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Spontaneous regeneration mechanism of inner ear outer hair cells

Research Project

Project/Area Number 20K06466
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 42040:Laboratory animal science-related
Research InstitutionTokyo Metropolitan Institute of Medical Science

Principal Investigator

MATSUOKA Kunie  公益財団法人東京都医学総合研究所, 基礎医科学研究分野, 研究員 (40291158)

Co-Investigator(Kenkyū-buntansha) 和田 健太  東京農業大学, 生物産業学部, 教授 (20508113)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords難聴 / 外有毛細胞 / 再生 / マウスモデル / 内耳外有毛細胞 / ダイテルス細胞 / RNA-seq
Outline of Research at the Start

「聞こえの調節」に重要な役割を担っている内耳外有毛細胞(OHC)は騒音などにより障害を受け、また加齢によっても減少する。哺乳類のOHCは一度失われると再生しないとされてきたが、我々はこれまでに開発したOHC破壊マウスを解析する過程で、OHCを急激に破壊するとOHCが自発的に再生する可能性があることを見出した。そこで、OHC破壊マウスを利用してOHC破壊後の遺伝子発現、形態、聴力の変化を詳細に観察してOHCの再生の可能性を探り、そのメカニズムを解明する。

Outline of Final Research Achievements

We obtained traces of spontaneous OHC regeneration after abrupt destruction using Prestin-hDTR mice. Regeneration seemed to mimic the natural process of development. We found that Agr3 whose function in hearing was unknown, were remarkably downregulated by OHC-depletion at a neonatal stage. Immunohistochemical studies revealed that AGR3 was not expressed in OHCs but in Deiters' cells which are the supporting cells of OHCs. Our finding in this study suggested that there are close crosstalk processes between OHCs and Deiters’ cells in OHC development. In contrast, we assayed the effects of Wnt signaling inhibitor RPI-724 on OHC regeneration. We observed recovery of hearing by administration of the RPI-724 three times a week for 12 weeks to adult OHC-depleted mice. It was suggested that inhibition of Wnt/β-catenin/CBP signaling promotes regeneration of OHCs.

Academic Significance and Societal Importance of the Research Achievements

内耳外有毛細胞(OHC)は鋭敏な聴覚を得るために極めて重要である。OHCは加齢・騒音・感染・アミノグリコシド系抗生剤の投与等によって損傷を受け、哺乳類では一度失われると再生しないとされてきたが、我々はOHCが急激に破壊されるとOHCの自発的な再生が誘導される可能性を見出した。現在、難聴の根本的な治療法はなく、補聴器や人工内耳の装用により聴力を補わざるを得ないが、OHCの自発的な再生のメカニズムが明らかになれば、再生を促進させるための創薬や治療法の確立に向けて極めて重要な情報を提供することとなる。

Report

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

    (9 results)

All 2023 2022 2021 2020 Other

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

  • [Journal Article] Two Loci Contribute to Age-Related Hearing Loss Resistance in the Japanese Wild-Derived Inbred MSMMs Mice2022

    • Author(s)
      Shumpei P. Yasuda, Yuki Miyasaka, Xuehan Hou, Yo Obara, Hiroshi Shitara, Yuta Seki, Kunie Matsuoka, Ai Takahashi, Eri Wakai, Hiroshi Hibino, Toyoyuki Takada, Toshihiko Shiroishi, Ryo Kominami and Yoshiaki Kikkawa
    • Journal Title

      Biomedicines

      Volume: 10 Issue: 9 Pages: 2221-2221

    • DOI

      10.3390/biomedicines10092221

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] c.753A>G genome editing of a Cdh23ahl allele delays age-related hearing loss and degeneration of cochlear hair cells in C57BL/6J mice.2020

    • Author(s)
      Yasuda SP, Seki Y, Suzuki S, Ohshiba Y, Hou X, Matsuoka K, Wada K, Shitara H, Miyasaka Y, Kikkawa Y
    • Journal Title

      Hear Res

      Volume: 389 Pages: 107926-107926

    • DOI

      10.1016/j.heares.2020.107926

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Functional analysis of downregulated genes after specific depletion of outer hair cells in mice2023

    • Author(s)
      Kikkawa Y, Yasuda SP, Takahashi A, Mao T, Prakhongcheep O, Seki Y, Shitara H, Matsuoka K
    • Organizer
      36th International Mammalian Genome Conference
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Two loci, ahl3 and ahl10, contribute to age-related hearing loss resistance in Japanese wild-derived inbred MSM/Ms mice2023

    • Author(s)
      Yasuda SP, Miyasaka Y, Hou X, Obara Y, Shitara H, Seki Y, Matsuoka K, Takahashi A, Wakai E, Hibino H, Takada T, Shiroishi T, Kominami R, Kikkawa Y
    • Organizer
      36th International Mammalian Genome Conference
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ahl3およびahl10遺伝子座は日本産野生マウス由来MSM系統の加齢性難聴抵抗性に関与する2022

    • Author(s)
      安田俊平,宮坂勇輝,侯 雪含,小原 央,設楽浩志,関 優太,松岡邦枝,髙橋あい,若井恵里,日比野浩,高田豊行,城石俊彦,木南 凌,吉川欣亮
    • Organizer
      日本遺伝学会第94回大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] C57BL/6マウスの高周波音域の加齢性難聴発症を抑制する新規遺伝子座の同定2021

    • Author(s)
      安田俊平,関優太,松岡邦枝,侯雪含,吉川欣亮
    • Organizer
      第31回日本耳科学会 総会・学術講演会
    • Related Report
      2021 Research-status Report
  • [Presentation] 選択的外有毛細胞破壊によって誘導された支持細胞発現遺伝子群の発現減少2021

    • Author(s)
      吉川欣亮,安田俊平,松岡邦枝
    • Organizer
      第31回日本耳科学会 総会・学術講演会
    • Related Report
      2021 Research-status Report
  • [Presentation] TRECK法による出生直後のマウス内耳外有毛細胞の破壊2020

    • Author(s)
      松岡邦枝,安田俊平,関優太,吉川欣亮
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Research-status Report
  • [Remarks] 公益財団法人東京都医学総合研究所 難聴プロジェクト

    • URL

      https://www.igakuken.or.jp/mammal/

    • Related Report
      2022 Annual Research Report 2021 Research-status Report 2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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