Retinal protection by changing gene expressions for glaucoma therapy

• Project/Area Number: 16K11308
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: HARADA Chikako 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, 研究員 (20435720)
• Research Collaborator: HARADA takayuki ; NAMEKATA kazuhiko ; KAKU gyorei ; KIMURA atsuko
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 緑内障 / 神経保護 / 軸索再生 / 遺伝子発現 / 視神経外傷 / 既存薬 / 神経栄養因子

Outline of Final Research Achievements

We demonstrated the neuroprotective effects of existing drugs, such as Rho/ROCK inhibitor eye drops, edaravone used for cerebral infarction, and N-acetylcysteine used as expectorant, and published these findings. In addition, we found that loss of neuritin, one of the trophic factors, increases neural cell death after optic nerve injury. We also found that loss of TrkB, one of the major neurotrophin receptors, induces normal tension glaucoma-like retinal degeneration after 6 months of age.

Academic Significance and Societal Importance of the Research Achievements

緑内障は我が国における最大の失明原因であり、眼圧降下以外の手法による神経保護療法の開発が期待されている。そこで本研究では複数の緑内障モデル動物を用いて、安全性が確立した既存薬による細胞保護療法の可能性を示した。また特定の遺伝子発現の変化が神経細胞の耐性に与える影響を検討して、将来の薬物開発や新たな疾患モデルの開発に道をつけた。

Research Products

• [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] 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] Topical Ripasudil Suppresses Retinal Ganglion Cell Death in a Mouse Model of Normal Tension Glaucoma (2018)
  • 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
  • Peer Reviewed / Open Access
• [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
  • Peer Reviewed
• [Journal Article] The renin-angiotensin system regulates neurodegeneration in a mouse model of optic neuritis (2017)
  • 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
  • Peer Reviewed
• [Journal Article] Edaravone suppresses retinal ganglion cell death in a mouse model of normal tension glaucoma (2017)
  • Author(s): Akaiwa K., Namekata K., Azuchi Y., Guo X., Kimura A., Harada C., Mitamura Y. & Harada T
  • Journal Title: Cell Death and Disease Volume: 8 Issue: 7 Pages: e2934-e2934
  • DOI: 10.1038/cddis.2017.341
  • Peer Reviewed / Open Access
• [Journal Article] ASK1 in neurodegeneration (2017)
  • Author(s): Guo X., Namekata K., Kimura A., Harada C. & Harada T
  • Journal Title: Advances in Biological Regulation Volume: 66 Pages: 63-71
  • DOI: 10.1016/j.jbior.2017.08.003
  • 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
  • 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
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dock3-NMDA receptor interaction as a target for glaucoma therapy. (2017)
  • Author(s): Kimura, A., Namekata, K., Guo, X., Harada, C., Harada, T.
  • Journal Title: Histology and Histopathology Volume: 32 Pages: 215-221
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Neuroprotection, growth factors and BDNF-TrkB signaling in retinal degeneration. (2016)
  • Author(s): Kimura, A., Namekata, K., Guo, X., Harada, C., Harada, T.
  • Journal Title: International Journal of Molecular Sciences Volume: 17 Issue: 9 Pages: 1584-1584
  • DOI: 10.3390/ijms17091584
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Caloric restriction promotes cell survival in a mouse model of normal tension glaucoma. (2016)
  • Author(s): Guo, X., Kimura, A., Azuchi, Y., Akiyama, G., Noro, T., Harada, C., Namekata, K., Harada, T.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 33950-33950
  • DOI: 10.1038/srep33950
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] 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] Manipulation of retinal glutamate levels by overexpression of GLAST reduces retinal ganglion cell death in an experimental model of glaucoma. (2018)
  • Author(s): Atsuko Kimura, Kazuhiko Namekata, Xiaoli Guo, Yuriko Azuchi, Chikako Harada, Takayuki Harada.
  • Organizer: 19th International Congress of Neuropathology
  • 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] 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] 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] Spontaneous normal tension glaucoma in aged marmosets. (2018)
  • 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] 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
• [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
• [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
• [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
• [Presentation] Dock8 deficiency suppresses microglial migration and neuroinflammation. (2016)
  • Author(s): Kazuhiko Namekata, Xiaoli Guo, Atsuko Kimura, Chikako Harada, Takayuki Harada.
  • Organizer: 46th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Dietary restriction promotes cell survival in a mouse model of normal tension glaucoma. (2016)
  • Author(s): Xiaoli Guo, Kazuhiko Namekata, Atsuko Kimura, Takahiko Noro, Goichi Akiyama, Yuriko Azuchi, Chikako Harada, Takayuki Harada.
  • Organizer: 46th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Neuroprotection and optic nerve regeneration for glaucoma therapy: contribution of oxidative stress in animal models of normal tension glaucoma (2016)
  • Author(s): Takayuki Harada, Kazuhiko Namekata, Atsuko Kimura, Takahiko Noro, Chikako Harada.
  • Organizer: XXII International Congress of Eye Research (ISER 2016)
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-09-25
  • Int'l Joint Research
• [Presentation] Overexpression of GLAST protects retinal ganglion cells following optic nerve injury. (2016)
  • Author(s): Atsuko Kimura, Kazuhiko Namekata, Xiaoli Guo, Yuriko Azuchi, Takahiko Noro, Goichi Akiyama, Chikako Harada, Takayuki Harada.
  • Organizer: XXII International Congress of Eye Research (ISER 2016)
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-09-25
  • Int'l Joint Research
• [Presentation] ASK1 deficiency and valproic acid synergistically reduce demyelination and visual impairment in experimental autoimmune encephalomyelitis. (2016)
  • Author(s): Yuriko Azuchi, Atsuko Kimura, Xiaoli Guo, Takahiko Noro, Goichi Akiyama, Magdalena Droztz, Chikako Harada, Atsuko Saito, Kazuhiko Namekata, Takayuki Harada.
  • Organizer: The 39th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-07-20
• [Presentation] レニンーアンジオテンシン系は正常眼圧緑内障モデルマウスにおける神経 変性を制御する (2016)
  • Author(s): 仙波賢太郎、行方和彦、郭 暁麗、原田知加子、原田高幸.
  • Organizer: 第120回 日本眼科学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-04-07
• [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] 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
• [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]
  • URL: http://www.igakuken.or.jp/retina/index.html
• [Remarks] 視覚病態プロジェクト
  • URL: http://www.igakuken.or.jp/project/detail/retina.html
• [Remarks] Visual Research Porject
  • URL: http://www.igakuken.or.jp/english/project/detail/retina.html