Identification of interrelationships between hypoxia in tumor and biological clock for chronotherapy

• Project/Area Number: 16K08532
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Environmental physiology(including physical medicine and nutritional physiology)
• Research Institution: Aichi Medical University
• Principal Investigator: Masubuchi Satoru 愛知医科大学, 医学部, 教授 (80362771)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: circadian / sleep / hypoxia / 低酸素 / 行動リズム / 時計遺伝子 / 担癌マウス / 癌 / 生物リズム / 腫瘍低酸素 / 概日リズム / 生物時計

Outline of Final Research Achievements

To know relationships between tumor hypoxia and behavior rhythm of host, mice were exposed to hypoxia of different timings in a day. The largest response were observed by daytime hypoxia (DHx). DHx reduced activity of active phase and increased activity ending phase. This biphasic response was occurred by overlap between active phase and clock gene independent wave like response by DHx. In addition, this biphasic response was involved in sleep substance increased by DHx. And, another factor increased by DHx acted against the effect of DHx.

Academic Significance and Societal Importance of the Research Achievements

休息期の低酸素により行動の2相性の変化、波様反応が起こることを初めて明らかにした。これは休息期の低酸素による病態（睡眠時無呼吸症候群、高山病の睡眠後の悪化）を理解するために有用である。特に治療抵抗性である睡眠時無呼吸症候群（Co-Morbid Insomnia and Sleep Apnea, COMISA)ではマウスの行動に対応した昼間の強い眠気と夜間の不眠が起こることから我々の研究結果から得られる示唆が多いと思われる。

Research Products

• [Journal Article] Increased supply from blood vessels promotes the activation of dormant primordial follicles in mouse ovaries (2020)
  • Author(s): Komatsu K, Masubuchi S.
  • Journal Title: Journal of Reproduction and Development Volume: 66 Issue: 2 Pages: 105-113
  • DOI: 10.1262/jrd.2019-091
  • NAID: 130007830117
  • ISSN: 0916-8818, 1348-4400
  • Peer Reviewed / Open Access
• [Journal Article] Circadian Regulation of IOP Rhythm by Dual Pathways of Glucocorticoids and the Sympathetic Nervous System. (2020)
  • Author(s): Ikegami K, Shigeyoshi Y, Masubuchi S.
  • Journal Title: Invest Ophthalmol Vis Sci. Volume: 61 Issue: 3 Pages: 26-26
  • DOI: 10.1167/iovs.61.3.26
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of expression alteration in flanking genes on phenotypes of St8sia2-deficient mice. (2019)
  • Author(s): Ikegami K, Saigoh K, Fujioka A, Nagano M, Kitajima K, Sato C, Masubuchi S, Kusunoki S, Shigeyoshi Y.
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 13634-13634
  • DOI: 10.1038/s41598-019-50006-5
  • Peer Reviewed
• [Journal Article] Ovarian Tissue Culture to Visualize Phenomena in Mouse Ovary (2018)
  • Author(s): Komatsu Kouji、Iwase Akira、Murase Tomohiko、Masubuchi Satoru
  • Journal Title: Journal of Visualized Experiments Volume: 136 Issue: 136
  • DOI: 10.3791/57794
  • Peer Reviewed
• [Journal Article] Mouse oocytes connect with granulosa cells by fusing with cell membranes and form a large complex during follicle development† (2018)
  • Author(s): Komatsu Kouji、Masubuchi Satoru
  • Journal Title: Biology of Reproduction Volume: 99 Issue: 3 Pages: 527-535
  • DOI: 10.1093/biolre/ioy072
  • Peer Reviewed
• [Journal Article] Observation of the dynamics of follicular development in the ovary (2017)
  • Author(s): Kouji Komatsu, Satoru Masubuchi
  • Journal Title: Reproductive Medicine and Biology Volume: 16 Issue: 1 Pages: 21-27
  • DOI: 10.1002/rmb2.12010
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The concentration-dependent effect of progesterone on follicle growth in the mouse ovary (2017)
  • Author(s): Kouji Komatsu, Satoru Masubuchi
  • Journal Title: Journal of Reproduction and Development Volume: 63 Issue: 3 Pages: 271-277
  • DOI: 10.1262/jrd.2016-154
  • NAID: 130007314610
  • ISSN: 0916-8818, 1348-4400
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 休息期の低酸素による活動期行動量変動の異常 (2019)
  • Author(s): 増渕悟
  • Organizer: 日本睡眠学会第44回定期学術集会 シンポジウム21 基礎医学から時間医療を考える
  • Invited
• [Presentation] 機械時計から体内時計と睡眠を考える (2019)
  • Author(s): 増渕悟 近藤孝男 成瀬拓郎 粂和彦 本間さと 西野精治
  • Organizer: 日本睡眠学会第44回定期学術集会 市民公開講座
  • Invited
• [Presentation] Hypoxia effect on daily activity is daily activity dependent wavelike response in mice (2019)
  • Author(s): Satoru Masubuchi , Takako Yano , Kouji Komatsu , Wataru Nakamura , Akinobu Ota, Sivasundaram Karnan, Kosei Takeuchi , Yoshitaka Hosokawa, Takeshi Todo, Kazuo Umezawa, Toshiaki Shiomi
  • Organizer: FAOPS2019
  • Int'l Joint Research
• [Presentation] 体内時計と運動 (2019)
  • Author(s): 増渕悟
  • Organizer: 第２３回日本体力医学会東海地方会学術集会
  • Invited
• [Presentation] 時計遺伝子と病気の関係 (2019)
  • Author(s): 増渕悟
  • Organizer: 【市民公開講座】がんにならない生活習慣を考える会～睡眠と生活習慣病・長寿遺伝子の関係を学ぼう～
  • Invited
• [Presentation] Hypoxia effect on circadian activity is molecular clock independent but daily activity dependent wave like response in mice (2018)
  • Author(s): Satoru Masubuchi
  • Organizer: Sapporo Symposium on Biological Rhythm in 2018
  • Int'l Joint Research / Invited
• [Presentation] Hypoxia effect on circadian activity is molecular clock independent but daily activity dependent wave like response in mice (2018)
  • Author(s): Satoru Masubuchi , Takako Yano , Kouji Komatsu , Wataru Nakamura , Akinobu Ota, Sivasundaram Karnan, Kosei Takeuchi , Yoshitaka Hosokawa, Takeshi Todo, Kazuo Umezawa, Toshiaki Shiomi
  • Organizer: Asian Forum on Chronobiology in 2018
  • Int'l Joint Research
• [Presentation] Hypoxia effect on daily activity is molecular clock independent but daily activity dependent wave like response in mice (2018)
  • Author(s): Satoru Masubuchi , Takako Yano , Kouji Komatsu , Wataru Nakamura , Akinobu Ota, Sivasundaram Karnan, Kosei Takeuchi , Yoshitaka Hosokawa, Takeshi Todo, Kazuo Umezawa, Toshiaki Shiomi
  • Organizer: International Symposium on Biological Rhythms “20 Years since Discovery of mammalian Clock Genes”
  • Int'l Joint Research
• [Presentation] 環境因子による行動リズムの制御 (2018)
  • Author(s): 増渕悟
  • Organizer: 第60回日本小児神経学会学術集会 シンポジウム2：周生期に始まる光環境と生体周期・疾病発症の関係を読み解く
  • Invited
• [Presentation] 低酸素によるマウス活動期活動量の変化は時計遺伝子によらない波様の反応が決定している。 (2018)
  • Author(s): 増渕悟
  • Organizer: 第65回 中部日本生理学会
• [Presentation] 低酸素によるマウス活動期活動量の変化は時計遺伝子に依存しない波様の反応が決定している。 (2018)
  • Author(s): 増渕悟
  • Organizer: 第16回 がんとハイポキシア研究会
• [Presentation] Effects of hypoxia on the daily locomotor activities of mice (2018)
  • Author(s): Satoru Masubuchi, Takako Yano, Kouji Komatsu, Wataru Nakamura, Akinobu Ota, Sivasundaram Karnan, Kosei Takeuchi, Yoshitaka Hosokawa, Takeshi Todo, Kazuo Umezawa and Toshiaki Shiomi
  • Organizer: 第95回日本生理学会大会
  • Invited
• [Presentation] Circadian effect of hypoxia on locomotor activities (2017)
  • Author(s): Satoru Masubuchi
  • Organizer: 第94回日本生理学会大会
  • Place of Presentation: アクトシティ浜松
  • Year and Date: 2017-03-28
• [Presentation] マウス活動量低酸素反応の日内変動の制御 (2017)
  • Author(s): 増渕悟 矢野多佳子 小松紘司 中村渉 太田明伸 シバスンダラン・カルナン 武内恒成 細川好孝 藤堂剛 塩見利明
  • Organizer: 第24回 日本時間生物学会学術大会
• [Presentation] Circadian hypoxia response to locomotor activity of mouse. (2016)
  • Author(s): Satoru Masubuchi
  • Organizer: 第23回日本時間生物学会学術大会
  • Place of Presentation: 名古屋大学 豊田講堂
  • Year and Date: 2016-11-12
• [Presentation] Circadian effect of hypoxia to mice locomotor activities (2016)
  • Author(s): Satoru Masubuchi
  • Organizer: Sapporo Symposium on Biological Rhythm in 2016
  • Place of Presentation: Hokkaido University Graduate School of Medicine, Special Conference Room
  • Year and Date: 2016-11-09
  • Int'l Joint Research / Invited