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Analysis of circadian misalignment using Mouse Cohort Model

Research Project

Project/Area Number 19K22516
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 48:Biomedical structure and function and related fields
Research InstitutionKyoto Prefectural University of Medicine

Principal Investigator

Yagita Kazuhiro  京都府立医科大学, 医学(系)研究科(研究院), 教授 (90324920)

Project Period (FY) 2019-06-28 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords概日リズム / 生体リズム / 体内時計 / 時計遺伝子 / シフトワーク / 未病制御 / 慢性炎症 / 免疫老化 / 概日リズム障害 / マウスコホート / 環境因子 / リバーストランスレーショナル研究
Outline of Research at the Start

24時間社会がもたらす生活時間と体内時計の「ズレ」は、様々な疾患リスクと相関があることがヒト疫学研究で示されている。しかし、現代社会の喫緊の健康課題であるにもかかわらず、因果性を検証した科学的エビデンスが極めて乏しく、未だに有効な予防法や対策を講じることができていない。本研究では、現実の課題解決に向けたリバーストランスレーショナル研究として、「マウスコホート」モデル系を用いて「環境と生体の時間的不適合」が引き起こす病態メカニズム解明を目指す。

Outline of Final Research Achievements

Modern society characterized by a 24/7 lifestyle leads to misalignment between environmental cycles and endogenous circadian rhythms. Persisting circadian misalignment leads to deleterious effects on health and healthspan. However, the underlying mechanism remains not fully understood. Here, we subjected adult, wild-type mice to distinct chronic jet-lag paradigms named “mouse cohort model”, which showed that long-term circadian misalignment induced significant early mortality. We observed enhanced steatohepatitis with infiltration of inflammatory cells. The investigation of senescence-associated immune cell subsets from the spleens and mesenteric lymph nodes revealed an increase in PD-1+CD44high CD4 T cells as well as CD95+GL7+ germinal center B cells, indicating that the long-term circadian misalignment exacerbates immune senescence and consequent chronic inflammation.

Academic Significance and Societal Importance of the Research Achievements

生物には最適な状況を維持する普遍的なメカニズムがあり、その一つが体内時計による生体リズムによる恒常性維持機構です。単に睡眠覚醒リズムや自律神経リズムなどを生み出す仕組みというよりは、全身の細胞の代謝秩序など生命維持に必須の原理を担うメカニズムが体内時計です。不規則な生活による恒常性破綻の原理解明のため、本研究では環境(明暗周期)の撹乱が様々な疾患発症を再現する動物モデル系を構築しました。本研究により、交替勤務などによる健康問題の本格的な予防法開発が可能になります。

Report

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

    (30 results)

All 2022 2021 2020 2019 Other

All Int'l Joint Research (1 results) Journal Article (13 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 13 results,  Open Access: 11 results) Presentation (11 results) (of which Int'l Joint Research: 3 results,  Invited: 11 results) Book (2 results) Remarks (1 results) Patent(Industrial Property Rights) (2 results)

  • [Int'l Joint Research] テキサス大学(米国)

    • Related Report
      2019 Research-status Report
  • [Journal Article] The clock modulator Nobiletin mitigates astrogliosis-associated neuroinflammation and disease hallmarks in an Altzheimer's disease model.2022

    • Author(s)
      4.Wiroanto M, Wang C-Y, Kim E, Koike N, Gomez-Gutierrez R, Nohara K, Escobedo Jr G, Choi JM, Han C, Yagita K, Jung SY, Soto C, Lee HK, Morales R, Yoo S-H, Chen Z.
    • Journal Title

      FASEB J.

      Volume: 36 Issue: 3

    • DOI

      10.1096/fj.202101633r

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Effects of constant light exposure on allergic and irritant contact dermatitis in mice reared under constant light conditions2021

    • Author(s)
      2.Mizutani H, Tamagawa-Mineoka R, Yasuike R, Minami Y, Yagita K, Katoh N.
    • Journal Title

      Experimental Dermatol

      Volume: in press Issue: 5 Pages: 739-744

    • DOI

      10.1111/exd.14308

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 環境時間との不適合による恒常性破綻:概日リズム障害の病態生理学2021

    • Author(s)
      八木田和弘
    • Journal Title

      京都府立医科大学雑誌

      Volume: 130 Pages: 521-538

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 体内時計のミスアライメントによる恒常性破綻2021

    • Author(s)
      土谷佳樹, 八木田和弘
    • Journal Title

      Medical Science Digest

      Volume: 47 Pages: 14-17

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Circadian regulation of chemotherapy-induced peripheral neuropathic pain and the underlying transcriptomic landscape2020

    • Author(s)
      Kim Hee Kee、Lee Sun-Yeul、Koike Nobuya、Kim Eunju、Wirianto Marvin、Burish Mark J.、Yagita Kazuhiro、Lee Hyun Kyoung、Chen Zheng、Chung Jin Mo、Abdi Salahadin、Yoo Seung-Hee
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 13844-13844

    • DOI

      10.1038/s41598-020-70757-w

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Circadian clock and cancer: From a viewpoint of cellular differentiation2020

    • Author(s)
      Tsuchiya Yoshiki, Umemura Yasuhiro, Yagita Kazuhiro
    • Journal Title

      International Journal of Urology

      Volume: - Issue: 6 Pages: 518-524

    • DOI

      10.1111/iju.14231

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of the Circadian Core Machinery in Mammals2020

    • Author(s)
      Umemura Yasuhiro, Yagita Kazuhiro
    • Journal Title

      Journal of Molecular Biology

      Volume: - Issue: 12 Pages: 3611-3617

    • DOI

      10.1016/j.jmb.2019.11.026

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Chronic circadian misalignment accelerates immune senescence and abbreviates lifespan in mice2020

    • Author(s)
      Inokawa Hitoshi, Umemura Yasuhiro, Shimba Akihiro, Kawakami Eiryo, Koike Nobuya, Tsuchiya Yoshiki, Ohashi Munehiro, Minami Yoichi, Cui Guangwei, Asahi Takuma, Ono Ryutaro, Sasawaki Yuh, Konishi Eiichi, Yoo Seung-Hee, Chen Zheng, Teramukai Satoshi, Ikuta Koichi, Yagita Kazuhiro
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 2569-2569

    • DOI

      10.1038/s41598-020-59541-y

    • NAID

      120006799241

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Incremental Growth Lines in Mouse Molar Dentin Represent 8-hr Ultradian Rhythm2019

    • Author(s)
      Ono Ryutaro, Koike Nobuya, Inokawa Hitoshi, Tsuchiya Yoshiki, Umemura Yasuhiro, Yamamoto Toshiro, Kanamura Narisato, Yagita Kazuhiro
    • Journal Title

      ACTA HISTOCHEMICA ET CYTOCHEMICA

      Volume: 52 Issue: 6 Pages: 93-99

    • DOI

      10.1267/ahc.19017

    • NAID

      130007776198

    • ISSN
      0044-5991, 1347-5800
    • Year and Date
      2019-12-27
    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Enhanced metastatic growth after local tumor resection in the presence of synchronous metastasis in a mouse allograft model of neuroblastoma2019

    • Author(s)
      Inoue M, Tsuchiya Y, Koike N, Umemura Y, Inokawa H, Togashi Y, Maniwa J, Higashi M, Fumino S, Tajiri T, Yagita K
    • Journal Title

      Pediatric Surgery International

      Volume: 35 Issue: 12 Pages: 1403-1411

    • DOI

      10.1007/s00383-019-04568-0

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Human Circadian Molecular Oscillation Development Using Induced Pluripotent Stem Cells.2019

    • Author(s)
      Umemura Y, Maki I, Tsuchiya Y, Koike N, Yagita K
    • Journal Title

      J Biol Rhythms

      Volume: 34 Issue: 5 Pages: 525-532

    • DOI

      10.1177/0748730419865436

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] REV-ERBα and REV-ERBβ function as key factors regulating Mammalian Circadian Output2019

    • Author(s)
      Ikeda Ryosuke、Tsuchiya Yoshiki、Koike Nobuya、Umemura Yasuhiro、Inokawa Hitoshi、Ono Ryutaro、Inoue Maho、Sasawaki Yuh、Grieten Tess、Okubo Naoki、Ikoma Kazuya、Fujiwara Hiroyoshi、Kubo Toshikazu、Yagita Kazuhiro
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 10171-10171

    • DOI

      10.1038/s41598-019-46656-0

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Non-coding cis-element of Period2 is essential for maintaining organismal circadian behaviour and body temperature rhythmicity2019

    • Author(s)
      Doi Masao、Shimatani Hiroyuki、Atobe Yuta、Murai Iori、Hayashi Hida、Takahashi Yukari、Fustin Jean-Michel、Yamaguchi Yoshiaki、Kiyonari Hiroshi、Koike Nobuya、Yagita Kazuhiro、Lee Choogon、Abe Manabu、Sakimura Kenji、Okamura Hitoshi
    • Journal Title

      Nature Communications

      Volume: 10 Issue: 1 Pages: 2563-2563

    • DOI

      10.1038/s41467-019-10532-2

    • NAID

      120006644061

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Circadian Rhythm Disorders: Chronic circadian misalignment-induced pathophysiology2021

    • Author(s)
      Yagita K.
    • Organizer
      5th Asian Forum on Chronobiology
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Circadian Clock-mediated Transition of Physiological State in Developmental and Ageing Process in Mice.2020

    • Author(s)
      Yagita K
    • Organizer
      Biannual Meeting of Society for Research on Biological Rhythm 2020
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Circadian clock-mediated state dynamics in developmental and ageing processes in mammals2020

    • Author(s)
      八木田和弘
    • Organizer
      第43回日本分子生物学会 ワークショップ
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] マウスコホートモデルのディープフェノタイプ研究:概日リズム撹乱による状態遷移2020

    • Author(s)
      八木田和弘
    • Organizer
      第93回日本生化学会大会 シンポジウム
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 概日リズム撹乱がもたらす病態2020

    • Author(s)
      八木田和弘
    • Organizer
      第54回糖尿病学の進歩
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 子どもの体内時計と生活リズム2020

    • Author(s)
      八木田和弘
    • Organizer
      第40回京都保育問題研究会(京都)
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Developmental Program and Environmental Reprogram of Mammalian Circadian Regulation System2019

    • Author(s)
      Yagita Kazuhiro
    • Organizer
      European Biological Rhythms Society Congress 2019 (Lyon)
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 体内時計はいつ形成されるか?2019

    • Author(s)
      八木田和弘
    • Organizer
      第7回新胎児学研究会(高松)
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 概日リズムと老化2019

    • Author(s)
      八木田和弘
    • Organizer
      第34回老化促進モデルマウス(SAM)学会学術集会(高松)
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 長期にわたる概日リズム撹乱による免疫恒常性破綻2019

    • Author(s)
      八木田和弘
    • Organizer
      第44回日本睡眠学会学術集会(名古屋)
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 哺乳類細胞の概日制御系成立プログラム2019

    • Author(s)
      八木田和弘
    • Organizer
      細胞自在操作のための分子科学技術の開発拠点形成2018年度成果報告会(京田辺)
    • Related Report
      2019 Research-status Report
    • Invited
  • [Book] 生体リズムと自律神経. 自律神経:初めて学ぶ方のためのマニュアル2022

    • Author(s)
      八木田和弘, 土谷佳樹.
    • Total Pages
      8
    • Publisher
      中外医学社
    • ISBN
      9784498328808
    • Related Report
      2021 Annual Research Report
  • [Book] 「2つの体内時計」の秘密2021

    • Author(s)
      八木田和弘
    • Total Pages
      185
    • Publisher
      青春出版
    • ISBN
      9784413211888
    • Related Report
      2021 Annual Research Report
  • [Remarks] 京都府立医科大学統合生理学ホームページ

    • URL

      https://yagita-lab.jp

    • Related Report
      2021 Annual Research Report
  • [Patent(Industrial Property Rights)] 被検者の概日リズムの質を解析するための解析装置、解析方法、及び解析プログラム2021

    • Inventor(s)
      八木田和弘、小池宣也、笹脇ゆふ
    • Industrial Property Rights Holder
      京都府公立大学法人
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2021-001351
    • Filing Date
      2021
    • Related Report
      2020 Research-status Report
  • [Patent(Industrial Property Rights)] 認知症の発症の兆候の検出を補助するための検出補助方法、検出補助装置、検出補助プログラムおよび検出補助システム2020

    • Inventor(s)
      八木田和弘
    • Industrial Property Rights Holder
      京都府公立大学法人
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-008252
    • Filing Date
      2020
    • Related Report
      2020 Research-status Report

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Published: 2019-07-04   Modified: 2023-01-30  

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