Optic nerve regeneration by utilizing neurotrophic factor signaling

• Project/Area Number: 19K09943
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56060:Ophthalmology-related
• 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, 疾患制御研究分野, 研究員 (20435720)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 緑内障 / 視神経保護 / 視神経再生

Outline of Research at the Start

緑内障は40歳以上の約6％に発症し、我が国における最大の失明原因となっている。緑内障では網膜にある「神経節細胞」と、そこから視覚野まで視覚情報を伝達する「視神経」の両者を生涯に渡って維持する必要がある。また可能であれば、一度傷んだ視神経を再生する新しい治療法などが望まれているが、現在はまだ確立されていない。本研究では緑内障のモデル動物を用いて、すでに他の疾患で使用されている既存薬を使ったり、遺伝子治療を行うことにより、視神経の保護や再生が可能かを検討する。

Outline of Final Research Achievements

In this study, we developed AAV vector with constitutive active form of TrkB, a neurotrophic factor receptor. We found that the vector protects retinal ganglion cells (RGCs) and stimulates optic nerve regeneration in a mouse model of optic nerve injury. In addition, the vector protected the form of RGC dendrites and increased the number of synapses between RGCs and bipolar cells.

Academic Significance and Societal Importance of the Research Achievements

我が国における失明原因の多くは網膜および視神経の変性疾患で占められる。特に最大の失明原因である緑内障に対しては、眼圧降下以外の手法による治療法の開発が期待されている。今回の我々の研究結果は視神経外傷に加えて、緑内障や視神経炎などによって低下した視機能を維持・回復させる上で重要な一歩となることが期待される。

Research Products

• [Int'l Joint Research] Memorial Sloan Kettering Cancer Center(米国)
• [Journal Article] ASK1 signaling regulates phase-specific glial interactions during neuroinflammation (2022)
  • Author(s): Guo Xiaoli、Kimura Atsuko、Namekata Kazuhiko、Harada Chikako、Arai Nobutaka、Takeda Kohsuke、Ichijo Hidenori、Harada Takayuki
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 119 Issue: 6
  • DOI: 10.1073/pnas.2103812119
  • Peer Reviewed / Open Access
• [Journal Article] Effects of lighting environment on the degeneration of retinal ganglion cells in glutamate/aspartate transporter deficient mice, a mouse model of normal tension glaucoma (2022)
  • Author(s): Ohashi Tsutomu、Namekata Kazuhiko、Guo Xiaoli、Kimura Atsuko、Harada Chikako、Harada Takayuki
  • Journal Title: Biochemistry and Biophysics Reports Volume: 29 Pages: 101197-101197
  • DOI: 10.1016/j.bbrep.2021.101197
  • Peer Reviewed / Open Access
• [Journal Article] Suppression of Oxidative Stress as Potential Therapeutic Approach for Normal Tension Glaucoma (2020)
  • Author(s): Harada Chikako、Noro Takahiko、Kimura Atsuko、Guo Xiaoli、Namekata Kazuhiko、Nakano Tadashi、Harada Takayuki
  • Journal Title: Antioxidants Volume: 9 Issue: 9 Pages: 874-874
  • DOI: 10.3390/antiox9090874
  • Peer Reviewed / Open Access
• [Journal Article] Topical ripasudil stimulates neuroprotection and axon regeneration in adult mice following optic nerve injury (2020)
  • Author(s): Nishijima Euido、Namekata Kazuhiko、Kimura Atsuko、Guo Xiaoli、Harada Chikako、Noro Takahiko、Nakano Tadashi、Harada Takayuki
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 15709-15709
  • DOI: 10.1038/s41598-020-72748-3
  • Peer Reviewed / Open Access
• [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] 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] 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
• [Presentation] AAV-mediated delivery of constitutively active TrkB promotes CNS axon regeneration and neuroprotection. (2021)
  • Author(s): Kimura A, Nishijima E, Kitamura Y, Honda S, Guo X, Harada C, Namekata K, Harada T.
  • Organizer: Neuroscience Meeting 2021
  • Int'l Joint Research
• [Presentation] 活性型TrkBを活用した遺伝子治療による神経保護と軸索再生. (2021)
  • Author(s): 行方和彦、西島義道、北村裕太、本田紗里、郭曉麗、木村敦子、原田知加子、原田高幸.
  • Organizer: 第９４回日本生化学会大会
• [Presentation] Microglial DOCK8 and neurodegeneration. (2021)
  • Author(s): Kimura A, Namekata K, Guo X, Arai N, Harada C, Harada T.
  • Organizer: The 4th International Conference on Applied Biochemistry and Biotechnology (ABB 2021)
  • Int'l Joint Research / Invited
• [Presentation] The renin-angiotensin system regulates neurodegeneration in a mouse model of optic neuritis. (2021)
  • Author(s): Guo X, Namekata K, Kimura A, Harada C, Harada T.
  • Organizer: Annual Global Conference on Neuroscience and Neurology
  • Int'l Joint Research / Invited
• [Presentation] Gene therapy with modified TrkB induces neuroprotection and axon regeneration. (2021)
  • Author(s): Kimura A, Nishijima E, Kitamura Y, Honda S, Guo X, Harada C, Namekata K, Harada T.
  • Organizer: 第４４回日本神経科学大会
• [Presentation] Gene therapy with mutant TrkB receptor protects retinal ganglion cell and retinal function in a mouse model of normal tension glaucoma. (2021)
  • Author(s): Nishijima E, Honda S, Namekata K, Kimura A, Guo X, Harada C, Nakano T, Harada T.
  • Organizer: World Glaucoma Congress 2021
  • Int'l Joint Research
• [Presentation] Gene therapy with mutant TrkB receptors protects retinal neurons and promotes optic nerve regeneration without ligands. (2021)
  • Author(s): Nishijima E, Namekata K, Kimura A, Kitamura Y, Honda S, Guo X, Harada C, Nakano T, Harada T.
  • Organizer: ARVO 2021 meeting
  • Int'l Joint Research
• [Presentation] Pathogenic roles of glial ASK1 signaling in neuroinflammation. (2021)
  • Author(s): Guo X, Kimura A, Namekata K, Harada C, Harada T.
  • Organizer: ARVO 2021 meeting
  • Int'l Joint Research
• [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] 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
• [Remarks] Visual Research Project
  • URL: https://www.igakuken.or.jp/english/project/detail/retina.html
• [Remarks] 未来を話そう！ プロジェクト研究の紹介
  • URL: https://www.igakuken.or.jp/project/to-tomin/to-pro26.html
• [Remarks] 視覚病態プロジェクト
  • URL: https://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: https://www.igakuken.or.jp/retina/index.html
• [Remarks] TOPICS「ASK1シグナルは神経炎症におけるグリア間相互作用を病期特異的に制御する」
  • URL: https://www.igakuken.or.jp/topics/2022/0201.html
• [Remarks] Visual Research Project
  • URL: http://www.igakuken.or.jp/english/project/detail/pro26/retina2.html
• [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