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Molecular mechanisms underlying circadian pruritic behavior for chronopharmacology

Research Project

Project/Area Number 19K16371
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 47040:Pharmacology-related
Research InstitutionKyoto University

Principal Investigator

Miyake Takahito  京都大学, 薬学研究科, 助教 (70836866)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywords体内時計 / 発現制御機構 / 翻訳 / かゆみ / 膜タンパク質 / 炎症応答
Outline of Research at the Start

生体時計は、地球の自転にともなう昼夜の規則正しい変動に基づき形成された、生命にとって最も根源的な「時間」の仕組みである. 本研究では『かゆみ』という神経感覚が一日のなかで消長する仕組みを、かゆみに関わるTRPチャネルや炎症に対する申請者の研究経験を基に解明する. 具体的には、所属研究室が所有するPer1/2/3・Cry1/2・Bmal1-KOマウスを用いて、TRPチャネルやその制御分子の発現及び翻訳後修飾の日内変動を分子レベルまで明らかにする. 本研究は、体内時計を基盤とした分子プログラムによるかゆみ症状の日内変動機構を明らかにし、かゆみ時間症状の実体の解明とその緩和を目指すことを目標とする.

Outline of Final Research Achievements

In the course of elucidating the molecular mechanisms underlying circadian pruritic behavior for chronopharmacology, we found that the N-type glycosylation of Gpr176, an orphan GPCR that sets the pace of the circadian clock, plays an important role in the regulation of its protein expression level (Wang and Nakagawa et al, Sci Rep, 2020), developed a system that enables us to observe a number of circadian rhythms in physiology simultaneously (Shimatani et al, PLoS ONE, 2021), and found that in meibomian gland dysfunction, in which local changes in peripheral organs are associated with the development of its pathogenesis like itch, an age-related decrease in NAD+ leads to a decrease in local steroid synthesis, which result in an exacerbation of the disease (Sasaki, Hamada, and Yarimizu et al, Nat Aging, 2022).

Academic Significance and Societal Importance of the Research Achievements

これまでかゆみをはじめとした末梢器官の機能異常が引き金となる疾患に関する多くの研究では、末梢器官に発現する分子に焦点を当てるものが多く、そこに時間の概念は無かった.生体内の時間を形成する体内時計の制御機構に関しては、体内時計コア遺伝子mRNAの発現リズム調節を介した機構がこれまで明らかになってきたが、非転写型の調節機構にはまだ未解明な部分が残されている. そのような中本研究では、体内時計制御分子の発現量が翻訳後修飾によって制御されること、眼瞼における低分子NAD+量の概日振動がマイボーム腺機能の維持に重要であることを見出した. 時間薬理学を行う上での重要な基礎を築くことができたといえる.

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (12 results)

All 2022 2021 2020 2019

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

  • [Journal Article] 特集 温度を感じる脳と身体の科学 体温の日内リズム制御における概日時計機構の役割2022

    • Author(s)
      Takahito Miyake, Masao Doi
    • Journal Title

      BRAIN and NERVE

      Volume: 74 Issue: 2 Pages: 159-166

    • DOI

      10.11477/mf.1416202001

    • ISSN
      1344-8129, 1881-6096
    • Year and Date
      2022-02-01
    • Related Report
      2021 Annual Research Report
  • [Journal Article] Intracrine activity involving NAD-dependent circadian steroidogenic activity governs age-associated meibomian gland dysfunction2022

    • Author(s)
      Sasaki Lena、Hamada Yuki、Yarimizu Daisuke、Morinaga Hironobu、Nishimura Emi K.、Kudo Fujimi、Manabe Ichiro、Haraguchi Shogo、Sugiura Yuki、Suematsu Makoto、Kinoshita Shigeru、Machida Mamiko、Nakajima Takeshi、Kiyonari Hiroshi、Okamura Hitoshi、Yamaguchi Yoshiaki、Miyake Takahito、Doi Masao
    • Journal Title

      Nature Aging

      Volume: 2 Issue: 2 Pages: 105-114

    • DOI

      10.1038/s43587-021-00167-8

    • NAID

      120007191374

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Gpr19 is a circadian clock-controlled orphan GPCR with a role in modulating free-running period and light resetting capacity of the circadian clock2021

    • Author(s)
      Yoshiaki Yamaguchi, Iori Murai, Kaoru Goto, Shotaro Doi, Huihua Zhou, Genzui Setsu, Hiroyuki Shimatani, Hitoshi Okamura, Takahito Miyake, Masao Doi
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 22406-22406

    • DOI

      10.1038/s41598-021-01764-8

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Thermographic imaging of mouse across circadian time reveals body surface temperature elevation associated with non-locomotor body movements2021

    • Author(s)
      Hiroyuki Shimatani, Yuichi Inoue, Yota Maekawa, Takahito Miyake, Yoshiaki Yamaguchi, Masao Doi
    • Journal Title

      PLoS One

      Volume: 16 Issue: 5 Pages: e0252447-e0252447

    • DOI

      10.1371/journal.pone.0252447

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Identification and functional characterisation of N-linked glycosylation of the orphan G protein-coupled receptor Gpr1762020

    • Author(s)
      Tianyu Wang, Shumpei Nakagawa, Takahito Miyake, Genzui Setsu, Sumihiro Kunisue, Kaoru Goto, Akira Hirasawa, Hitoshi Okamura, Yoshiaki Yamaguchi, Masao Doi
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 4429-4429

    • DOI

      10.1038/s41598-020-61370-y

    • NAID

      120006822520

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Reconstitution of Organismal Liver Clock Function Requires Light.2019

    • Author(s)
      Takahito Miyake, Masao Doi
    • Journal Title

      Trends in endocrinology and metabolism

      Volume: 30 Issue: 9 Pages: 569-571

    • DOI

      10.1016/j.tem.2019.07.017

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] 微小な温度変化がもたらすmRNA翻訳速度調節と概日時計制御2021

    • Author(s)
      三宅崇仁、井ノ上雄一、土居雅夫
    • Organizer
      Biothermology Workshop - 2021's Annual Workshop
    • Related Report
      2021 Annual Research Report
  • [Presentation] 翻訳速度制御を介した体内時計のパラメトリック制御2021

    • Author(s)
      三宅崇仁、井ノ上雄一、土居雅夫
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 生理的体温変化による体内時計のパラメトリック制御2021

    • Author(s)
      三宅崇仁、井ノ上雄一、土居雅夫
    • Organizer
      第59回日本生物物理学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] A robust and sustained circadian rhythm of Per2::Luc expression in the mouse meibomian gland acinar cells2021

    • Author(s)
      グエン ファム カン ティエン、三宅崇仁、土居雅夫
    • Organizer
      第28回日本時間生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Circadian PER2 protein oscillations do not persist when de novo translation is inhibited in cultured mouse embryonic fibroblasts2020

    • Author(s)
      Xinyan Shao, Takahito Miyake, and Masao Doi
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 体内時計の温度同調機構:生理的な範囲の温度変化が培養マウス繊維芽細胞の分子時計に与える影響について2020

    • Author(s)
      井ノ上 雄一、三宅 崇仁、土居 雅夫
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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