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Development of treatment strategies for intervertebral disc degeneration by modulating mTOR signaling

Research Project

Project/Area Number 16K20051
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Orthopaedic surgery
Research InstitutionKobe University

Principal Investigator

YURUBE Takashi  神戸大学, 医学部附属病院, 特定助教 (10514648)

Project Period (FY) 2016-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
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椎間板変性 / mTOR / オートファジー / 脊椎 / 整形外科
Outline of Final Research Achievements

This study aimed to clarify effectiveness of biological therapies for intervertebral disc degeneration by modulating mTOR signaling. In our study, RNA interference technique revealed that suppression of the mTOR complex 1 (mTORC1) had protective effects against disc cellular apoptosis, senescence, and extracellular matrix degradation. Furthermore, administration of mTORC1 inhibitors to find potential clinical applications showed similar beneficial effects on disc cells through Akt induction. Then, specific autophagy inhibition by RNA interference clearly presented anti-apoptotic and anti-senescent effects of autophagy. Based on these findings, biological modulation of mTOR signaling and autophagy is a potential therapeutic strategy for degenerative disc disease.

Report

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

    (32 results)

All 2018 2017 2016

All Journal Article (4 results) (of which Peer Reviewed: 3 results,  Open Access: 1 results,  Acknowledgement Compliant: 2 results) Presentation (28 results) (of which Int'l Joint Research: 14 results,  Invited: 1 results)

  • [Journal Article] Selective interference of mTORC1/RAPTOR protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism with Akt and autophagy induction.2017

    • Author(s)
      Ito M, Yurube T, Kakutani K, Maeno K, Takada T, Terashima Y, Kakiuchi Y, Takeoka Y, Miyazaki S, Kuroda R, Nishida K.
    • Journal Title

      Osteoarthritis Cartilage

      Volume: 25 Issue: 12 Pages: 2134-2146

    • DOI

      10.1016/j.joca.2017.08.019

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 脊椎椎間板髄核におけるオートファジーの重要性とその誘導による椎間板変性予防の可能性2017

    • Author(s)
      由留部崇、伊藤雅明、角谷賢一朗、前野耕一郎、黒田良祐、西田康太郎
    • Journal Title

      中部日本整形外科災害外科学会雑誌

      Volume: 60(3) Pages: 547-548

    • NAID

      130006108244

    • Related Report
      2017 Annual Research Report
  • [Journal Article] 椎間板では他の筋骨格系組織よりもオートファジーの関与が大きく、その活性は変性とともに減少する2017

    • Author(s)
      由留部崇、平田裕亮、伊藤雅明、垣内裕司、寺嶋良樹、武岡由樹、角谷賢一朗、前野耕一郎、高田徹、黒田良佑、西田康太郎
    • Journal Title

      Journal of Spine Research

      Volume: 8 Pages: 106-111

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] 椎間板の微小環境-細胞代謝、オートファジーの観点から2017

    • Author(s)
      由留部崇、伊藤雅明、角谷賢一朗、前野耕一郎、黒田良佑、西田康太郎
    • Journal Title

      整形・災害外科

      Volume: 60 Pages: 279-285

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] Involvement of autophagy in intervertebral disc degeneration and its contribution to cell homeostasis with the maintenance of notochordal phenotype2018

    • Author(s)
      Yurube T, Ito M, Kakiuchi Y, Takeoka Y, Kakutani K, Takada T, Kanda Y, Miyazaki S, Kuroda R, Nishida K
    • Organizer
      The 64th Annual Meeting, Orthopaedic Research Society
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Temsirolimus is a candidate of the optimal mTOR inhibitor to protect human disc cells through AKT rather than autophagy induction2018

    • Author(s)
      Kakiuchi Y, Yurube T, Takeoka Y, Ito M, Kanda Y, Kakutani K, Takada T, Kuroda R, Nishida K
    • Organizer
      The 64th Annual Meeting, Orthopaedic Research Society
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Involvement and roles of autophagy in maintaining notochordal cell homeostasis of the intervertebral disc nucleus pulposus2017

    • Author(s)
      Yurube T, Ito M, Kakiuchi Y, Terashima Y, Takeoka Y, Kakutani K, Maeno K, Takada T, Kuroda R, Nishida K
    • Organizer
      The 63rd Annual Meeting of the Orthopaedic Research Society
    • Place of Presentation
      San Diego (USA)
    • Year and Date
      2017-03-19
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Selective mTORC1 inhibition through RNA interference for Raptor is protective against human disc cellular apoptosis, senescence, and extracellular matrix degradation with Akt and autophagy induction2017

    • Author(s)
      Ito M, Yurube T, Kakutani K, Maeno K, Takada T, Terashima Y, Kakiuchi Y, Takeoka Y, Kuroda R, Nishida K
    • Organizer
      The 63rd Annual Meeting of the Orthopaedic Research Society
    • Place of Presentation
      San Diego (USA)
    • Year and Date
      2017-03-19
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Autophagy contributes to cell survival, anti-apoptosis, anti-senescence and extracellular matrix homeostasis in human disc nucleus pulposus cells2017

    • Author(s)
      Ito M, Yurube T, Kakutani K, Maeno K, Takada T, Terashima Y, Kakiuchi Y, Takeoka Y, Kuroda R, Nishida K
    • Organizer
      The 63rd Annual Meeting of the Orthopaedic Research Society
    • Place of Presentation
      San Diego (USA)
    • Year and Date
      2017-03-19
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Temsirolimus is a candidate of the optimal mTOR inhibitor in human intervertebral disc nucleus pulposus cells2017

    • Author(s)
      Kakiuchi Y, Yurube T, Ito M, Takeoka Y, Terashima Y, Kakutani K, Maeno K, Takada T, Kuroda R, Nishida K
    • Organizer
      The 63rd Annual Meeting of the Orthopaedic Research Society
    • Place of Presentation
      San Diego (USA)
    • Year and Date
      2017-03-19
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Inhibition of autophagy through ATG5 knock down induces apoptosis and senescence in human intervertebral disc cells2017

    • Author(s)
      Ito M, Yurube T, Kakutani K, Maeno K, Takada T, Terashima Y, Kakiuchi Y, Takeoka Y, Kuroda R, Nishida K
    • Organizer
      The 8th Annual Meeting of the Cervical Spine Research Society Asia Pacific Section
    • Place of Presentation
      神戸国際会議場(兵庫県神戸市)
    • Year and Date
      2017-03-09
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Temsirolimus is a candidate of the optimal mTOR inhibitor for protecting human intervertebral disc nucleus pulposus cells2017

    • Author(s)
      Kakiuchi Y, Yurube T, Takeoka Y, Ito M, Kakutani K, Maeno K, Takada T, Terashima Y, Kuroda R, Nishida K
    • Organizer
      The 8th Annual Meeting of the Cervical Spine Research Society Asia Pacific Section
    • Place of Presentation
      神戸国際会議場(兵庫県神戸市)
    • Year and Date
      2017-03-09
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] mTORシグナル経路におけるRAPTORへの選択的な干渉はヒト椎間板細胞における細胞死,細胞老化と細胞外基質分解を抑制する2017

    • Author(s)
      由留部崇、伊藤雅明、角谷賢一朗、前野耕一郎、高田徹、寺嶋良樹、垣内裕司、武岡由樹、黒田良佑、西田康太郎
    • Organizer
      第30回日本軟骨代謝学会
    • Place of Presentation
      京都市勧業館みやこめっせ(京都府京都市)
    • Year and Date
      2017-03-03
    • Related Report
      2016 Research-status Report
  • [Presentation] 椎間板髄核におけるオートファジーの重要性とその脊索表現型保持への関与の可能性2017

    • Author(s)
      由留部崇、伊藤雅明、垣内裕司、寺嶋良樹、武岡由樹、角谷賢一朗、前野耕一郎、高田徹、黒田良祐、西田康太郎
    • Organizer
      第46回日本脊椎脊髄病学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] ATG5のノックダウンによるオートファジーの抑制はヒト椎間板細胞のアポトーシスとセネッセンスを誘導し、細胞数を減少させる2017

    • Author(s)
      伊藤雅明、由留部崇、角谷賢一朗、前野耕一郎、高田徹、寺嶋良樹、垣内裕司、武岡由樹、黒田良祐、西田康太郎
    • Organizer
      第46回日本脊椎脊髄病学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] ヒト椎間板髄核臍傍におけるmTOR阻害薬の細胞死、細胞老化、細胞外基質分解抑止効果の比較2017

    • Author(s)
      垣内裕司、由留部崇、角谷賢一朗、前野耕一郎、高田徹、寺嶋良樹、伊藤雅明、武岡由樹、黒田良祐、西田康太郎
    • Organizer
      第46回日本脊椎脊髄病学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Involvement of autophagy in intervertebral disc degeneration and its possible contribution to the maintenance of notochordal cell homeostasis2017

    • Author(s)
      Yurube T, Hirata H, Ito M, Terashima Y, Kakiuchi Y, Takeoka Y, Miyazaki S, Kakutani K, Maeno K, Takada T, Kuroda R, Nishida K
    • Organizer
      The 44th Annual Meeting, International Society for the Study of the Lumbar Spine
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Inhibition of autophagy through ATG5 knock down induces apoptosis and senescence in human intervertebral disc cells2017

    • Author(s)
      Ito M, Yurube T, Kakutani K, Maeno K, Takada T, Terashima Y, Kakiuchi Y, Takeoka Y, Kuroda R, Nishida K
    • Organizer
      The 44th Annual Meeting, International Society for the Study of the Lumbar Spine
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Temsirolimus is a candidate of the optimal mTOR inhibitor for protecting human intervertebral disc nucleus pulposus cells2017

    • Author(s)
      Kakiuchi Y, Yurube T, Takeoka Y, Ito M, Kakutani K, Maeno K, Takada T, Terashima Y, Kuroda R, Nishida K
    • Organizer
      The 44th Annual Meeting, International Society for the Study of the Lumbar Spine
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] mTORC1阻害薬テムシロリムスはヒト椎間板髄核細胞において細胞死、細胞老化、細胞外基質分解を抑制する2017

    • Author(s)
      垣内裕司、由留部崇、角谷賢一朗、前野耕一郎、高田徹、寺嶋良樹、伊藤雅明、武岡由樹、黒田良祐、西田康太郎
    • Organizer
      第36回運動器移植再生医学研究会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 脊椎椎間板変性へのオートファジーの関与とその脊索由来細胞における恒常性維持機構の可能性2017

    • Author(s)
      由留部崇、伊藤雅明、寺嶋良樹、垣内裕司、武岡由樹、角谷賢一朗、前野耕一郎、高田徹、土井田稔、黒田良祐、西田康太郎
    • Organizer
      第32回日本整形外科学会基礎学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] オートファジーの抑制はヒト椎間板細胞においてアポトーシス、セネッセンスを誘導し、細胞数を減少させる2017

    • Author(s)
      伊藤雅明、由留部崇、角谷賢一朗、前野耕一郎、高田徹、寺嶋良樹、垣内裕司、武岡由樹、土井田稔、黒田良祐、西田康太郎
    • Organizer
      第32回日本整形外科学会基礎学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] mTORC1阻害薬テムシロリスムはヒト椎間板髄核細胞において細胞死、細胞老化、細胞外基質分解を抑制する2017

    • Author(s)
      垣内裕司、由留部崇、角谷賢一朗、前野耕一郎、高田徹、寺嶋良樹、伊藤雅明、武岡由樹、土井田稔、黒田良祐、西田康太郎
    • Organizer
      第32回日本整形外科学会基礎学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Involvement of autophagy in intervertebral disc degeneration and its contribution to cell survival with the maintenance of notochordal phenotype2017

    • Author(s)
      Yurube T, Hirata H, Ito M, Terashima Y, Kakiuchi Y, Takeoka Y, Kakutani K, Takada T, Miyazaki S, Kuroda R, Nishida K
    • Organizer
      The 45th Annual Meeting, Cervical Spine Research Society
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 脊椎椎間板髄核では他の筋骨格・神経組織よりもオートファジーの関与が大きく、変性が進行するとその活性は減少する2016

    • Author(s)
      由留部崇、平田裕亮、伊藤雅明、垣内裕司、寺嶋良樹、角谷賢一朗、前野耕一郎、高田徹、黒坂昌弘、西田康太郎
    • Organizer
      第31回日本整形外科学会基礎学術集会
    • Place of Presentation
      福岡国際会議場(福岡県福岡市)
    • Year and Date
      2016-10-13
    • Related Report
      2016 Research-status Report
  • [Presentation] 椎間板変性モデルについて2016

    • Author(s)
      西田康太郎、由留部崇、高田徹、角谷賢一朗、前野耕一郎、伊藤雅明、寺嶋良樹、垣内裕司、武岡由樹
    • Organizer
      第31回日本整形外科学会基礎学術集会
    • Place of Presentation
      福岡国際会議場(福岡県福岡市)
    • Year and Date
      2016-10-13
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] mTORシグナル経路への選択的な干渉はオートファジーとAktの活性化を誘導し、ヒト椎間板細胞における細胞死、細胞老化と細胞外基質分解を抑制する:椎間板遺伝子治療の可能性2016

    • Author(s)
      伊藤雅明、由留部崇、角谷賢一朗、前野耕一郎、高田徹、宮崎真吾、寺嶋良樹、垣内裕司、黒坂昌弘、西田康太郎
    • Organizer
      第31回日本整形外科学会基礎学術集会
    • Place of Presentation
      福岡国際会議場(福岡県福岡市)
    • Year and Date
      2016-10-13
    • Related Report
      2016 Research-status Report
  • [Presentation] 脊椎椎間板髄核におけるオートファジーの重要性とその誘導による椎間板変性予防の可能性2016

    • Author(s)
      由留部崇、伊藤雅明、角谷賢一朗、前野耕一郎、黒田良佑、西田康太郎
    • Organizer
      第127回中部日本整形外科災害外科学会学術集会
    • Place of Presentation
      まつもと市民芸術館・ホテルブエナビスタ(長野県松本市)
    • Year and Date
      2016-09-30
    • Related Report
      2016 Research-status Report
  • [Presentation] Intervertebral disc nucleus pulposus has intensive involvement of autophagy compared to other musculoskeletal tissues and its degeneration is linked with decreased autophagy2016

    • Author(s)
      Yurube T, Hirata H, Ito M, Kakiuchi Y, Kakutani K, Maeno K, Takada T, Miyazaki S, Terashima Y, Kurosaka M, Nishida K
    • Organizer
      The 43rd Annual Meeting of the International Society for the Study of the Lumbar Spine (Spineweek 2016)
    • Place of Presentation
      Singapore (Singapore)
    • Year and Date
      2016-05-16
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Selective interference of mTOR signaling is protective against human disc cellular apoptosis, senescence, and extracellular matrix degradation with autophagy induction2016

    • Author(s)
      Ito M, Yurube T, Kakutani K, Maeno K, Takada T, Miyazaki S, Terashima Y, Kakiuchi Y, Kurosaka M, Nishida K
    • Organizer
      The 43rd Annual Meeting of the International Society for the Study of the Lumbar Spine (Spineweek 2016)
    • Place of Presentation
      Singapore (Singapore)
    • Year and Date
      2016-05-16
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 椎間板では他の筋骨格系組織よりもオートファジーの関与が大きく、その活性は変性とともに減少する:オートファジー制御による椎間板変性予防の可能性2016

    • Author(s)
      由留部崇、平田裕亮、伊藤雅明、垣内裕司、角谷賢一朗、前野耕一郎、宮崎真吾、寺嶋良樹、黒坂昌弘、西田康太郎
    • Organizer
      第45回日本脊椎脊髄病学会
    • Place of Presentation
      幕張メッセ(千葉県千葉市)
    • Year and Date
      2016-04-14
    • Related Report
      2016 Research-status Report
  • [Presentation] mTORシグナル経路への選択的な干渉はオートファジーとAktの活性化を誘導し、ヒト椎間板細胞における細胞死、老化と細胞外基質分解を抑制する2016

    • Author(s)
      伊藤雅明、由留部崇、角谷賢一朗、前野耕一郎、高田徹、宮崎真吾、寺嶋良樹、垣内裕司、黒坂昌弘、西田康太郎
    • Organizer
      第45回日本脊椎脊髄病学会
    • Place of Presentation
      幕張メッセ(千葉県千葉市)
    • Year and Date
      2016-04-14
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2019-03-29  

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