーム / 脂質 / オートファジー / リソソーム / 寿命
Outline of Research at the Start

本研究の概要は、リソソームからの脂質供給を促進させたモデル生物の作製とリピドミクス解析を組み合わせることで、リソソーム由来の脂質代謝産物の中から寿命制御に関与する脂質因子同定に取り組む研究である。また並行して、リソソーム膜上に存在するホスファチジルイノシトールリン脂質を高感度に認識する脂質プローブ開発にも取り組み、加齢によるリソソーム膜の脂質組成変化やその寿命・老化との関連を解析する研究である。

Outline of Final Research Achievements

This project aimed to address the key factors responsible for lysosome-derived longevity signals in lysosome-degraded lipid metabolites and lysosomal membrane lipids. A vertebrate model organism, killifish, and cultured cell systems with enhanced lipid supply from lysosomes have been established. Comprehensive lipidomics analysis of these, along with morphological observations using electron microscopy, revealed that enhanced lipid supply from lysosomes not only dramatically changes lipid metabolism in the liver, but also alters the aging phenomena of the killifish. Additionally, we succeeded in producing a new lipid probe that could serve as a highly useful analytical tool in future studies of post-lysosomal signaling.

Academic Significance and Societal Importance of the Research Achievements

本研究課題を通して、線虫などの無脊椎動物を用いた研究から見出されたリソソームを起点とする脂質分解依存的な寿命制御シグナルが、キリフィッシュなどの脊椎動物にも保存されていることが分かってきた。さらに、関連する脂質代謝産物は線虫とキリフィッシュでは一部異なっており、寿命制御に関わる未知の脂質代謝シグナル経路が存在する可能性が考えられた。本研究はまだ萌芽的なステージではあるものの、学術的に新たな脂質研究分野、および寿命研究分野の創成に繋がる興味深い知見であるとともに、超高齢化社会という喫緊の課題の解決の糸口にもなり得る研究成果であると考えられる。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (21 results)

All 2024 2023 2022 Other

All Int'l Joint Research (5 results) Journal Article (5 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 5 results,  Open Access: 2 results) Presentation (10 results) (of which Int'l Joint Research: 1 results,  Invited: 4 results) Remarks (1 results)

  • [Int'l Joint Research] The Francis Crick Institute(英国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Frankfurt Institute for Advanced Studies(ドイツ)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] The Francis Crick Institute(英国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Frankfurt Institute for Advanced Studies(ドイツ)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] The Francis Crick Institute(英国)

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Real-Time Monitoring of ATG8 Lipidation In Vitro Using Fluorescence Spectroscopy2024

    • Author(s)
      Zhang Wenxin、Nishimura Taki、Tooze Sharon
    • Journal Title

      BIO-PROTOCOL

      Volume: 14 Issue: 1

    • DOI

      10.21769/bioprotoc.4917

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Autophagosome membrane expansion is mediated by the N-terminus and cis-membrane association of human ATG8s2023

    • Author(s)
      Zhang Wenxin、Nishimura Taki、Gahlot Deepanshi、Saito Chieko、Davis Colin、Jefferies Harold BJ、Schreiber Anne、Thukral Lipi、Tooze Sharon A
    • Journal Title

      eLife

      Volume: 12

    • DOI

      10.7554/elife.89185

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Unique amphipathic α helix drives membrane insertion and enzymatic activity of ATG32023

    • Author(s)
      Nishimura Taki、Lazzeri Gianmarco、Mizushima Noboru、Covino Roberto、Tooze Sharon A.
    • Journal Title

      Science Advances

      Volume: 9 Issue: 25

    • DOI

      10.1126/sciadv.adh1281

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Membrane association of the <scp>ATG8</scp> conjugation machinery emerges as a key regulatory feature for autophagosome biogenesis2023

    • Author(s)
      Tooze Sharon A.、Zhang Wenxin、Lazzeri Gianmarco、Gahlot Deepanshi、Thukral Lipi、Covino Roberto、Nishimura Taki
    • Journal Title

      FEBS Letters

      Volume: 598 Issue: 1 Pages: 107-113

    • DOI

      10.1002/1873-3468.14676

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] ATG3 proteins possess a unique amphipathic α-helix essential for the Atg8/LC3 lipidation reaction2023

    • Author(s)
      Nishimura Taki、Lazzeri Gianmarco、Tooze Sharon A.、Covino Roberto
    • Journal Title

      Autophagy

      Volume: 20 Issue: 1 Pages: 212-213

    • DOI

      10.1080/15548627.2023.2255458

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Deciphering the Secret Code Hidden in the ATG3 Amphipathic α-Helix2024

    • Author(s)
      Taki Nishimura
    • Organizer
      The 25th iCeMS International Symposium
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] レドックス研究における人工脂質プローブの可能性2024

    • Author(s)
      西村多喜
    • Organizer
      レドックスR&D戦略委員会 第4回 春のシンポジウム
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 多様なオルガネラ膜脂質環境の可視化を目指した脂質プローブ作製技術2023

    • Author(s)
      西村多喜, 水島昇
    • Organizer
      第75回 日本細胞生物学会大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] リソソーム膜脂質を可視化する脂質プローブの作製2023

    • Author(s)
      西村多喜
    • Organizer
      第23回 日本蛋白質科学会年会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] オンデマンド脂質プローブ作製技術2023

    • Author(s)
      西村多喜
    • Organizer
      第96回 日本生化学会大会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] リソソームでの脂質分解を促進させた脊椎動物モデル2023

    • Author(s)
      西村多喜
    • Organizer
      [ワークショップ] ポストリソソーム脂肪酸代謝経路の解明
    • Related Report
      2023 Annual Research Report
  • [Presentation] オートファジー関連分子ATG3の両親媒性αヘリックスのユニークな性質2023

    • Author(s)
      Taki Nishimura, Gianmarco Lazzeri, Noboru Mizushima, Roberto Covino, Sharon A. Tooze
    • Organizer
      第15回 オートファジー研究会
    • Related Report
      2023 Annual Research Report
  • [Presentation] オートファジー関連分子ATG3の両親媒性αヘリックスはユニークな機能を有する2022

    • Author(s)
      西村 多喜, Gianmarco Lazzeri, 水島 昇, Roberto Covino, Sharon A. Tooze
    • Organizer
      第74回日本細胞生物学会大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Conserved ATG3 Amphipathic a-helix Ensures LC3 Lipidation Reaction2022

    • Author(s)
      Taki Nishimura, Gianmarco Lazzeri, Noboru Mizushima, Roberto Covino, Sharon A. Tooze
    • Organizer
      The 10th International Symposium on Autophagy
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Human ATG8のN末を介したシス型膜相互作用はオートファジー活性制御に関与する2022

    • Author(s)
      Taki Nishimura, Wenxin Zhang, Deepanshi Gahlot, Chieko Saito, Colin Davis, Harold B. J. Jefferies, Anne Schreiber, Lipi Thukral, Sharon A. Tooze
    • Organizer
      第95回日本生化学会大会
    • Related Report
      2022 Annual Research Report
  • [Remarks] 細胞内高次構造体の膜上でのダイナミックな挙動はどのように制御されているの?

    • URL

      https://www.u-tokyo.ac.jp/content/400217609.pdf

    • Related Report
      2023 Annual Research Report

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Published: 2021-10-22   Modified: 2025-01-30  

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