Dockファミリーの分子間相互作用が神経炎症に与える影響の解明

2014 Fiscal Year Annual Research Report

• Project/Area Number: 25640043
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: 行方 和彦 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)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: Dock3 / Dock8 / 脱髄疾患

Outline of Annual Research Achievements

近年に新たなGEFとして発見されたDockファミリー分子は様々な臓器や細胞に発現しており喘息、がん、アルツハイマー病、注意欠陥・多動性障害など、多様な疾患に関与する。本研究ではDockファミリー分子であるDock3やDock8が脱髄疾患に与える影響について検討を行なった。Dock3は神経保護や視神経再生の促進に寄与することが明らかとなっているが、髄鞘を形成するオリゴデンドログリアにおける機能は不明であった。申請者らは初めてDock3がオリゴデンドログリアに発現していることを見出しており、Dock3によるオリゴデンドログリア保護効果の可能性について解析を行なった。Dock3を過剰発現するマウス(Dock3 Tg)に、銅キレート剤であるcuprizoneを用いて脱髄を誘発した後、残存する髄鞘の量を測定し野生型マウスと比較検討した。その結果、Dock3 Tgマウスでは、脱髄障害が軽減しており髄鞘がより多く残存していることが判明した。Dock3 Tgマウスのオリゴデンドロサイトでは、Dock3の活性化因子であるElmoの発現が増強されていることがwestern blotや免疫組織染色により判明している。さらに、MAPキナーゼであるERKの活性が野生型マウスに比べて増大していることが明らかとなった(Namekata et al. Cell Death and Disease 2014, 28;5:e1395.)。これらのことからDock3の過剰発現はERK活性を介して髄鞘の保護に関与する可能性が示された。一方、これまでの解析からDock8も脱髄疾患モデルであるExperimental autoimmune encephalomyelitis (EAE)の軽減に関与することを見出しており、今後はDockファミリー分子を利用した脱髄疾患の治療応用に期待したい。

Remarks

抗てんかん薬から緑内障治療へ　～バルプロ酸の神経保護作用メカニズムの解明～
http://www.igakuken.or.jp/retina/topics/topics7.html

Research Products

• [Journal Article] Spermidine promotes retinal ganglion cell survival and optic nerve regeneration in adult mice following optic nerve injury. (2015)
  • Author(s): Noro, T., Namekata, K., Kimura, A., Guo, X., Azuchi, Y., Harada, C., Nakano, T., Tsuneoka, H. and Harada, T.
  • Journal Title: Cell Death and Disease Volume: 6 Pages: e1720
  • DOI: 10.1038/cddis.2015.93.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Valproic acid prevents NMDA-induced retinal ganglion cell death via stimulation of neuronal TrkB receptor signaling. (2015)
  • Author(s): Kimura, A., Namekata, K., Guo, X., Noro, T., Harada, C. and Harada, T.
  • Journal Title: American Journal of Pathology Volume: 185 Pages: 756-764
  • DOI: 10.1016/j.ajpath.2014.11.005.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Brimonidine suppresses loss of retinal neurons and visual function in a murine model of optic neuritis. (2015)
  • Author(s): Guo, X., Namekata, K., Kimura, A., Noro, T., Azuchi, Y., Semba, K., Harada, C., Yoshida, H., Mitamura, Y. and Harada, T
  • Journal Title: Neuroscience Letters Volume: 592 Pages: 27-31
  • DOI: 10.1016/j.neulet.2015.02.059.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Valproic acid prevents retinal degeneration in a murine model of normal tension glaucoma. (2015)
  • Author(s): Kimura, A., Guo, X., Noro, T., Harada, C., Tanaka, K., Namekata, K. and Harada, T.
  • Journal Title: Neuroscience Letters Volume: 588 Pages: 108-113
  • DOI: 10.1016/j.neulet.2014.12.054.
  • Peer Reviewed
• [Journal Article] Expression of intraocular peroxisome proliferator-activated receptor gamma in patients with proliferative diabetic retinopathy. (2015)
  • Author(s): Katome, T., Namekata, K., *Mitamura, Y., Semba, K., Egawa, M., Naito, T., Harada, C. and Harada, T.
  • Journal Title: Journal of Diabetes and its Complications Volume: 29 Pages: 275-281
  • DOI: 10.1016/j.jdiacomp.2014.10.010.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Arundic acid attenuates retinal ganglion cell death by increasing glutamate/aspartate transporter expression in a model of normal tension glaucoma. (2015)
  • Author(s): Yanagisawa, M., Aida, T., Takeda, T., Namekata, K., Harada, T., Shinagawa, R. and *Tanaka. K.
  • Journal Title: Cell Death and Disease Volume: 6 Pages: e1963
  • DOI: doi:10.1038/cddis.2015.45
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dock3 protects myelin in the cuprizone model for demyelination. (2014)
  • Author(s): Namekata, K., Kimura, A., Harada, C., Yoshida, H., Matsumoto, Y. and *Harada, T.
  • Journal Title: Cell Death and Disease Volume: 5 Pages: e1395
  • DOI: doi: 10.1038/cddis.2014.357.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Brimonidine prevents neurodegeneration in a mouse model of normal tension glaucoma. (2014)
  • Author(s): Semba, K., Namekata, K., Kimura, A., Harada, C., Mitamura, Y. and *Harada, T.
  • Journal Title: Cell Death and Disease Volume: 5 Pages: e1341
  • DOI: 10.1038/cddis.2014.306.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Renin-angiotensin system regulates neurodegeneration in a mouse model of normal tension glaucoma. (2014)
  • Author(s): Semba, K., Namekata, K., Guo, X., Harada, C., *Harada T., Mitamura, Y.
  • Journal Title: Cell Death and Disease Volume: 5 Pages: e1333
  • DOI: 10.1038/cddis.2014.296.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dock3 overexpression and p38 MAPK inhibition synergistically stimulate neuroprotection and axon regeneration after optic nerve injury (2014)
  • Author(s): Semba, K., Namekata, K., Kimura, A., Harada, C., Katome. T., Yoshida, H., Mitamura, Y. and *Harada, T.
  • Journal Title: Neuroscience Letters Volume: 581 Pages: 89-93
  • DOI: 10.1016/j.neulet.2014.08.034.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Dock GEFs and their therapeutic potential:Neuroprotection and axon regeneration. (2014)
  • Author(s): Namekata, K., Kimura, A., Kawamura, K., Harada, C., Harada, T.
  • Journal Title: Progress in Retinal and Eye Research Volume: 43 Pages: 1-16
  • DOI: 10.1016/j.preteyeres.2014.06.005.
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] permidine stimulates neuroprotection and optic nerve regeneration following optic nerve injury. (2015)
  • Author(s): Takahiko Noro, Kazuhiko Namekata, Xiaoli Guo, Atsuko Kimura, Yuriko Azuchi, Tadashi Nakano, Hiroshi Tsuneoka, Takayuki Harada.
  • Organizer: Asia-ARVO
  • Place of Presentation: Pacifico Yokohama, Yokohama
  • Year and Date: 2015-02-18
• [Presentation] Valproic acid protects retinal neurons from NMDA-induced neurotoxicity via stimulation of neuronal TrkB receptors. (2015)
  • Author(s): Atsuko Kimura, Kazuhiko Namekata, Xiaoli Guo, Takahiko Noro, Chikako Harada, Takayuki Harada.
  • Organizer: Asia-ARVO
  • Place of Presentation: Pacifico Yokohama, Yokohama
  • Year and Date: 2015-02-18
• [Presentation] 神経変性疾患における神経保護・軸索再生の研究. (2015)
  • Author(s): 行方和彦
  • Organizer: 第１７回東邦大学理学部生物分子科学賞記念講演
  • Place of Presentation: 東邦大学 千葉県習志野市
  • Year and Date: 2015-01-06
  • Invited
• [Presentation] Dock8/10 regulate severity of inflammatory demyelination disorder. (2014)
  • Author(s): Kazuhiko Namekata, Xiaoli Guo, Atsuko Kimura, Chikako Harada, Takayuki Harada.
  • Organizer: The ARVO (The Association for Research in Vision and Ophthalmology)
  • Place of Presentation: U.S.A. Orlando
  • Year and Date: 2014-05-08
• [Presentation] Combined inhibition of angiotensin II type 1 receptor and ASK1 significantly attenuates autoimmune optic neuritis. (2014)
  • Author(s): Xiaoli Guo, Kazuhiko Namekata, Chikako Harada, Takayuki Harada.
  • Organizer: The ARVO (The Association for Research in Vision and Ophthalmology)
  • Place of Presentation: U.S.A. Orlando
  • Year and Date: 2014-05-08
• [Presentation] Dock3 protects retinal neurons in a mouse model of normal tension glaucoma. (2014)
  • Author(s): Kazuhiko Namekata, Xiaoli Guo, Chikako Harada, Takayuki Harada.
  • Organizer: The 2014 World Ophthalmology Congress
  • Place of Presentation: 東京国際ファーラム 東京
  • Year and Date: 2014-04-03
• [Presentation] Inhibition of Angiotensin II Ameliorates Autoimmune Optic Neuritis by Suppressing Innate Immune Responses. (2014)
  • Author(s): Xiaoli Guo, Kazuhiko Namekata, Chikako Harada, Takayuki Harada.
  • Organizer: The 2014 World Ophthalmology Congress
  • Place of Presentation: 東京国際ファーラム 東京
  • Year and Date: 2014-04-03
• [Book] Optic nerve regeneration. Neuroprotection and Neuroregeneration for Retinal Diseases. (2014)
  • Author(s): Kazuhiko Namekata, Takayuki Harada (Toru Nakazawa, Yasushi Kitaoka, Takayuki Harada, eds)
  • Total Pages: 356
  • Publisher: Springer Japan