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

2018 Fiscal Year Annual Research Report

• Project/Area Number: 16K07076
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: 郭 暁麗 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
• Keywords: 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

Outline of Annual Research Achievements

Microglia/macrophage特異的なASK1欠損マウス、即ちASK1 flox/flox : LysM-Cre EAEマウスはearly stageから症状が軽減し、astrocyte特異的なASK1欠損マウス、即ちASK1 flox/flox : GFAP-Cre EAEマウスはlate stageから症状が軽減することが見出されている。本年度はその症状軽減のメカニズムの解析から、microglial-astrocyte crosstalkが関わる可能性を見出した。MicrogliaにおけるASK1は神経毒性を持つastrocyte (A1 astrocyte)の誘導に関与し、astrocyteからはmicrogliaの増殖やpolarizationを刺激する物質が産生され、ASK1はこのcrosstalkに関わることを見出した。
また、網膜神経節細胞および脊髄のastrocyteをFACSで単離して遺伝子発現を検討する手法を確立した。

Research Products

• [Journal Article] Differential effects of N-acetylcysteine on retinal degeneration in two mouse models of normal tension glaucoma (2019)
  • Author(s): Sano H., Namekata K., Kimura A., Shitara H., Guo X., Harada C., Mitamura Y. & Harada T
  • Journal Title: Cell Death and Disease Volume: 10 Pages: 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 (2019)
  • Author(s): Harada, C., Kimura, A., Guo, X., Namekata, K. & Harada, T
  • Journal Title: British Journal of Ophthalmology Volume: 103 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, K., Namekata, K., Azuchi, Y., Sano, H., Guo, X., Kimura, A., Harada, C., Mitamura, Y. & Harada, T
  • Journal Title: Investigative Ophthalmology & Visual Science Volume: 59 Pages: 2080-2089
  • DOI: 10.1167/iovs.17-23276
  • Peer Reviewed
• [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., Nishigaki, A., Yamagata, K. & Harada, T
  • Journal Title: Scientific Reports Volume: 8 Pages: 10132
  • DOI: 10.1038/s41598-018-28425-7
  • 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
• [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
• [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
• [Remarks] MEDICINE INNOVATES
  • URL: https://medicineinnovates.com/mechanism-of-action/role-renin-angiotensin-system-optic-neuritis/