Investigating methods to prevent obstetrics and gynecology diseases by regulating the contraction of the uterus through the circadian rhythm

• Project/Area Number: 19K09776
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Tokyo Medical University (2021-2022); Kanazawa University (2019-2020)
• Principal Investigator: Ono Masanori 東京医科大学, 医学部, 准教授 (70348712)
• Co-Investigator(Kenkyū-buntansha): 毎田 佳子 金沢大学, 保健学系, 教授 (20397219) ; 藤原 浩 金沢大学, 医学系, 教授 (30252456) ; 大黒 多希子 金沢大学, 学際科学実験センター, 教授 (30767249) ; 安藤 仁 金沢大学, 医学系, 教授 (50382875) ; 藤原 智子 京都ノートルダム女子大学, 現代人間学部, 教授 (60310744)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 概日リズム / 時計遺伝子 / 末梢時計 / 子宮 / 概日時計 / 朝食欠食 / 月経困難症 / 妊娠高血圧症候群 / 生殖 / 子宮筋腫 / 子宮内膜症 / 摂食リズム / 生活習慣 / 子宮平滑筋 / 子宮収縮 / 産婦人科疾患 / 子宮筋

Outline of Research at the Start

概日時計による概日リズムは各臓器内の末梢概日時計と同期して基本的な生命活動を維持しており，その障害は臓器の機能低下をきたすことが知られている．一方で，女性は月経周期など中・長期にわたる生殖リズムを有しており，これに連動して子宮や卵管の収縮様式が変化する．中でも子宮の収縮は月経，妊娠や分娩現象に直接関わっており，その異常は月経困難症，子宮内膜症，着床障害さらに早産などを誘発すると推察される．我々は概日時計が生殖臓器の運動機能を制御する可能性を推定し，「概日リズムの乱れは子宮収縮リズムの 異常を誘導して産科婦人科疾患の発症を誘発する」という新しい仮説を掲げてこれを検証する．

Outline of Final Research Achievements

We verified that the mouse uterus exhibits circadian rhythmic expression of clock genes. Additionally, to examine the relation between the delay of feeding and uterine circadian rhythms, we investigated the effects of the first meal occasion in the active phase on the uterine clock. We found that time-restricted feeding regulates a circadian rhythm of the uterine clock that is synchronized throughout the uterine body. To investigate the pathological roles of uterine clock genes during pregnancy, we produced conditional deletion of uterine Bmal1 (cKO) mice and found that cKO mice could receive embryo implantation but not sustain pregnancy. These findings indicate that the uterine clock system may be critical for pregnancy maintenance after embryo implantation. A significant prevalence of gestational hypertension, which is assumed to be brought on by placental dysplasia in early pregnancy, was found in a cohort study of pregnant women who had menstruation pain at a young age.

Academic Significance and Societal Importance of the Research Achievements

本研究では、概日リズムの乱れと月経困難症、子宮筋腫、子宮内膜症、妊娠高血圧症候群などの産婦人科疾患との関係を明らかにするための研究を行った。また概日リズムの乱れによる新たな病態生理を提言するために、子宮特異的な時計遺伝子改変マウスを作出し解析した。加えてモデル動物のみならず、ヒト検体を用いた実験系、そしてコホート研究を基にした臨床研究を行い、多角的に概日リズムの乱れと産婦人科疾患の関連について解析した。本研究により、子宮における末梢時計機能が生殖機能に関わっていることが明らかとなった。少子化が極めて深刻な本邦において、生殖・周産期予後改善の観点から医学的意義は重要な成果と考える。

Research Products

• [Journal Article] The Circadian Clock, Nutritional Signals and Reproduction: A Close Relationship (2023)
  • Author(s): Ono Masanori、Ando Hitoshi、Daikoku Takiko、Fujiwara Tomoko、Mieda Michihiro、Mizumoto Yasunari、Iizuka Takashi、Kagami Kyosuke、Hosono Takashi、Nomura Satoshi、Toyoda Natsumi、Sekizuka-Kagami Naomi、Maida Yoshiko、Kuji Naoaki、Nishi Hirotaka、Fujiwara Hiroshi
  • Journal Title: International Journal of Molecular Sciences Volume: 24 Issue: 2 Pages: 1545-1545
  • DOI: 10.3390/ijms24021545
  • Peer Reviewed / Open Access
• [Journal Article] Uterine Deletion of Bmal1 Impairs Placental Vascularization and Induces Intrauterine Fetal Death in Mice (2022)
  • Author(s): Ono M, Toyoda N, Kagami K, Hosono T, Matsumoto T, Horike SI, Yamazaki R, Nakamura M, Mizumoto Y, Fujiwara T, Ando H, Fujiwara H, Daikoku T.
  • Journal Title: Int J Mol Sci. Volume: 23 Issue: 14 Pages: 7637-7652
  • DOI: 10.3390/ijms23147637
  • Peer Reviewed / Open Access
• [Journal Article] Sustained effect of habitual feeding time on daily rhythm of core body temperature in mice (2022)
  • Author(s): Ando Hitoshi、Nagata Naoto、Hosono Takashi、Hasan Nazmul、Morishige Jun-ichi、Daikoku Takiko、Maida Yoshiko、Ono Masanori、Fujiwara Tomoko、Fujiwara Hiroshi
  • Journal Title: Frontiers in Nutrition Volume: 9 Pages: 966788-966788
  • DOI: 10.3389/fnut.2022.966788
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Time-Restricted Feeding Regulates Circadian Rhythm of Murine Uterine Clock (2021)
  • Author(s): Takashi Hosono, Masanori Ono, Takiko Daikoku, Michihiro Mieda, Satoshi Nomura, Kyosuke Kagami, Takashi Iizuka, Rieko Nakata, Tomoko Fujiwara, Hiroshi Fujiwara, Hitoshi Ando
  • Journal Title: Current Developments in Nutrition Volume: 5 Issue: 5 Pages: nzab064-nzab064
  • DOI: 10.1093/cdn/nzab064
  • Peer Reviewed / Open Access
• [Journal Article] Brown adipocyte-specific knockout of Bmal1 causes mild but significant thermogenesis impairment in mice (2021)
  • Author(s): Hasan Nazmul、Nagata Naoto、Morishige Jun-ichi、Islam Md Tarikul、Jing Zheng、Harada Ken-ichi、Mieda Michihiro、Ono Masanori、Fujiwara Hiroshi、Daikoku Takiko、Fujiwara Tomoko、Maida Yoshiko、Ota Tsuguhito、Shimba Shigeki、Kaneko Shuichi、Fujimura Akio、Ando Hitoshi
  • Journal Title: Molecular Metabolism Volume: 49 Pages: 101202-101202
  • DOI: 10.1016/j.molmet.2021.101202
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Wavy Floating Greater Omentum Findings Are Useful for Differentiating the Etiology of Fetal Ascites (2021)
  • Author(s): Iizuka Takashi、Ono Masanori、Yamazaki Rena、Kagami Kyosuke、Mitani Yusuke、Sakai Seisho、Fujiwara Hiroshi
  • Journal Title: Diagnostics Volume: 11 Issue: 2 Pages: 326-326
  • DOI: 10.3390/diagnostics11020326
  • Peer Reviewed
• [Journal Article] Activation-induced cytidine deaminase is a possible regulator of cross-talk between oocytes and granulosa cells through GDF-9 and SCF feedback system (2021)
  • Author(s): Iizuka Takashi、Wakae Kousho、Ono Masanori、Suzuki Takuma、Mizumoto Yasunari、Kitamura Kouichi、Horike Shin-ichi、Muramatsu Masamichi、Fujiwara Hiroshi
  • Journal Title: Scientific Reports Volume: 11 Issue: 1
  • DOI: 10.1038/s41598-021-83529-x
  • Peer Reviewed / Open Access
• [Journal Article] Hypertensive disorders of pregnancy are associated with dysmenorrhea in early adulthood: A cohort study (2020)
  • Author(s): Nakayama Midori, Ono Masanori, Iizuka Takashi, Kagami Kyosuke, Fujiwara Tomoko, Sekizuka‐Kagami Naomi, Maida Yoshiko, Obata Takeshi, Yamazaki Rena, Daikoku Takiko, Fujiwara Hiroshi
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 46 Issue: 11 Pages: 2292-2297
  • DOI: 10.1111/jog.14431
  • Peer Reviewed / Open Access
• [Journal Article] Breakfast Skipping in Female College Students Is a Potential and Preventable Predictor of Gynecologic Disorders at Health Service Centers (2020)
  • Author(s): Fujiwara Tomoko, Ono Masanori, Iizuka Takashi, Sekizuka-Kagami Naomi, Maida Yoshiko, Adachi Yumi, Fujiwara Hiroshi, Yoshikawa Hiroaki
  • Journal Title: Diagnostics Volume: 10 Issue: 7 Pages: 476-476
  • DOI: 10.3390/diagnostics10070476
  • Peer Reviewed / Open Access
• [Journal Article] A novel third mesh-like myometrial layer connects the longitudinal and circular muscle fibers -A potential stratum to coordinate uterine contractions- (2020)
  • Author(s): Kagami Kyosuke, Ono Masanori, Iizuka Takashi, Matsumoto Takeo, Hosono Takashi, Sekizuka-Kagami Naomi, Shinmyo Yohei, Kawasaki Hiroshi, Fujiwara Hiroshi
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 8274-8274
  • DOI: 10.1038/s41598-020-65299-0
  • Peer Reviewed / Open Access
• [Journal Article] Adolescent Dietary Habit-induced Obstetric and Gynecologic Disease (ADHOGD) as a New Hypothesis?Possible Involvement of Clock System (2020)
  • Author(s): Fujiwara Tomoko, Ono Masanori, Mieda Michihiro, Yoshikawa Hiroaki, Nakata Rieko, Daikoku Takiko, Sekizuka-Kagami Naomi, Maida Yoshiko, Ando Hitoshi, Fujiwara Hiroshi
  • Journal Title: Nutrients Volume: 12 Issue: 5 Pages: 1294-1294
  • DOI: 10.3390/nu12051294
  • Peer Reviewed / Open Access
• [Journal Article] Promoting Roles of Embryonic Signals in Embryo Implantation and Placentation in Cooperation with Endocrine and Immune Systems (2020)
  • Author(s): Fujiwara Hiroshi、Ono Masanori、Sato Yukiyasu、Imakawa Kazuhiko、Iizuka Takashi、Kagami Kyosuke、Fujiwara Tomoko、Horie Akihito、Tani Hirohiko、Hattori Akira、Daikoku Takiko、Araki Yoshihiko
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 5 Pages: 1885-1885
  • DOI: 10.3390/ijms21051885
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ovarian hyperstimulation closely associated (2020)
  • Author(s): Rena Yamazaki1, Masafumi Inokuchi2, Satoko Ishikawa3, Takuya Ayabe4, Hiromitsu Jinno5, Takashi Iizuka1,
  • Journal Title: ＢＭＣ ｃａｎｃｅｒ Volume: ２０ Issue: 1
  • DOI: 10.1186/s12885-020-6549-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nationwide survey of Japanese breast oncology and reproductive endocrinology departments about the impact of breast cancer treatment on fertility (2020)
  • Author(s): Yamazaki Rena、Ono Masanori、Sugie Tomoharu、Inokuchi Masafumi、Ishikawa Satoko、Iizuka Takashi、Masumoto Sakiko、Myojo Subaru、Uchida Soko、Horie Akihito、Matsuzaki Toshiya
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 46 Issue: 12 Pages: 2488-2496
  • DOI: 10.1111/jog.14469
  • Peer Reviewed / Open Access
• [Journal Article] Prenatal diagnosis facilitated prompt enzyme replacement therapy for prenatal benign hypophosphatasia. (2020)
  • Author(s): Ishijima Y, Iizuka T, Kagami K, Masumoto S, Nakade K, Mitani Y, Niida Y, Watanabe A, Yamazaki R, Ono M, Fujiwara H.
  • Journal Title: J Obstet Gynaecol. Volume: 40 Issue: 1 Pages: 132-134
  • DOI: 10.1080/01443615.2019.1606177
  • Peer Reviewed / Open Access
• [Journal Article] A direct endoscopic approach for left-sided infrarenal para-aortic lymphadenectomy immediately after hysterectomy for endometrial cancer treatment: left dome formation (LDF). (2019)
  • Author(s): Mizumoto Y, Iwadare J, Nakade K, Obata T, Matsumoto T, Kagami K, Iizuka T, Matsuoka A, Ono M, Nakamura M, Fujiwara H.
  • Journal Title: Surg Endosc. Volume: Sep 5 Issue: 8 Pages: 3338-3343
  • DOI: 10.1007/s00464-019-07103-3
  • Peer Reviewed / Open Access
• [Journal Article] Embryo transfer associated with hormone replacement therapy cycles using assisted reproductive technology increases placenta accreta spectrum. (2019)
  • Author(s): Sakai Y, Ono M, Iizuka T, Kagami K, Masumoto S, Nakayama M, Nakade K, Shitano Y, Yamazaki R, Fujiwara H.
  • Journal Title: J Obstet Gynaecol Res. Volume: 45 Issue: 12 Pages: 2394-2399
  • DOI: 10.1111/jog.14111
  • Peer Reviewed / Open Access
• [Journal Article] Amniotic epithelial cells damage by oxidative stress in cases of diffuse chorioamniotic hemosiderosis. (2019)
  • Author(s): Iizuka T, Ono M, Masumoto S, Mitani Y, Yamazaki R, Fujiwara H.
  • Journal Title: J Obstet Gynaecol Res. Volume: 45 Issue: 10 Pages: 2095-2099
  • DOI: 10.1111/jog.14084
  • Peer Reviewed / Open Access
• [Journal Article] Novel strategy of ovarian cancer implantation: Pre-invasive growth of fibrin-anchored cells with neovascularization. (2019)
  • Author(s): Matsuoka A, Mizumoto Y, Ono M, Kagami K, Obata T, Terakawa J, Maida Y, Nakamura M, Daikoku T, Fujiwara H.
  • Journal Title: Cancer Sci. Volume: 110 Issue: 8 Pages: 2658-2666
  • DOI: 10.1111/cas.14098
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Twin anemia-polycythemia sequence with blood chimerism in monochorionic dizygotic opposite-sex twins (2019)
  • Author(s): Suzuki Takuma、Kagami Kyosuke、Mitani Yusuke、Yamazaki Rena、Ono Masanori、Fujiwara Hiroshi
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 2019 Issue: 6 Pages: 1-4
  • DOI: 10.1111/jog.13949
  • Peer Reviewed / Open Access
• [Presentation] 摂餌行動はマウス子宮における概日リズムを調整する (2022)
  • Author(s): 細野 隆, 小野 政徳, 大黒 多希子, 三枝 理博, 野村 学史, 鏡 京介, 飯塚 崇, 中田 理恵子, 藤原 智子, 安藤 仁, 藤原 浩
  • Organizer: 第26回日本生殖内分泌学会学術集会
• [Presentation] 産婦人科時間生物学による子宮機能の新たな展開 (2022)
  • Author(s): 小野 政徳
  • Organizer: 第26回日本生殖内分泌学会学術集会
  • Invited
• [Presentation] 時刻制限給餌はマウス子宮における概日リズムを調整する (2021)
  • Author(s): 細野 隆, 小野 政徳, 大黒 多希子, 三枝 理博, 野村 学史, 鏡 京介, 飯塚 崇, 中田 理恵子, 藤原 智子, 安藤 仁, 藤原 浩
  • Organizer: 第68回北日本産科婦人科学会総会・学術講演会
• [Presentation] Fibrin網を利用した卵巣癌細胞集塊の腹膜播種戦略機序の解明 (2021)
  • Author(s): 松岡 歩, 水本 泰成, 小野 政徳, 鏡 京介, 小幡 武司, 寺川 純平, 毎田 佳子, 中村 充宏, 大黒 多希子, 藤原 浩
  • Organizer: 日本婦人科腫瘍学会
• [Presentation] 子宮筋腫-病態生理から薬物治療まで- 幹細胞生物学からみた子宮筋腫の病態メカニズムと治療戦略 (2020)
  • Author(s): 小野 政徳
  • Organizer: 日本エンドメトリオーシス学会
• [Presentation] 乳癌治療が妊孕性に及ぼす影響の実態調査に関する全国アンケート結果 (2020)
  • Author(s): 山崎 玲奈, 小野 政徳, 井口 雅史, 内田 聡子, 杉江 知治, 堀江 昭史, 松崎 利也, 藤原 浩
  • Organizer: 日本女性医学学会
• [Presentation] 若年成人期の月経困難症は将来の妊娠高血圧症候群罹患と関連する (2020)
  • Author(s): 小野 政徳, 中山 みどり, 飯塚 崇, 鏡 京介, 藤原 智子, 鏡 真美, 毎田 佳子, 小幡 武司, 山崎 玲奈, 大黒 多希子, 藤原 浩
  • Organizer: 日本女性医学学会
• [Presentation] 月経困難症既往は妊娠高血圧発症のリスク因子となる (2019)
  • Author(s): 中山 みどり, 飯塚 崇, 小幡 武司, 折坂 俊介, 舌野 靖, 山崎 玲奈, 鏡 真美, 毎田 佳子, 小野 政徳, 藤原 浩
  • Organizer: 第67回北日本産科婦人科学会総会・学術講演会
• [Book] 【着床を考える】着床の生理 (2020)
  • Author(s): 藤原 浩, 鏡 京介, 小野 政徳
  • Total Pages: 6
  • Publisher: 診断と治療社
• [Book] ホルモンQ&A 悪性腫瘍で化学療法を行う閉経前患者に対する卵巣保護について教えてください (2020)
  • Author(s): 小野 政徳
  • Total Pages: 2
  • Publisher: メディカルレビュー社
• [Book] 生殖生理 (2019)
  • Author(s): 大須賀 穣、藤井知行
  • Total Pages: 330
  • Publisher: 中山書店
  • ISBN: 9784521747613
• [Book] 新不妊ケアABC (2019)
  • Author(s): 小野政徳
  • Total Pages: 276
  • Publisher: 医歯薬出版
  • ISBN: 9784263237236
• [Remarks] 金沢大学産科婦人科学教室
  • URL: http://obgyn.w3.kanazawa-u.ac.jp/
• [Remarks] researchmap
  • URL: https://researchmap.jp/read0129495