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Exploration of ER-phagy substrates involved in brain aging and its application to the control of neuronal senescence

Research Project

Project/Area Number 20K21751
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 59:Sports sciences, physical education, health sciences, and related fields
Research InstitutionGifu University

Principal Investigator

Oh-hashi Kentaro  岐阜大学, 工学部, 准教授 (50332953)

Co-Investigator(Kenkyū-buntansha) 石垣 診祐  名古屋大学, 医学系研究科, 特任准教授 (40378170)
天谷 文昌  京都府立医科大学, 医学(系)研究科(研究院), 教授 (60347466)
内尾 こずえ  国立研究開発法人医薬基盤・健康・栄養研究所, 医薬基盤研究所 難治性疾患研究開発・支援センター, 主任研究員 (70373397)
Project Period (FY) 2020-07-30 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2022: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2021: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
KeywordsER-phagy / ER stress / ERAD / Golgi stress / FAM134B / オートファジー / ERストレス / 小胞体
Outline of Research at the Start

加齢による神経変性疾患には、持続的な炎症・ストレスの関与に加えて、神経細胞内外での異常タンパク質蓄積が病因の一つあると考えられている。そこで本研究では、細胞内小器官の一つ”小胞体”の品質管理機構『小胞体選択的オートファジー』に着目し、解析を行う。具体的には“ゲノム編集技術”と組み合わせることで、小胞体の機能不全や劣化により蓄積するタンパク質群の探索を試みる 。それにより、神経老化など老年病に関わる因子の同定および解析を目指す。さらに、神経老化の過程で異常蓄積するこれら因子の制御・補充法を開発することによる新たな神経変性疾患治療法を提案したいと考える。

Outline of Final Research Achievements

In this study, we investigated ER-autophagy (ER-phagy), one of the ER regulatory mechanisms. In particular, we focused on FAM134B, one of the ER-phagy receptors, which is involved in hereditary sensory nerve abnormalities. First, we analyzed endogenous FAM134B protein expression under various nutritional deficiency conditions and found that the protein was significantly decreased by serum and amino acid deprivation. Next, we established FAM134B-deficient Neuro2a cells by genome editing technology, and transfected wild-type and HSAN2B-linked FAM134B into the cells and characterized their features. These findings are expected to lead to the development of new drugs targeting the ER.

Academic Significance and Societal Importance of the Research Achievements

本研究では、ER-phagy受容体の1つFAM134Bタンパク質の発現制御および変異FAM134BがER-phagyに及ぼす影響について検討を行った。とりわけ、本研究において樹立したFAM134B欠損細胞株をはじめとする小胞体制御因子欠損細胞株や生細胞にてER-phagy解析が検討可能なNanoBiT reporterシステムは、今後の詳細な解析や薬剤開発に役立つものと考えられる。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (4 results)

All 2023 2022 2021

All Journal Article (4 results) (of which Peer Reviewed: 4 results,  Open Access: 2 results)

  • [Journal Article] Elucidation of OSW-1-Induced Stress Responses in Neuro2a Cells2023

    • Author(s)
      Oh-hashi Kentaro、Nakamura Hibiki、Ogawa Hirotaka、Hirata Yoko、Sakurai Kaori
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 24 Issue: 6 Pages: 5787-5787

    • DOI

      10.3390/ijms24065787

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Expression analysis and functional characterization of thioredoxin domain-containing protein 112022

    • Author(s)
      Murase Ryoichi、Yamamoto Ayumi、Hirata Yoko、Oh-hashi Kentaro
    • Journal Title

      Molecular Biology Reports

      Volume: 49 Issue: 11 Pages: 10541-10556

    • DOI

      10.1007/s11033-022-07932-x

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Molecular characterization of mouse CREB3 regulatory factor in Neuro2a cells.2021

    • Author(s)
      Oh-hashi K, Hasegawa T, Naruse Y, Hirata Y
    • Journal Title

      Mol Biol Rep.

      Volume: 48 Issue: 7 Pages: 5411-5420

    • DOI

      10.1007/s11033-021-06543-2

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Comparative Analysis of CREB3 and CREB3L2 Protein Expression in HEK293 Cells.2021

    • Author(s)
      Oh-hashi K, Yamamoto A, Murase R, Hirata Y
    • Journal Title

      Int J Mol Sci

      Volume: 22 Issue: 5 Pages: 2767-2767

    • DOI

      10.3390/ijms22052767

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access

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Published: 2020-08-03   Modified: 2024-01-30  

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