Elucidation of chronification mechanism and critical period of chronic fatigue and development anti-fatigue health promoting strategy

• Project/Area Number: 17H02172
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied health science
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: CUI Yilong 国立研究開発法人理化学研究所, 生命機能科学研究センター, チームリーダー (60312229)
• Co-Investigator(Kenkyū-buntansha): 鈴木 治和 国立研究開発法人理化学研究所, 生命医科学研究センター, チームリーダー (80333293)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: 恒常性 / 慢性疲労 / ストレス / トランスクリプトーム / PET / 生体恒常性 / 疲労 / ストレスマネジメント / 自律神経機能 / 炎症性サイトカイン / 体温調節 / 睡眠調節機構

Outline of Final Research Achievements

Deviation from internal optimum state is known to suppress functional performance and repeated or prolonged disruption of homeostatic functions could sustain such individual fatigue state. In the present study, we developed a unique fatigue animal model in which repeated short-term rest periods during the long-lasting fatigue loading were utilized for gradual disruption of homeostatic function and accumulation of fatigue. Using this animal model, we demonstrated that the sleep- and thermoregulatory functions adaptively changed in the early phase, but disrupted by long-lasting fatigue loading. Especially, we found that the autonomic heat dissipation appeared at a lower body temperature rather than a higher body temperature in the late phase, indicating thermoregulatory dysfunction. Furthermore, we also demonstrated that plasma level of some inflammatory cytokine, such as IL-1β, and autoimmune disease related gene expression increased in the late phase of fatigue loading.

Academic Significance and Societal Importance of the Research Achievements

疲労は日常的に誰もが経験する主観的な感覚で、通常は生体内の恒常性維持機構の活性化によって適切な休息や睡眠をとることで解消される。一方では、恒常性維持機構の機能異常は疲労の慢性化を引き起こすと考えられ、その慢性化の持続または更なる悪化は慢性疲労症候群などの疾患に進行していくと考えられる。本研究による、疲労の慢性化を伴う睡眠・体温調節などの恒常性維持機能の動態変化は不可逆的な病的な疲労困憊を事前に予測し、疾患の発症を事前に防ぐ先制医療戦略に繋がる。また慢性疲労によって引き起こされる炎症性サイトカインや自己免疫関連遺伝子群の上昇は慢性疲労を克服する介入法の確立につなげることができる。

Research Products

• [Journal Article] Practical Synthesis of [18F]Pitavastatin and Evaluation of Hepatobiliary Transport Activity in Rats by Positron Emission Tomography (2020)
  • Author(s): Nakaoka T, Uetake Y, Kaneko K, Niwa T, Ochiai H, Irie S, SuezakiY, Otsuka N, Hayashinaka E, Wada Y, Cui YL, Maeda K, Kusuhara H, Sugiyama Y, Hosoya T, and Watanabe Y
  • Journal Title: Mol. Pharmaceutics Volume: in press Issue: 6 Pages: 1884-1898
  • DOI: 10.1021/acs.molpharmaceut.9b01284
  • Peer Reviewed
• [Journal Article] Homeostatic disturbance of thermoregulatory functions in rats with chronic fatigue (2020)
  • Author(s): Li D, Hu D, Shigeta M, Ochi Y. Watanabe Y, Li F, Cui YL
  • Journal Title: Neuroscience Research Volume: in press Pages: 45-50
  • DOI: 10.1016/j.neures.2020.04.005
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pain matrix shift in the rat brain following persistent colonic inflammation revealed by voxel-based statistical analysis (2019)
  • Author(s): Huang T, Okauchi, T, Hu D, Shigeta M, Wu Y, Wada Y, Hayashinaka E, Wang S, Kogure Y, Noguchi K, Watanabe Y, Dai Y, Cui YL
  • Journal Title: Molecular Pain Volume: 15 Pages: 1-12
  • DOI: 10.1177/1744806919891327
  • Peer Reviewed / Open Access
• [Journal Article] A voxel-based analysis of neurobiological mechanisms in placebo analgesia in rats. (2018)
  • Author(s): Zeng Y, Hu D, Yang W, Hayashinaka E, Wada Y, Watanabe Y, Zeng Q. Cui YL
  • Journal Title: NeuroImage Volume: 178 Pages: 602-612
  • DOI: 10.1016/j.neuroimage.2018.06.009
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A clinical quantitative evaluation of hepatobiliary transport of [11C]Dehydropravastatin in humans using positron emission tomography (2018)
  • Author(s): Kaneko, K., Tanaka, M., Ishii, A., Katayama, Y., Nakaoka, T., Irie, S., Kawahata, H., Yamanaga, T., Wada, Y., Miyake, T., Toshimoto, K., Maeda, K., Cui, Y.L., Enomoto, M., Kawamura, E., Kawada, N., Kawabe, J., Shiomi, S., Kusuhara, H., Sugiyama Y. and Watanabe Y.
  • Journal Title: Drug Metabolism and Disposition Volume: 46 Issue: 5 Pages: 719-728
  • DOI: 10.1124/dmd.118.080408
  • Peer Reviewed
• [Journal Article] 疲労の慢性化と恒常性の破綻 (2017)
  • Author(s): 崔翼龍
  • Journal Title: 日本疲労学会誌 Volume: １２（２） Pages: 26-31
  • Peer Reviewed
• [Presentation] 疲労動物モデルに対する電解水素水の疲労軽減効果研究 (2019)
  • Author(s): 胡迪、李丹溪、重田美香、岡内隆、橘孝士、樺山繁、大崎雄介、渡辺恭良、崔翼龍
  • Organizer: 第15回日本疲労学会総会・学術集会
• [Presentation] 慢性疲労動物を用いた疲労の慢性化機序の解析 (2018)
  • Author(s): 胡迪、李丹渓、重田美香、岡内隆、渡辺恭良、崔翼龍
  • Organizer: 第14回日本疲労学会総会・学術集会
• [Presentation] Functinal change of the thermoregulatory system during chronic fatigue formation in rats (2018)
  • Author(s): 李丹渓、胡迪、重田美香、岡内隆、渡辺恭良、崔翼龍
  • Organizer: 第14回日本疲労学会総会・学術集会
• [Presentation] 新しい慢性疲労モデルの確立および慢性化形成に関わる血中ホルモンの動態変化の解析 (2017)
  • Author(s): 胡迪、李丹渓、重田美香、岡内隆、渡辺恭良、崔翼龍
  • Organizer: 第1３回日本疲労学会総会
• [Presentation] Functional change of the thermoregulatory system during chronic fatigue formation in rats (2017)
  • Author(s): 李丹渓、胡迪、重田美香、岡内隆、李峰、渡辺恭良、崔翼龍
  • Organizer: 第1３回日本疲労学会総会
• [Book] ストレス・疲労のセンシングとその評価技術 (2019)
  • Author(s): 崔翼龍
  • Publisher: 技術情報協会