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

• Project/Area Number: 18K19625
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
• Research Institution: Tokyo 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: ¥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)
• Keywords: Optogenetics / 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。

Research Products

• [Int'l Joint Research] University of Alabama/Cincinnati Children’s Hospital/University of South Florida(米国)
• [Journal Article] Roles of the DOCK-D family proteins in a mouse model of neuroinflammation (2020)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Role of animal models in glaucoma research (2020)
  • 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
  • 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
• [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
• [Journal Article] Normal tension glaucoma-like degeneration of the visual system in aged marmosets (2019)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] DOCK8 is expressed in microglia, and it regulates microglial activity during neurodegeneration in murine disease models (2019)
  • 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
  • Peer Reviewed
• [Journal Article] Survival of Alpha and Intrinsically Photosensitive Retinal Ganglion Cells in NMDA-Induced Neurotoxicity and a Mouse Model of Normal Tension Glaucoma (2019)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Differential effects of N-acetylcysteine on retinal degeneration in two mouse models of normal tension glaucoma (2019)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Variants in DOCK3 cause developmental delay and hypotonia (2019)
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Recent advances in genetically modified animal models of glaucoma and their roles in drug repositioning (2018)
  • 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
  • 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
• [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
  • Invited
• [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
  • Int'l Joint Research
• [Presentation] Survival of αRGC and ipRGC in a mouse model of glaucoma (2019)
  • Author(s): Sari Honda, Kazuhiko Namekata, Atsuko Kimura, Xiaoli Guo, Akira Matsuda, Akira Murakami, Takayuki Harada.
  • Organizer: ARVO Annual Meeting 2019
  • 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
• [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
• [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
• [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
• [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
• [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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
• [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
• [Remarks] 視覚病態プロジェクト
  • URL: http://www.igakuken.or.jp/project/detail/retina.html
• [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
• [Remarks] Visual Research Project
  • URL: http://www.igakuken.or.jp/english/project/detail/pro26/retina2.html
• [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