New therapy of multiple sclerosis through regulating cell-type specific ASK1 and Dock proteins

• Project/Area Number: 16K07076
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: GUO Xiaoli 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 (50443114)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: グリア細胞 / ASK1 / Astrocyte / Microglia/macrophage / cross-talk / 多発性硬化症 / 視神経炎 / レニン・アンジオテンシン系 / M1 microglia / A1 astrocyte / cytokine/chemokine / 神経保護 / 緑内障 / カロリー制限

Outline of Final Research Achievements

We generated four lines of cell-specific ASK1 knockout mice to examine the roles of ASK1 during EAE. ASK1 signaling in microglia/macrophages induces a pro-inflammatory phenotype in microglia/macrophages, which subsequently promotes the activation of astrocytes. Also, ASK1 signaling in astrocytes stimulated the production of key inflammatory mediators that further activated microglia/macrophages. Neuroinflammation was reduced from the early stages of EAE in in microglia/macrophage-specific ASK1 knockout mice, while only the late-phase neuroinflammation was ameliorated in astrocyte-specific ASK1 knockout mice.
We also found that the Renin-Angiotensin System regulates neuro-degeneration in a mouse model of optic neuritis and demonstrated that caloric restriction promotes cell survival in a mouse model of normal tension glaucoma.

Academic Significance and Societal Importance of the Research Achievements

ASK1の細胞特異的な機能や既存薬剤による治療研究から網膜および視神経変性疾患など難病の発症メカニズムを解明し、治療法の開発に有用な情報を提供した。特にMSによる視神経変性に対する治療薬の開発に有用である。
我々の研究成果を参考にASK1阻害剤がTocris社から発売された。また研究成果は研究所HPや医学専門websiteでも紹介されている。中国での招待講演でも研究発表を行うなど、研究成果を積極的に社会に公開する。

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] 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] 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
  • 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] Ripasudil点眼は正常眼圧緑内障モデルマウスにおいて網膜神経節細胞死を抑制する (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
  • Journal Title: 日本眼科学会雑誌 Volume: 122 Pages: 593-594
• [Journal Article] レニン・アンジオテンシン系は視神経炎モデル動物における神経変性を制御する (2018)
  • Author(s): 郭 暁麗、行方和彦、木村敦子、原田知加子、原田高幸
  • Journal Title: 日本眼科学会雑誌 Volume: 122 Pages: 140-140
• [Journal Article] エダラボンは視神経外傷後の網膜神経節細胞死を抑制する (2018)
  • Author(s): 秋山悟一、安土ゆり子、郭 暁麗、野呂隆彦、木村敦子、原田知加子、行方和彦、原田高幸
  • Journal Title: 日本眼科学会雑誌 Volume: 122 Pages: 63-63
• [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] 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] 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] 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
• [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] Edaravoneは正常眼圧緑内障モデルマウスにおいて網膜神経節細胞死を抑制する (2017)
  • 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
  • Journal Title: 日本眼科学会雑誌 Volume: 121 Pages: 784-784
• [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
• [Journal Article] カロリー制限は正常眼圧緑内障モデルマウスにおける神経変性を改善する (2016)
  • 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
  • Journal Title: 日本眼科学会雑誌 Volume: 120 Pages: 871-871
• [Journal Article] Neuroprotection, Growth Factors and BDNF-TrkB Signalling in Retinal Degeneration (2016)
  • Author(s): Kimura A., Namekata K., Guo X., Harada C. and Harada T
  • Journal Title: International Journal of Molecular Sciences Volume: 17
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] グリア細胞におけるTrkB受容体シグナルは視神経外傷後の神経保護を促進する (2016)
  • Author(s): 原田知加子、安土ゆり子、野呂隆彦、郭 暁麗、木村敦子、行方和彦、原田高幸
  • Journal Title: 日本眼科学会雑誌120 Volume: 120 Pages: 139-139
• [Journal Article] Spermidineは正常眼圧緑内障モデルマウスにおける神経変性を改善する (2016)
  • Author(s): 野呂隆彦、行方和彦、安土ゆり子、木村敦子、郭 暁麗、原田知加子、中野 匡、常岡 寛、原田高幸
  • Journal Title: 日本眼科学会雑誌120 Volume: 120 Pages: 56-56
• [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 Cogress
  • Int'l Joint Research
• [Presentation] New therapeutic targets on neurodegenerative and demyelination diseases (2018)
  • Author(s): 郭 暁麗
  • Organizer: Overseas Chinese, Chinese and High-level Talents Travel to Jiangsu
  • Invited
• [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] 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: The ARVO 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] 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] カロリー制限による正常眼圧緑内障モデルにおける神経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] Dietary restriction promotes cell survival in a mouse model of normal tension glaucoma (2017)
  • Author(s): Guo X., Namekata K., Kimura A., Noro T., Akiyama G., Azuchi Y., Harada C. & Harada T
  • Organizer: 第2回 TMEDフォーラム
• [Presentation] Dietary restriction promotes cell survival in a mouse model of normal tension glaucoma (2016)
  • Author(s): Guo X., Namekata K., Kimura A., Noro T., Akiyama G., Azuchi Y., Harada C. and Harada T
  • Organizer: 46th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2016-11-13
• [Presentation] Dock8 deficiency suppresses microglial migration and neuroinflammation (2016)
  • Author(s): Namekata K., Guo X., Kimura A., Harada C. and Harada T
  • Organizer: 46th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2016-11-13
• [Presentation] Overexpression of GLAST protects retinal ganglion cells following optic nerve injury (2016)
  • Author(s): Kimura A., Namekata K., Guo X., Azuchi Y., Noro T., Akiyama G., Harada C. and Harada T
  • 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: 2016-09-26
• [Presentation] ASK1 deficiency and valproic acid synergistically reduce demyelination and visual impairment in experimental autoimmune encephalomyelitis (2016)
  • Author(s): Azuchi Y., Kimura A., Guo X., Noro T., Akiyama G., Drozdz M., Harada C., Saito A., Namakata K. and Harada T
  • 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: 2016-07-22
• [Presentation] Valproic acid suppresses retinal ganglion cell death in mouse models of normal tension glaucoma (2016)
  • Author(s): Kimura, A., Namekata, K., Guo, X., Noro, T., Azuchi, Y., Harada, C. and Harada, T
  • Organizer: 14th IGAKUKEN International Symposium, IGAKUKEN Summit for Japan and Korea Science Leaders 2016
  • Place of Presentation: 東京都医学総合研究所（東京都世田谷区）
  • Year and Date: 2016-06-30
• [Presentation] Spermidine stimulates neuroprotection and optic nerve regeneration following optic nerve injury. (2016)
  • Author(s): Noro, T., Namekata, K., Kimura, A., Guo, X., Azuchi, Y., Harada C. and Harada, T.
  • Organizer: 14th IGAKUKEN International Symposium, IGAKUKEN Summit for Japan and Korea Science Leaders 2016
  • Place of Presentation: 東京都医学総合研究所（東京都世田谷区）
  • Year and Date: 2016-06-30
• [Presentation] Combinatorial therapy with ASK1 deficiency and valproic acid in a murine model of multiple sclerosis (2016)
  • Author(s): Azuchi, Y., Guo, X., Kimura, A., Noro, T., Akiyama, G., Drozdz M., Harada, C., Saito, A., Namekata K. and Harada, T
  • Organizer: 14th IGAKUKEN International Symposium, IGAKUKEN Summit for Japan and Korea Science Leaders 2016
  • Place of Presentation: 東京都医学総合研究所（東京都世田谷区）
  • Year and Date: 2016-06-30
• [Presentation] Neuroprotective effects of valproic acid in mouse models of normal tension glaucoma (2016)
  • Author(s): Kimura, A., Namekata, K., Guo, X., Noro, T., Harada, C. and Harada, T
  • Organizer: TOBIRA 第５回研究交流フォーラム
  • Place of Presentation: 御茶ノ水ソラシティ（東京都千代田区）
  • Year and Date: 2016-05-23
• [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: 2016-04-09
• [Remarks] MEDICINE INNOVATES
  • URL: https://medicineinnovates.com/mechanism-of-action/role-renin-angiotensin-system-optic-neuritis/
• [Remarks] 東京都医学総合研究所 視覚病態プロジェクト
  • URL: http://www.igakuken.or.jp/retina/