The function of Dock3 in neuroprotection and neuroregeneration

• Project/Area Number: 16K08635
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: NAMEKATA Kazuhiko 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, 副参事研究員 (70392355)
• Research Collaborator: HARADA takayuki ; GUO xiaoli ; 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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Dock3 / 神経変性 / 神経再生 / 神経保護・軸索再生 / Dock family / 神経変性疾患 / Dockファミリー / 緑内障 / アルツハイマー病 / Dockファミリー分子 / Dock family protein

Outline of Final Research Achievements

We investigated whether the gene therapy using AAV can promote axonal regeneration and neuroprotection after optic nerve injury. We demonstrated that overexpression of active TrkB in the retina by AAV induced axonal regeneration in wild-type mice after optic nerve injury. in addition, optic nerve injury-induced neural cell death in the retina was also suppressed. Our finding is suggests that activation of TrkB signaling by AAV is useful for therapy of retinal degeneration such as glaucoma.

Academic Significance and Societal Importance of the Research Achievements

神経細胞の再生はこれまで非常に困難であると考えられてきた。しかし、本研究によって遺伝子治療などを活用して細胞内シグナル伝達を活性化することにより、軸索が再生することが改めて確認された。多発性硬化症、緑内障、脊髄損傷などの神経軸索が障害をうける疾病などに対して、遺伝子治療を活用した新たな治療法として有益な情報をもたらすことが推測される。

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] 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] 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] 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
  • NAID: 120006956850
  • 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] 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] Purinergic dysregulation causes hypertensive glaucoma-like optic neuropathy. (2017)
  • Author(s): Shinozaki Y, Kashiwagi K, Namekata K, Takeda A, Ohno N, Robaye B, Harada T, Iwata T, *Koizumi S
  • Journal Title: JCI Insight Volume: 2 Issue: 19
  • DOI: 10.1172/jci.insight.93456
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] 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 / Open Access
• [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] 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: 日眼会誌 Volume: 120 Pages: 871-871
  • Open Access
• [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] 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: 日眼会誌 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: 日眼会誌 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 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 / Invited
• [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
• [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学術研究会
• [Presentation] Role of glial and neuronal TrkB signaling in protection of retinal ganglion cells following optic nerve injury. (2017)
  • Author(s): Yuriko Azuchi, Atsuko Kimura, Chikako Harada, Kazuhiko Namekata, Takayuki Harada.
  • Organizer: 47 th Annual Meeting of the Society for Neuroscience
  • Int'l Joint Research
• [Presentation] 透明化組織の立体イメージング (2017)
  • Author(s): 行方和彦、原田高幸.
  • Organizer: 第58回日本神経病理学会総会学術研究会
  • Invited
• [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] コモン・マーモセットを用いた緑内障研究. (2017)
  • Author(s): 野呂隆彦、行方和彦、木村敦子、中野匡、常岡寛、原田高幸.
  • Organizer: 第１２１回日本眼科学会総会
• [Presentation] 視神経挫滅モデルマウスにおけるエダラボンの神経保護効果 (2017)
  • Author(s): 秋山悟一、安土ゆり子、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. (2016)
  • Author(s): Guo X., Namekata K., Kimura A., Noro T., Akiyama G., Azuchi Y., Harada C. & Harada T.
  • Organizer: 46th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [Presentation] Dock8 deficiency suppresses microglial migration and neuroinflammation. (2016)
  • Author(s): Namekata K., Guo X., Kimura A., Harada C. & Harada T.
  • Organizer: 46th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [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. & 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
  • Int'l Joint Research
• [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. & 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
  • Int'l Joint Research
• [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. & 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
  • Int'l Joint Research
• [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. & 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
  • Int'l Joint Research
• [Presentation] Combinatorial therapy with ASK1 deficiency and valproic acid in a murine model of multiple sclerosis. (2016)
  • Author(s): Azuchi Y., Kimura A., Guo X., Noro T., Akiyama G., Drozdz M., Harada C., Saito A., Namakata K. & 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
  • Int'l Joint Research
• [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. & 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 日本眼科学会学術奨励賞記念講演
  • Place of Presentation: 仙台国際センター (宮城県仙台市）
  • Year and Date: 2016-04-09
• [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] 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