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Development of neuroprotective strategies for treatment of neurodegenerative diseases

Research Project

Project/Area Number 17K07123
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurochemistry/Neuropharmacology
Research InstitutionTokyo Metropolitan Institute of Medical Science

Principal Investigator

KIMURA Atsuko  公益財団法人東京都医学総合研究所, 運動・感覚システム研究分野, 主任研究員 (60569143)

Project Period (FY) 2017-02-23 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords神経変性疾患 / 緑内障 / グルタミン酸毒性 / グルタミン酸トランスポーター / 網膜神経節細胞 / グルタミン酸 / 神経保護 / 視神経炎 / HDAC阻害剤
Outline of Final Research Achievements

Glaucoma is a neurodegenerative disease of the eye and causes irreversible blindness, which is associated with retinal ganglion cell (RGC) death. Studies indicate multiple factors are involved in the pathogenesis of glaucoma. In this study, we explored potential therapeutic strategies for glaucoma.
We generated a novel mouse line overexpressing a glutamate transporter, GLAST (GLAST Tg). RGC death was reduced in GLAST Tg mice compared with WT mice in the optic nerve injury model, an animal model of glaucoma, suggesting that overexpression of GLAST may be effective for treatment of glaucoma. On the other hand, when we examined αRGCs and ipRGCs, subtypes of RGCs, in two glaucoma mouse models, the survival rate of these cell types was very high compared with other RGC cell types. These data suggested understanding characteristics of these cell types might help developing new neuroprotective strategies for glaucoma.

Academic Significance and Societal Importance of the Research Achievements

超高齢化社会に突入した我が国では、緑内障の患者数が加齢と共に増大し続けることが予想されている。緑内障の治療法としては眼圧降下法が主流であるが、特に日本人に最も多い「正常眼圧緑内障」に対しては眼圧を下げる治療だけでは限界がある。そこで、神経保護に着目した今回の研究とその発見は緑内障の新たな治療法開発に大きく寄与することが期待される。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (32 results)

All 2020 2019 2018 2017 Other

All Journal Article (14 results) (of which Peer Reviewed: 13 results,  Open Access: 10 results,  Acknowledgement Compliant: 2 results) Presentation (15 results) (of which Int'l Joint Research: 6 results,  Invited: 1 results) Remarks (3 results)

  • [Journal Article] Role of animal models in glaucoma research2020

    • Author(s)
      Kimura Atsuko、Noro Takahiko、Harada Takayuki
    • Journal Title

      Neural Regeneration Research

      Volume: 15 Issue: 7 Pages: 1257-1258

    • DOI

      10.4103/1673-5374.272578

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Roles of the DOCK-D family proteins in a mouse model of neuroinflammation2020

    • Author(s)
      Namekata Kazuhiko、Guo Xiaoli、Kimura Atsuko、Azuchi Yuriko、Kitamura Yuta、Harada Chikako、Harada Takayuki
    • Journal Title

      Journal of Biological Chemistry

      Volume: in press Issue: 19 Pages: 6710-6720

    • DOI

      10.1074/jbc.ra119.010438

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Survival of Alpha and Intrinsically Photosensitive Retinal Ganglion Cells in NMDA-Induced Neurotoxicity and a Mouse Model of Normal Tension Glaucoma2019

    • Author(s)
      Honda Sari、Namekata Kazuhiko、Kimura Atsuko、Guo Xiaoli、Harada Chikako、Murakami Akira、Matsuda Akira、Harada Takayuki
    • Journal Title

      Investigative Opthalmology & Visual Science

      Volume: 60 Issue: 12 Pages: 3696-3707

    • DOI

      10.1167/iovs.19-27145

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] DOCK8 is expressed in microglia, and it regulates microglial activity during neurodegeneration in murine disease models2019

    • Author(s)
      Namekata Kazuhiko、Guo Xiaoli、Kimura Atsuko、Arai Nobutaka、Harada Chikako、Harada Takayuki
    • Journal Title

      Journal of Biological Chemistry

      Volume: 294 Issue: 36 Pages: 13421-13433

    • DOI

      10.1074/jbc.ra119.007645

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Normal tension glaucoma-like degeneration of the visual system in aged marmosets2019

    • Author(s)
      Noro Takahiko、Namekata Kazuhiko、Kimura Atsuko、Azuchi Yuriko、Hashimoto Nanako、Moriya-Ito Keiko、Komaki Yuji、Lee Chia-Ying、Okahara Norio、Guo Xiaoli、Harada Chikako、Kim Euido、Nakano Tadashi、Tsuneoka Hiroshi、Inoue Takashi、Sasaki Erika、Tokuno Hironobu、Harada Takayuki
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 14852-14852

    • DOI

      10.1038/s41598-019-51281-y

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 2種類の正常眼圧緑内障モデルマウスの網膜変性にないするN-acetylcysteineの異なる効果2019

    • Author(s)
      佐埜弘樹、行方和彦、木村敦子、設楽浩志、郭暁麗、原田知加子、三田村佳典、原田高幸
    • Journal Title

      日本眼科学会雑誌

      Volume: 123 Pages: 619-619

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Differential effects of N-acetylcysteine on retinal degeneration in two mouse models of normal tension glaucoma2019

    • Author(s)
      Sano Hiroki、Namekata Kazuhiko、Kimura Atsuko、Shitara Hiroshi、Guo Xiaoli、Harada Chikako、Mitamura Yoshinori、Harada Takayuki
    • Journal Title

      Cell Death & Disease

      Volume: 10 Issue: 2 Pages: 75-75

    • DOI

      10.1038/s41419-019-1365-z

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Role of neuritin in retinal ganglion cell death in adult mice following optic nerve injury.2018

    • Author(s)
      Azuchi Y, Namekata K, Shimada T, Guo X, Kimura A, Harada C, Saito A, Yamagata K, Harada T.
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 10132-10132

    • DOI

      10.1038/s41598-018-28425-7

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Topical Ripasudil Suppresses Retinal Ganglion Cell Death in a Mouse Model of Normal Tension Glaucoma2018

    • Author(s)
      Akaiwa Kei、Namekata Kazuhiko、Azuchi Yuriko、Sano Hiroki、Guo Xiaoli、Kimura Atsuko、Harada Chikako、Mitamura Yoshinori、Harada Takayuki
    • Journal Title

      Investigative Opthalmology & Visual Science

      Volume: 59 Issue: 5 Pages: 2080-2089

    • DOI

      10.1167/iovs.17-23276

    • NAID

      120006956850

    • Related Report
      2018 Research-status Report 2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Recent advances in genetically modified animal models of glaucoma and their roles in drug repositioning2018

    • Author(s)
      Harada Chikako、Kimura Atsuko、Guo Xiaoli、Namekata Kazuhiko、Harada Takayuki
    • Journal Title

      British Journal of Ophthalmology

      Volume: 103 Issue: 2 Pages: 161-166

    • DOI

      10.1136/bjophthalmol-2018-312724

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Valproic acid and ASK1 deficiency ameliorate optic neuritis and neurodegeneration in an animal model of multiple sclerosis.2017

    • Author(s)
      Azuchi, Y., Kimura, A., Guo, X., Akiyama, G., Noro, T., Harada, C., Nishigaki, A., Namekata, K., Harada, T.
    • Journal Title

      Neuroscience Letters

      Volume: 639 Pages: 82-87

    • DOI

      10.1016/j.neulet.2016.12.057

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Targeting oxidative stress for treatment of glaucoma and optic neuritis.2017

    • Author(s)
      Kimura, A., Namekata, K., Guo, X., Noro, T., Harada, C., Harada, T.
    • Journal Title

      Oxidative Medicine and Cellular Longevity

      Volume: 2017 Issue: 1 Pages: 2817252-2817252

    • DOI

      10.1155/2017/2817252

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] The renin-angiotensin system regulates neurodegeneration in a mouse model of optic neuritis2017

    • Author(s)
      Guo X., Namekata K., Kimura A., Harada C. & Harada T
    • Journal Title

      American journal of pathology

      Volume: 187 Issue: 12 Pages: 2876-2885

    • DOI

      10.1016/j.ajpath.2017.08.012

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Edaravone prevents retinal degeneration in adult mice following optic nerve injury.2017

    • Author(s)
      Akiyama G, Azuchi Y, Guo X, Noro T, Kimura A, Harada C, *Namekata K, Harada T
    • Journal Title

      Investigative Ophthalmology & Visual Science

      Volume: 58 Issue: 11 Pages: 4908-4914

    • DOI

      10.1167/iovs.17-22250

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] 緑内障モデルマウスにおけるaRGCおよびipRGCの障害耐性2019

    • Author(s)
      本田沙里、行方和彦、木村敦子、郭 暁麗、松田彰、村上晶、原田高幸
    • Organizer
      第123回日本眼科学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 活性型TrkBを用いた遺伝子治療による神経保護と視神経軸索の再生効果2019

    • Author(s)
      金 義道、本田沙里、安土ゆり子、郭 暁麗、木村敦子、行方和彦、中野匡、原田高幸
    • Organizer
      第123回日本眼科学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 2種類の緑内障モデルマウスにおけるN-acetylcysteineの異なる神経保護効果2019

    • Author(s)
      佐埜弘樹、行方和彦、木村敦子、郭 暁麗、原田知加子、三田村佳典、原田高幸
    • Organizer
      第123回日本眼科学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Spontaneous normal tension glaucoma in aged marmosets2019

    • Author(s)
      Takayuki Harada, Takahiko Noro, Kazuhiko Namekata, Atsuko Kimura, Nanako Hashimoto, Keiko Moriya-Ito, Xiaoli Guo, Chikako Harada, Tadashi Nakano, Takashi Inoue, Erika Sasaki
    • Organizer
      8th World Glaucoma Cogress
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 正常眼圧緑内障モデルマウスを用いたEdaravoneによる網膜神経節細胞保護効果の検討2018

    • Author(s)
      赤岩慶、行方和彦、安土ゆり子、郭 暁麗、木村敦子、原田知加子、三田村佳典、原田高幸
    • Organizer
      第122回日本眼科学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Topical ripasudil prevents retinal ganglion cell death in a mouse model of normal tension glaucoma2018

    • Author(s)
      Takayuki Harada, Kei Akaiwa, Kazuhiko Namekata, Yuriko Azuchi, Xiaoli Guo, Atsuko Kimura, Chikako Harada, Yoshinori Mitamura
    • Organizer
      13th European Glaucoma Society Congress
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Manipulation of retinal glutamate levels by overexpression of GLAST reduces retinal ganglion cell death in an experimental model of glaucoma2018

    • Author(s)
      Atsuko Kimura, Kazuhiko Namekata, Xiaoli Guo, Yuriko Azuchi, Chikako Harada, Takayuki Harada
    • Organizer
      19th International Congress of Neuropathology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] DOCK8 regulates microglial activity in neuroinflammation2018

    • Author(s)
      Kazuhiko Namekata, Xiaoli Guo, Atsuko Kimura, Nobutaka Arai, Chikako Harada, Takayuki Harada
    • Organizer
      19th International Congress of Neuropathology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Can valproic acid treat neurodegenerative diseases?2018

    • Author(s)
      Atsuko Kimura, Kazuhiko Namekata, Xiaoli Guo, Yuriko Azuchi, Chikako Harada, Takayuki Harada
    • Organizer
      International Conference on Neurovascular and Neurodegenerative Diseases
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Loss of neuritin accelerates RGC loss and retinal degeneration in adult mice following optic nerve injury2018

    • Author(s)
      Yuriko Azuchi, Kazuhiko Namekata, Tadayuki Shimada, Xiaoli Guo, Atsuko Kimura, Chikako Harada, Atsuko Nishigaki, Kanato Yamagata, Takayuki Harada
    • Organizer
      48th Annual Meeting of the Society for Neuroscience
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] カロリー制限による正常眼圧緑内障モデルにおける網膜神経節細胞及び視機能の保護2017

    • Author(s)
      郭暁麗、木村敦子、安土ゆり子、秋山悟一、野呂隆彦、原田知加子、行方和彦、原田高幸
    • Organizer
      第121回日本眼科学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] コモン・マーモセットを用いた緑内障研究2017

    • Author(s)
      野呂隆彦、行方和彦、木村敦子、中野匡、常岡寛、原田高幸
    • Organizer
      第121回日本眼科学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 細胞種特異的なASK1遺伝子の欠損が神経炎症に与える影響の検討2017

    • Author(s)
      郭暁麗、行方和彦、木村敦子、原田知加子、新井信隆、原田高幸
    • Organizer
      第58回日本神経病理学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 神経炎症におけるDock8の機能解析2017

    • Author(s)
      行方和彦、郭 暁麗、木村敦子、原田知加子、新井信隆、原田高幸
    • Organizer
      第58回日本神経病理学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] Role of glial and neuronal TrkB signaling in protection of retinal ganglion cells following optic nerve injury2017

    • Author(s)
      Yuriko Azuchi, Atsuko Kimura, Chikako Harada, Kazuhiko Namekata, Takayuki Harada
    • Organizer
      47 th Annual Meeting of the Society for Neuroscience(国際学会)
    • Related Report
      2017 Research-status Report
  • [Remarks] 未来を話そう!プロジェクト研究の紹介

    • URL

      http://www.igakuken.or.jp/project/to-tomin/to-pro26.html

    • Related Report
      2017 Research-status Report
  • [Remarks] プロジェクト研究等 医学研で行なわれている研究活動

    • URL

      http://www.igakuken.or.jp/project/detail/retina.html

    • Related Report
      2017 Research-status Report
  • [Remarks] 網膜・視神経変性疾患の病態解明と治療法

    • URL

      http://www.igakuken.or.jp/retina/index.html

    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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