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Functional analysis of the metabotropic glutamate receptor and the acid-sensitive ion channels as a urine collection control molecule

Research Project

Project/Area Number 16K11042
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Urology
Research InstitutionUniversity of Yamanashi

Principal Investigator

YOSHIYAMA Mitsuharu  山梨大学, 大学院総合研究部, 医学研究員 (20422694)

Research Collaborator IHARA Tatsuya  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywordsマウス / 代謝型グルタミン酸受容体 / 酸感受性イオンチャンネル / 下部尿路機能 / 膀胱 / 尿道 / 中枢神経 / 末梢神経 / 酸感受性チャネル / 膀胱過活動 / 求心路 / 蓄尿障害 / 外尿道括約筋 / 興奮性グルタミン酸受容体 / 酸感受性イオンチャネル / 排尿機能学
Outline of Final Research Achievements

The study using metabotropic glutamate receptor subtype 1 (mGluR1) gene deficit (KO) mice and mGluR5 antagonist revealed that mGluR1 and mGluR5 are involved in excitatory afferent signal transmission from the bladder in control of lower urinary tract (LUT) function and that the mGluR phenotype has a sex difference in the LUT function. Moreover, another study showed that acid-sensing ion channels (ASICs) are associated with excitatory afferent signal transduction in acid-induced bladder hyperreflexia as well as normal bladder activity. The present studies show that mGluR1, mGluR5 and ASICs can be target molecules for development of pharmacotherapy of lower urinary tract dysfunction such as bladder overactivity and thus these results would contribute to ameliorating a quality of life of patients who suffer from such dysfunction and to improving social productivity.

Academic Significance and Societal Importance of the Research Achievements

膀胱過活動症状はヒトの日常生活の質と生産活動性を著しく低下させる。故に、その発症機構の解明と治療法の開発は、同症状による損失を回避する上で重要である。本研究は、膀胱からの興奮性求心性信号伝達に代謝型グルタミン酸受容体(mGluR)と酸感受性イオンチャネル(ASICs)が関与することを解明した。一方、このmGluR関与の程度には雌雄差があることも明らかにした。この結果は、標的分子の表現型に性差がある可能性を念頭に研究を実施するべきであることを示唆する。近年、医学研究において、遺伝子関連の表現型や薬物療法への反応性に性別を考慮することの重要性が提唱されており、本研究結果はそれに同調する。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (38 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (9 results) Journal Article (13 results) (of which Int'l Joint Research: 12 results,  Peer Reviewed: 13 results,  Open Access: 11 results,  Acknowledgement Compliant: 2 results) Presentation (15 results) (of which Int'l Joint Research: 13 results) Book (1 results)

  • [Int'l Joint Research] Ohio State University/University of Vermont/University of Pittsburgh(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] McGill University(カナダ)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] University of Kahramanmaras/University of Cukurova(トルコ)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] University of Pittsburgh/Ohio State University/University of Vermont(U.S.A.)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] McGill University(Canada)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] University of Pittsburgh/Wake Forest University(米国)

    • Related Report
      2016 Research-status Report
  • [Int'l Joint Research] UROsphere S.A.S.(フランス)

    • Related Report
      2016 Research-status Report
  • [Int'l Joint Research] Helsinn Healthcare S.A.(スイス)

    • Related Report
      2016 Research-status Report
  • [Int'l Joint Research] Yonsei University(韓国)

    • Related Report
      2016 Research-status Report
  • [Journal Article] The effect of Ferula elaeochytris root extract on erectile dysfunction in streptozotocin-induced diabetic rat2019

    • Author(s)
      Eser Nadire、Buyuknacar Hacer Sinem、Cimentepe Ozge Ozturk、Gocmen Cemil、Ucar Yilmaz、Erdogan Seyda、Yoshiyama Mitsuharu
    • Journal Title

      International Journal of Impotence Research

      Volume: 印刷中 Issue: 2 Pages: 186-194

    • DOI

      10.1038/s41443-019-0137-8

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The oscillation of intracellular Ca2+ influx associated with the circadian expression of Piezo1 and TRPV4 in the bladder urothelium2018

    • Author(s)
      Ihara Tatsuya、Mitsui Takahiko、Nakamura Yuki、Kanda Mie、Tsuchiya Sachiko、Kira Satoru、Nakagomi Hiroshi、Sawada Norifumi、Kamiyama Manabu、Hirayama Yuri、Shigetomi Eiji、Shinozaki Youichi、Yoshiyama Mitsuharu、Nakao Atsuhito、Takeda Masayuki、Koizumi Schuichi
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 5699-5699

    • DOI

      10.1038/s41598-018-23115-w

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury2018

    • Author(s)
      Ryu Jae Cheon、Tooke Katharine、Malley Susan E.、Soulas Anastasia、Weiss Tirzah、Ganesh Nisha、Saidi Nabila、Daugherty Stephanie、Saragovi Uri、Ikeda Youko、Zabbarova Irina、Kanai Anthony J.、Yoshiyama Mitsuharu、Farhadi H. Francis、de Groat William C.、Vizzard Margaret A.、Yoon Sung Ok
    • Journal Title

      Journal of Clinical Investigation

      Volume: 128 Issue: 5 Pages: 1772-1786

    • DOI

      10.1172/jci97837

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The time-dependent variation of ATP release in mouse primary cultured urothelial cells is regulated by the Clock gene.2018

    • Author(s)
      Ihara T, Mitsui T, Nakamura Y, Kanda M, Tsuchiya S, Kira S, Nakagomi H, Sawada N, Kamiyama M, Hirayama Y, Shigetomi E, Shinozaki Y, Yoshiyama M, Nakao A, Takeda M Koizumi S
    • Journal Title

      Neurourology and urodynamics

      Volume: 37 Issue: 8 Pages: 2535-2543

    • DOI

      10.1002/nau.23793

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The Circadian expression of Piezo1, TRPV4, Connexin26, and VNUT, associated with the expression levels of the clock genes in mouse primary cultured urothelial cells2017

    • Author(s)
      Ihara Tatsuya、Mitsui Takahiko、Nakamura Yuki、Kanda Mie、Tsuchiya Sachiko、Kira Satoru、Nakagomi Hiroshi、Sawada Norifumi、Hirayama Yuri、Shibata Keisuke、Shigetomi Eiji、Shinozaki Yoichi、Yoshiyama Mitsuharu、Nakao Atsuhito、Takeda Masayuki、Koizumi Schuichi
    • Journal Title

      Neurourology and Urodynamics

      Volume: 37 Issue: 3 Pages: 942-951

    • DOI

      10.1002/nau.23400

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] P2Y6-deficiency increases micturition frequency and attenuates sustained contractility of the urinary bladder in mice2017

    • Author(s)
      Kira S,Yoshiyama M,Tsuchiya S,Shigetomi E,Miyamoto T,Nakagomi H,Shibata K,Mochizuki T,Takeda M,Koizumi S
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 771-771

    • DOI

      10.1038/s41598-017-00824-2

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] The role of capsaicin-sensitive C-fiber afferent pathways in the control of micturition in spinal-intact and spinal cord-injured mice2017

    • Author(s)
      Kadekawa Katsumi、Majima Tsuyoshi、Shimizu Takahiro、Wada Naoki、de Groat William C.、Kanai Anthony J.、Goto Momokazu、Yoshiyama Mitsuharu、Sugaya Kimio、Yoshimura Naoki
    • Journal Title

      American Journal of Physiology Renal Physiology

      Volume: 313 Issue: 3 Pages: F796-F804

    • DOI

      10.1152/ajprenal.00097.2017

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Clock Genes Regulate the Circadian Expression of Piezo1, TRPV4, Connexin26, and VNUT in an Ex Vivo Mouse Bladder Mucosa.2017

    • Author(s)
      5.Ihara T, Mitsui T, Nakamura Y, Kira S, Nakagomi H, Sawada N, Hirayama Y, Shibata K, Shigetomi E, Shinozaki Y, Yoshiyama M, Andersson KE, Nakao A, Takeda M, Koizumi S
    • Journal Title

      PLoS One

      Volume: 12 Issue: 1 Pages: e0168234-e0168234

    • DOI

      10.1371/journal.pone.0168234

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Ketanserin and naftopidil enhance the potentiating effect of alpha-methyl-serotonin on the neurally-induced contraction of human isolated urinary bladder muscle strips2017

    • Author(s)
      Hattori T, Lluel P, Rouget C, Rekik M, Yoshiyama M
    • Journal Title

      International Neurourology Journal

      Volume: 21 Issue: 1 Pages: 20-28

    • DOI

      10.5213/inj.1732758.379

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Characterization of bladder and external urethral activity in mice with or without spinal cord injury - a comparison study with rats2016

    • Author(s)
      Kadekawa K, Yoshimura N, Majima T, Wada N, Shimizu T, Birder LA, Kanai AJ, de Groat WC, Sugaya K, Yoshiyama M
    • Journal Title

      American Journal of Physiology Regulatory Integrative Comparative Physiology

      Volume: 310 Issue: 8 Pages: R752-R758

    • DOI

      10.1152/ajpregu.00450.2015

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Urothelial ATP exocytosis: regulation of bladder compliance in the urine storage phase2016

    • Author(s)
      Nakagomi H,Yoshiyama M,Mochizuki T,Miyamoto T,Komatsu R,Imura Y,Morizawa Y,Hiasa M,Kira S,Fujishita K,Shibata K,Shigetomi E,Shinozaki Y,Takeda M,Koizumi S
    • Journal Title

      Scientific Reports

      Volume: 6 Issue: 1 Pages: 29761-29761

    • DOI

      10.1038/srep29761

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Netupitant, a potent and highly selective NK1 receptor antagonist, alleviates acetic acid-induced bladder overactivity in anesthetized guinea-pigs2016

    • Author(s)
      Palea S, Guilloteau V, Rekik M, Lovati E, Guerard M, Guardia MA, Lluel P, Pietra C, Yoshiyama M
    • Journal Title

      Frontiers in Pharmacology

      Volume: 7

    • DOI

      10.3389/fphar.2016.00234

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The Clock mutant mouse is a novel experimental model for nocturia and nocturnal polyuria.2016

    • Author(s)
      Ihara, T., Mitsui, T., Nakamura, Y., Kira, S., Miyamoto, T., Nakagomi, H., Sawada, N., Hirayama, Y., Shibata, K., Shigetomi, E., Shinozaki, Y., Yoshiyama, M., Nakao, A., *Takeda, M. *Koizumi, S.
    • Journal Title

      Neurourology and Urodynamics

      Volume: 36 Issue: 4 Pages: 1034-1038

    • DOI

      10.1002/nau.23062

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Metabotropic glutamate receptor subtypes 1 and 5 are necessary for synergic activity of bladder and external urethral sphincter in mice with spinal cord injury2018

    • Author(s)
      Yoshiyama Mitsuharu、Takeda Masayuki
    • Organizer
      The 33rd Annual Congress of the European Association of Urology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The sex influences metabotropic glutamate receptor subtype 1 phenotype in control of lower urinary tract activity2018

    • Author(s)
      Yoshiyama Mitsuharu、Mochizuki Tsutomu、Takeda Masayuki
    • Organizer
      International Continence Society 48th Annual meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] マウス下部尿路機能制御において性別は代謝型グルタミン酸受容体サブタイプ1表現型へ有意に影響する2018

    • Author(s)
      芳山充晴、望月勉、武田正之
    • Organizer
      第25回日本排尿機能学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Metabotropic glutamate receptor subtypes 1 and 5 are necessary for synergic activity of bladder and external urethral sphincter in mice with spinal cord injury2018

    • Author(s)
      M Yoshiyama, M Takeda
    • Organizer
      European Association of Urology Annual congress
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Pelvic floor supportive underwear enhances alleviating effect of pelvic floor muscle training on lower urinary tract symptoms in pelvic organ prolapse patients2017

    • Author(s)
      T Taniguchi,Y Kobayashi,S Takaoka,H Kobayashi,T Mitsui,M Yoshiyama,M Takeda
    • Organizer
      International Continence Society 47th Annual meeting,
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Effect of restraint stress on alternation of circadian bladder function to induce nocturia2017

    • Author(s)
      T Ihara,Y Nakamura,T Mitsui,Y Otake,Y Imai,S Kira,H Nakagomi,N Sawada,M Yoshiyama,S Koizumi,A Nakao,M Takeda
    • Organizer
      International Continence Society 47th Annual meeting
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Blockade of metabotropic glutamatergic pathways worsens voiding dysfunction in mice with chronically-transected spinal cord2017

    • Author(s)
      M Yoshiyama,M Takeda
    • Organizer
      International Continence Society 47th Annual meeting
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 代謝型グルタミン酸受容体経路遮断は完全脊髄損傷マウスの排尿機能不全を増悪する2017

    • Author(s)
      芳山充晴、武田正之
    • Organizer
      第24回日本排尿機能学会
    • Related Report
      2017 Research-status Report
  • [Presentation] Circadian regulations of Piezo1, TRPV4, Connexin26 and VNUT by clock genes in the mouse bladder urothelium2016

    • Author(s)
      Ihara T, Nakamura Y, Mitsui T, Kira S, Nakagomi H, Sawada N, Shinozaki Y, Yoshiyama M, Nakao A, Takeda M, Koizumi S
    • Organizer
      International Continence Society 46th Annual meeting
    • Place of Presentation
      東京国際フォーラム(東京都千代田区)
    • Year and Date
      2016-09-15
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] The role of capsaicin-sensitive C-fiber afferent pathways in the control of micturition in normal mice and lower urinary tract dysfunction in mice with spinal cord injury2016

    • Author(s)
      Kadekawa K, Yoshiyama M, Wada N, Shimizu T, Majima T, Tyagi P, Kanai A, de Groat W, Sugaya K, Yoshimura N
    • Organizer
      International Continence Society 46th Annual meeting
    • Place of Presentation
      東京国際フォーラム(東京都千代田区)
    • Year and Date
      2016-09-14
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Evaluation of a novel underwear which supports the pelvic floor in pelvic organ prolapse patients2016

    • Author(s)
      Taniguchi T, Kobayashi Y, Kobayashi H, Mitsui T, Takaoka T, Yoshiyama M, Takeda M
    • Organizer
      International Continence Society 46th Annual meeting
    • Place of Presentation
      東京国際フォーラム(東京都千代田区)
    • Year and Date
      2016-09-13
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Preclinical Urodynamics - Optimisation of Techniques, Measurements and Interpretation2016

    • Author(s)
      Yoshiyama M
    • Organizer
      International Continence Society 46th Annual meeting
    • Place of Presentation
      東京国際フォーラム(東京都千代田区)
    • Year and Date
      2016-09-13
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Clock genes regulate circadian rhythm of VNUT expression,Connexin26 expression and stretch-evoked ATP release in the cultured urothelial cells2016

    • Author(s)
      Ihara T, Kira S, Miyamoto T, Sawada N, Nakagomi H, Mitsui T, Kobayashi H, Yoshiyama M, Takeda M, Nakamura Y, Nakao A, Shigetomi E, Shinozaki Y, Koizumi S
    • Organizer
      American Urological Association Annual Meeting
    • Place of Presentation
      San Diego, California, U.S.A.
    • Year and Date
      2016-05-09
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Glycine transporter type 2 (GlyT2) inhibitor ameliorates autonomic dysreflexia during bladder hydrodistention and detrusor overactivity in IC/BPS rat model2016

    • Author(s)
      Kim SW, Moon SY, Son HS, Yoshiyama M, Kim JH
    • Organizer
      American Urological Association Annual Meeting
    • Place of Presentation
      San Diego, California, U.S.A.
    • Year and Date
      2016-05-07
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Characterization of tonic activity of external urethral sphincter during voiding underlying inefficient voiding after spinal cord injury in rats2016

    • Author(s)
      Kadekawa K, Yoshiyama M, Majima T, Tyagi P, Sugaya K, Yoshimura N
    • Organizer
      American Urological Association Annual Meeting
    • Place of Presentation
      San Diego, California, U.S.A.
    • Year and Date
      2016-05-06
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Book] Spinal cord, In: Neurourology: theory and practice (Eds. Limin Liao, Helmut Madersbacher)2019

    • Author(s)
      Yoshiyama Mitsuharu、Kakizaki Hidehiro
    • Total Pages
      583
    • Publisher
      Springer, Dordrecht
    • ISBN
      9789401775090
    • Related Report
      2018 Annual Research Report

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Published: 2016-04-21   Modified: 2022-02-16  

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