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A chronobiological approach to elucidate nocturia focusing on the urothelium

Research Project

Project/Area Number 15H05682
Research Category

Grant-in-Aid for Young Scientists (A)

Allocation TypeSingle-year Grants
Research Field Urology
Research InstitutionUniversity of Tsukuba (2018)
Kyoto University (2015-2017)

Principal Investigator

Negoro Hiromitsu  筑波大学, 附属病院, 病院講師 (80708595)

Project Period (FY) 2015-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥23,920,000 (Direct Cost: ¥18,400,000、Indirect Cost: ¥5,520,000)
Fiscal Year 2018: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2017: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2016: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2015: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
Keywords排尿障害 / 時間生物学 / 尿路上皮 / コネキシン43 / Bmal1 / 時計遺伝子 / ATP / コネキシン43 / コネキシン / 概日リズム
Outline of Final Research Achievements

We have found that a functional circadian rhythm exists in the urothelium, and it coordinates connexin43 (Cx43) expression and function as hemichannels that provide a direct pathway of ATP release for mechanotransduction and signaling in the urothelium. In addition, we have generated conditional knockout C57BL/6 mice lacking a major clock gene Bmal1 or Cx43 in the urothelium only. Furthermore, we have generated P(Bmal1)-dLuc reporter cell lines derived from immortalized human urothelial cells and have identified a few candidate compounds that could modify the circadian rhythm of the urothelium.
We presently progress the research to investigate the role of peripheral clock in the urothelium for the bladder function and diseases characterized as disorders of micturition rhythm including nocturnal enuresis and nocturia.

Academic Significance and Societal Importance of the Research Achievements

膀胱は夜間にしっかりと尿を溜め、日中はしっかり排尿するようにその機能の日内変動を有し、個体の生命活動をサポートしている。膀胱機能の昼夜差の形成メカニズムを解明することは、夜間頻尿や夜尿症など、排尿の昼夜差が乱れた疾患の機序解明に貢献すると考えられる。本研究から、尿路上皮でのCx43の発現や機能を制御すること、それに伴うATP放出を制御すること、概日時計に作用することをターゲットとした薬剤が夜間頻尿や夜尿症の新たな治療薬の候補となることが期待される。

Report

(5 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (41 results)

All 2019 2018 2017 2016 2015

All Journal Article (10 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 7 results,  Open Access: 5 results) Presentation (31 results) (of which Int'l Joint Research: 4 results,  Invited: 14 results)

  • [Journal Article] Sleep disturbance worsens lower urinary tract symptoms (LUTS): The Nagahama study2019

    • Author(s)
      Fukunaga Arinobu、Kawaguchi Takahisa、Funada Satoshi、Yoshino Takayuki、Tabara Yasuharu、Matsuda Fumihiko、Yoshimura Koji、Ogawa Osamu、Negoro Hiromitsu、on behalf of the Nagahama Study Group
    • Journal Title

      Journal of Urology

      Volume: in press Issue: 2 Pages: 354-354

    • DOI

      10.1097/ju.0000000000000212

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] <b>Circadian rhythms of micturition during jet </b><b>lag </b>2018

    • Author(s)
      Ito K, Yasuda M, Maeda Y, Fustin JM, Yamaguchi Y, Kono Y, Negoro H, Kanematsu A, Ogawa O, Doi M, and Okamura H
    • Journal Title

      Biomedical Research

      Volume: 39 Issue: 2 Pages: 57-63

    • DOI

      10.2220/biomedres.39.57

    • NAID

      130006708567

    • ISSN
      0388-6107, 1880-313X
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Epidemiology, pathophysiology and diagnosis of nocturia2018

    • Author(s)
      Negoro H
    • Journal Title

      Japanese Journal of Clinical Urology

      Volume: 72 Pages: 104-110

    • NAID

      40021455399

    • Related Report
      2018 Annual Research Report
    • Open Access
  • [Journal Article] [Biological clock and nocturia]2018

    • Author(s)
      Negoro H, Sengiku A
    • Journal Title

      Journal of Clinical and Experimental Medicine

      Volume: 267 Pages: 457-461

    • NAID

      40021711911

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Circadian coordination of ATP release in the urothelium via connexin43 hemichannels2018

    • Author(s)
      Sengiku A, Ueda M, Kono J, Sano T, Nishikawa N, Kunisue S, Tsujihana K, Liou L, Kanematsu A, Shimba S, Doi M, Okamura H, Ogawa O, and Negoro H
    • Journal Title

      Sci. Rep.

      Volume: 8 Issue: 1 Pages: 1996-1996

    • DOI

      10.1038/s41598-018-20379-0

    • NAID

      120006510288

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 概日リズムと排尿機能2017

    • Author(s)
      根来 宏光
    • Journal Title

      腎臓内科・泌尿器科

      Volume: 6 Pages: 154-158

    • NAID

      40021296395

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Cross-Sectional Epidemiological Analysis of the Nagahama Study for Correlates of Overactive Bladder: Genetic and Environmental Considerations.2017

    • Author(s)
      Funada S. Kawaguchi T. Terada N. Negoro H. Tabara Y. Kosugi S. Yamada R. Nakayama T. Akamatsu S. Yoshimura K. Matsuda F. Ogawa O. Nagahama Study Group.
    • Journal Title

      J Urol.

      Volume: in press Issue: 3 Pages: 774-778

    • DOI

      10.1016/j.juro.2017.09.146

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Nocturia increases the incidence of depressive symptoms: a longitudinal study of the HEIJO-KYO cohort.2017

    • Author(s)
      Obayashi K, Saeki K, Negoro H, Kurumatani N
    • Journal Title

      BJU Int

      Volume: 120 Pages: 280-285

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dietary Sodium Restriction Reduces Nocturnal Urine Volume and Nocturnal Polyuria Index in Renal Allograft Recipients With Nocturnal Polyuria.2017

    • Author(s)
      Okumura Y, Asai K, Kobayashi T, Miyata H, Tanaka Y, Okada Y, Sakai K, Kamba T, Tsuji H, Shide K, Nagashima K, Yanagita M, Inagaki N, Ogawa O, Negoro H
    • Journal Title

      Urology

      Volume: 106 Pages: 60-64

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Intravital imaging of mouse urothelium reveals activation of extracellular signal-regulated kinase by stretch-induced intravesical release of ATP.2016

    • Author(s)
      Sano T, Kobayashi T, Negoro H, Sengiku A, Hiratsuka T, Kamioka Y, Liou LS, Ogawa O, Matsuda M
    • Journal Title

      Physiological reports

      Volume: 21 Issue: 21

    • DOI

      10.14814/phy2.13033

    • NAID

      120005895398

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 夜間頻尿-その深淵に迫る Circadian rhythmから夜間頻尿に迫る2018

    • Author(s)
      根来 宏光
    • Organizer
      第106回日本泌尿器科学会総会 (シンポジウム)
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Insomnia induces lower urinary tract symptoms: The natural history and risk factors for LUTS from the Nagahama longitudinal study2018

    • Author(s)
      Hiromitsu Negoro
    • Organizer
      AUA 2018 Oral presentation
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 夜間頻尿と睡眠障害の関係からみえてくるもの2018

    • Author(s)
      根来 宏光
    • Organizer
      第 25 回 日本排尿機能学会ランチョンセミナー
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 夜尿の既往があると夜間頻尿になりやすい:ながはまコホート研究から2018

    • Author(s)
      根来 宏光
    • Organizer
      第25回 日本時間生物学会学術大会2018/10/20-21 (10/21)
    • Related Report
      2018 Annual Research Report
  • [Presentation] Medical history of nocturnal enuresis at school age is a risk factor for nocturia in adults: The Nagahama study2018

    • Author(s)
      Hiromitsu Negoro
    • Organizer
      EAU2019 (34th Annual European Association Of Urology Congress)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Abyss of Nocturia -looking into the depth from circadian rhythm2018

    • Author(s)
      根来 宏光
    • Organizer
      131th WPI-IIISセミナー
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 概日時計の破綻と夜間頻尿 -疫学・基礎からのアプローチ-2018

    • Author(s)
      根来 宏光
    • Organizer
      第4回アカシア研究会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 体内時計から夜間頻尿を考える -疫学・基礎の視点から-2018

    • Author(s)
      根来 宏光
    • Organizer
      第219回宮崎県泌尿器科医会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 尿路上皮のコネキシン43は時計遺伝子の制御下に細胞間情報伝達機能を有する2018

    • Author(s)
      千菊 敦士, 根来 宏光, 上田 政克, 河野 仁, 佐野 剛視, 國末 純宏, 辻花 光次郎, 岡村 均, 小川 修
    • Organizer
      第27回泌尿器科分子・細胞研究会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 体内時計の破綻と夜間頻尿(講演)2018

    • Author(s)
      根来 宏光
    • Organizer
      山形臨床泌尿器科懇話会2018.1.10
    • Related Report
      2017 Annual Research Report
  • [Presentation] 過活動膀胱の成因を考える(講演)2018

    • Author(s)
      根来 宏光
    • Organizer
      女性泌尿器疾患を考える会2018.1.23
    • Related Report
      2017 Annual Research Report
  • [Presentation] 膀胱における時計遺伝子発現と膀胱容量変動のメカニズム(講演)2018

    • Author(s)
      根来 宏光
    • Organizer
      第5階時間疫学研究会2018.2.17
    • Related Report
      2017 Annual Research Report
  • [Presentation] 体内時計の破綻と下部尿路症状‐タダラフィルの話題も交えて‐(講演)2018

    • Author(s)
      根来 宏光
    • Organizer
      第8回熊本泌尿器疾患研究会2018.3.10
    • Related Report
      2017 Annual Research Report
  • [Presentation] 日内排尿リズムを司る膀胱時計2017

    • Author(s)
      根来宏光
    • Organizer
      第87回日本衛生学会学術総会
    • Place of Presentation
      フェニックス・シーガイア・リゾート
    • Year and Date
      2017-03-26
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] The circadian rhythm coordinates the ATP release in the urothelium via the connexin43 hemichannel2017

    • Author(s)
      Atsushi Sengiku, Hiromitsu Negoro, Takeshi Sano, Masakatsu Ueda, Jin Kono, Kyoto, Japan, Louis Liou, Cambridge, MA, Hitoshi Okamura, Osamu Ogawa
    • Organizer
      AUA 2017 Annual Meeting
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Circadian rhythm in urothelium coordinates its ATP release via connexin43 hemichannel2017

    • Author(s)
      Atsushi Sengiku, Hiromitsu Negoro, Jin Kono, Masakatsu Ueda, Takeshi Sano, Sumihiro Kunisue, Kojiro Tsujihana, Hitoshi Okamura, Osamu Ogawa
    • Organizer
      第105回日本泌尿器科学会総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 尿路上皮のコネキシン43は時計遺伝子の制御下に細胞間情報伝達機能を有する2017

    • Author(s)
      千菊 敦士、根来 宏光、上田 政克、河野 仁、佐野 剛視、國末 純宏、辻花 光次郎、 岡村 均、小川 修
    • Organizer
      第24回日本排尿機能学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Mechanically-induced ATP release had oscillations in correlation with the Cx43 expression in urothelial cells.2017

    • Author(s)
      Atsushi Sengiku, Hiromitsu Negoro, Masakatsu Ueda, Jin Kono, Takeshi Sano, Louis S. Liou, Hitoshi Okamura, Osamu Ogawa
    • Organizer
      15th Urological Association of Asia Congress
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 日内排尿リズムを構成する膀胱時計2017

    • Author(s)
      根来 宏光
    • Organizer
      第24回日本排尿機能学会(シンポジウム)2017.9.29
    • Related Report
      2017 Annual Research Report
  • [Presentation] 過活動膀胱の成因から治療まで-抗コリン薬の役割‐(講演)2017

    • Author(s)
      根来 宏光
    • Organizer
      舞鶴医師会 学術講演会2017.4.20
    • Related Report
      2017 Annual Research Report
  • [Presentation] 体内時計と排尿障害の関わり(講演)2017

    • Author(s)
      根来 宏光
    • Organizer
      2017年石川県泌尿器科医会2017.6.22
    • Related Report
      2017 Annual Research Report
  • [Presentation] 体内時計と排尿障害の関わり(講演)2017

    • Author(s)
      根来 宏光
    • Organizer
      male LUTS治療戦略セミナー2017.7.14
    • Related Report
      2017 Annual Research Report
  • [Presentation] 体内時計と排尿障害の関わり(講演)2017

    • Author(s)
      根来 宏光
    • Organizer
      前立腺研究会 in 能登2017.7.21
    • Related Report
      2017 Annual Research Report
  • [Presentation] 体内時計と夜間頻尿とタダラフィル2017

    • Author(s)
      根来宏光
    • Organizer
      第18回神戸地区泌尿器科カンファレンス
    • Place of Presentation
      ホテルオークラ 京都
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 体内時計と膀胱機能2016

    • Author(s)
      根来宏光
    • Organizer
      第72回NGB研究会
    • Place of Presentation
      日本新薬大阪営業所
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 体内時計と膀胱機能2016

    • Author(s)
      根来宏光
    • Organizer
      第104回泌尿器科学会総会
    • Place of Presentation
      仙台国際センター
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 概日時計と日内排尿リズム2016

    • Author(s)
      根来宏光
    • Organizer
      第11回Urology Study
    • Place of Presentation
      ソラリア西鉄ホテル
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 概日時計はLUTSに関与するのか?-そのメカニズムから治療を考える-2016

    • Author(s)
      根来宏光
    • Organizer
      第4回排尿イノベーションミーティングinさいたま
    • Place of Presentation
      ラフォーレ清水園
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] ギャップジャンクションファミリーの膀胱での役割2015

    • Author(s)
      根来宏光, 千菊敦士, Sylvia. O Suadicani, 小川修
    • Organizer
      BMB2015ギャッ プジャンクションワークショップ
    • Place of Presentation
      神戸
    • Year and Date
      2015-12-02
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] ギャップ結合ファミリーの尿路上皮における役割2015

    • Author(s)
      根来宏光, 千菊敦士, Sylvia. O Suadicani, 小川修
    • Organizer
      第22回日本排尿機能学会ワークショップ
    • Place of Presentation
      札幌
    • Year and Date
      2015-09-09
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] 概日時計と夜間頻尿2015

    • Author(s)
      根来宏光 兼松明弘 小川修
    • Organizer
      第30回日本睡眠学会(シンポジウム 睡眠障害と夜間頻尿の密接な関係)
    • Place of Presentation
      宇都宮
    • Year and Date
      2015-07-02
    • Related Report
      2015 Annual Research Report
    • Invited

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Published: 2015-04-16   Modified: 2020-03-30  

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