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Establishment of animal models of neurodegenerative diseases and development of therapeutic strategies utilizing optogenetics

Research Project

Project/Area Number 18K19625
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
Research InstitutionTokyo Metropolitan Institute of Medical Science

Principal Investigator

HARADA Takayuki  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, 分野長 (90345306)

Project Period (FY) 2018-06-29 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
KeywordsOptogenetics / 緑内障 / 疾患モデル / 網膜変性 / 神経保護 / optogenetics / 神経変性疾患
Outline of Final Research Achievements

We previously reported that mice with deletion of the glutamate aspartate transporter (GLAST), one of the glutamate transporters, serve as a good model of normal tension glaucoma (NTG). In this project, we generated GLAST flox/flox mice. We administered light-activatable adeno-associated virus (AAV)-cre into the eye of GLAST flox/flox mice and we successfully induced GLAST deletion by light stimulation. These studies indicated that selective and partial deletion of GLAST is possible by controlling light intensity and exposure areas and time, which will lead to development of a NTG model that mimics visual field defects observed in humans. Furthermore, we reported naturally occurring NTG in non-human primates (common marmosets) and demonstrated similar pathology to human NTG.

Academic Significance and Societal Importance of the Research Achievements

高齢化社会の到来とともに緑内障患者数はさらに増加することが予想されている。そこで適切な緑内障疾患モデルを活用した薬剤や治療法の研究が、今後ますます求められる状況にある。これまでマウスでは視野欠損部位を限局させることが困難であったが、本研究ではこの点で進歩が見られた。一方、ヒトと類似した視覚システムを持つマーモセットは、今後のトランスレーショナルリサーチにおいて極めて有用と考えられる。

Report

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

    (32 results)

All 2020 2019 2018 Other

All Int'l Joint Research (1 results) Journal Article (11 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 8 results,  Open Access: 6 results) Presentation (15 results) (of which Int'l Joint Research: 8 results,  Invited: 1 results) Remarks (5 results)

  • [Int'l Joint Research] University of Alabama/Cincinnati Children’s Hospital/University of South Florida(米国)

    • Related Report
      2019 Annual Research Report
  • [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] 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] 視神経と再生医療2020

    • Author(s)
      野呂隆彦、原田高幸
    • Journal Title

      日本の眼科

      Volume: 91 Pages: 24-28

    • Related Report
      2019 Annual Research Report
  • [Journal Article] 睡眠時無呼吸症候群における緑内障発症リスク2020

    • Author(s)
      原田高幸
    • Journal Title

      THE LUNG perspectives

      Volume: 28 Pages: 46-48

    • Related Report
      2019 Annual Research Report
  • [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] 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] 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] 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
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Variants in DOCK3 cause developmental delay and hypotonia2019

    • Author(s)
      Wiltrout Kimberly、Ferrer Alejandro、van de Laar Ingrid、Namekata Kazuhiko、Harada Takayuki、 Klee Eric W.、Zimmerman Michael T.、Cousin Margot A.、Kempainen Jennifer L.、Babovic- Vuksanovic Dusica、van Slegtenhorst Marjon A.、Aarts-Tesselaar Coranne D.、Schnur Rhonda E.、 Andrews Marisa、Shinawi Marwan
    • Journal Title

      European Journal of Human Genetics

      Volume: 印刷中 Issue: 8 Pages: 1225-1234

    • DOI

      10.1038/s41431-019-0397-2

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [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
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 網膜神経保護と軸索再生研究2018

    • Author(s)
      原田高幸
    • Journal Title

      眼薬理

      Volume: 32 Pages: 40-42

    • Related Report
      2018 Research-status Report
  • [Presentation] 緑内障治療への新たなアプローチ2019

    • Author(s)
      原田高幸
    • Organizer
      第39回 日本眼薬理学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [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 Congress
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Survival of αRGC and ipRGC in a mouse model of glaucoma2019

    • Author(s)
      Sari Honda, Kazuhiko Namekata, Atsuko Kimura, Xiaoli Guo, Akira Matsuda, Akira Murakami, Takayuki Harada.
    • Organizer
      ARVO Annual Meeting 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 緑内障モデルマウスにおけるαRGCおよびipRGCの障害耐性2019

    • Author(s)
      本田紗里、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、本田紗里、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] AAV-TrkB投与による網膜神経節細胞樹状突起の保護効果2019

    • Author(s)
      北村裕太、行方和彦、木村敦子、郭暁麗、山本修一、原田高幸
    • Organizer
      第30回 日本緑内障学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] アデノ随伴ウイルスを用いた活性型TrkAによる神経保護と視神経軸索の再生効果2019

    • Author(s)
      金義道、行方和彦、本田紗里、郭暁麗、木村敦子、中野匡、原田高幸
    • Organizer
      第30回 日本緑内障学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Spontaneous normal tension glaucoma in aged marmosets.2019

    • 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 Congress
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Topical ripasudil prevents retinal ganglion cell death in a mouse model of normal tension glaucoma.2018

    • 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] Loss of neuritin accelerates RGC loss and retinal degeneration in adult mice following optic nerve injury.2018

    • 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] 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
  • [Presentation] DOCK8 regulates microglial activity in neuroinflammation.2018

    • 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] Dock10 deficiency reduces neuroinflammation in optic neuritis.2018

    • Author(s)
      Xiaoli Guo, Kazuhiko Namekata, Yuriko Azuchi, Atsuko Kimura, Takahiko Noro, Chikako Harada, Takayuki Harada.
    • Organizer
      ARVO Annual Meeting 2018
    • Related Report
      2018 Research-status 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
  • [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
      2019 Annual Research Report 2018 Research-status Report
  • [Remarks] 視覚病態プロジェクト

    • URL

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

    • Related Report
      2019 Annual Research 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
      2019 Annual Research Report 2018 Research-status Report
  • [Remarks] Visual Research Project

    • URL

      http://www.igakuken.or.jp/english/project/detail/pro26/retina2.html

    • Related Report
      2019 Annual Research Report
  • [Remarks] プロジェクト研究等 医学研で行われている研究活動

    • URL

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

    • Related Report
      2018 Research-status Report

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Published: 2018-07-25   Modified: 2021-02-19  

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