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Development of new therapeutic avenues of multiple sclerosis with a focus on glial activation

Research Project

Project/Area Number 23700459
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Neurochemistry/Neuropharmacology
Research Institution公益財団法人東京都医学総合研究所 (2012)
Tokyo Metropolitan Organization for Medical Research (2011)

Principal Investigator

KAKU Gyourei  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) 2011 – 2012
Project Status Completed (Fiscal Year 2012)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2011: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Keywords多発性硬化症 / グリア / 自然免疫 / Angiotensin II / 抗炎症性物質 / angiotensin II / ASK1 / Dock8 / RASシステム / 視神経炎 / 抗酸化物質 / EAE / GEF
Research Abstract

Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), was used in our study to develop new therapeutic avenues of multiple sclerosis. Firstly, we found that oral administration of spermidine, a natural component of our diet, reduced the severity of EAE, suggesting that spermidine might be suitable for the treatment of MS. Secondly, we revealed a novel pathway of RAS-NF.B-TLR4-ASK1 in neural and immune cells as a valid therapeutic target for autoimmune disorders in the central nervous system. Thirdly, we found that Dock8 deficiency or overexpression both reduced the severity of EAE, suggesting that modulation of Dock8 expression might be effective for the treatment of MS.

Report

(3 results)
  • 2012 Annual Research Report   Final Research Report ( PDF )
  • 2011 Research-status Report
  • Research Products

    (29 results)

All 2013 2012 2011 Other

All Journal Article (17 results) (of which Peer Reviewed: 12 results) Presentation (8 results) Remarks (2 results) Patent(Industrial Property Rights) (2 results)

  • [Journal Article] ASK1-p38 経路の阻害は視神経外傷後の神経細胞死を抑制する2013

    • Author(s)
      香留 崇、行方和彦、郭 暁麗、仙波賢太郎、橘高大二、川村和人、木村敦子、原田知加子、一條秀憲、三田村佳典、原田高幸
    • Journal Title

      日眼会誌

      Volume: 117(2) Pages: 161-161

    • Related Report
      2012 Final Research Report
  • [Journal Article] Inhibition of ASK1-p38 pathway prevents neural cell death following optic nerve injury2013

    • Author(s)
      Katome T., Namekata K., Guo X., Semba K., Kittaka D., Kawamura K., Kimura A., Harada C., Ichijo H., Mitamura Y. & Harada T
    • Journal Title

      Cell Death and Differentiation

      Volume: 20 Pages: 270-280

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of ASK1-p38 pathway prevents neural cell death following optic nerve injury.2013

    • Author(s)
      Katome, T., Namekata, K., Guo, X., Semba, K., Kittaka, D., Kawamura, K., Kimura, A., Harada, C., Ichijo, H., Mitamura, Y. and Harada, T.
    • Journal Title

      Cell Death Differ.

      Volume: 20 Issue: 2 Pages: 270-280

    • DOI

      10.1038/cdd.2012.122

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Expression of promyelocytic leukemia protein and vascular endothelial growth factor in aqueous humor and vitreous fluid in patients with proliferative diabetic retinopathy2012

    • Author(s)
      Katome T., Namekata K., Naito T., Semba K., Guo X., Harada C., Harada T. & Mitamura Y
    • Journal Title

      Diabetes Research and Clinical Practice

      Volume: 98(2) Pages: 9-11

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Dock3 regulates BDNF-TrkB signaling for neurite outgrowth by forming a ternary complex with Elmo and RhoG2012

    • Author(s)
      Namekata K., Watanabe H., Guo X., Kittaka D., Kawamura K., Kimura A., Harada C. & Harada T
    • Journal Title

      Genes to Cells

      Volume: 17(8) Pages: 688-697

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Dock3 stimulates axonal outgrowth via GSK-3β-mediated microtubule assembly2012

    • Author(s)
      Namekata K., Harada C., Guo X., Kimura A., Kittaka D., Watanabe H. & Harada T
    • Journal Title

      Journal of Neuroscience

      Volume: 32(1) Pages: 264-274

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Dock3はグリコーゲン合成酵素キナーゼ-3β (GSK-3β)による微小管重合を介して軸索伸長を促進する2012

    • Author(s)
      行方和彦、原田知加子、郭 暁麗、木村敦子、橘高大二、渡邉快記、原田高幸
    • Journal Title

      日眼会誌

      Volume: 116(5) Pages: 527-527

    • Related Report
      2012 Final Research Report
  • [Journal Article] Expression of promyelocytic leukemia protein and vascular endothelial growth factor in aqueous humor and vitreous fluid in patients with proliferative diabetic retinopathy2012

    • Author(s)
      2. Katome T, Namekata K, Naito T, Semba K, Guo X, Harada C, Harada T, Mitamura Y
    • Journal Title

      Diabetes Research and Clinical Practice

      Volume: 98 Pages: 9-11

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dock3 regulates BDNF-TrkB signaling for neurite outgrowth by forming a ternary complex with Elmo and RhoG2012

    • Author(s)
      3. Namekata K, Watanabe H, Guo X, Kittaka D, Kawamura K, Kimura A, Harada, C, Harada T
    • Journal Title

      Genes to Cells

      Volume: 17 Pages: 688-697

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dock3 stimulates axonal outgrowth via GSK-3β-mediated microtubule assembly2012

    • Author(s)
      Namekata K., Harada C., Guo X., Kimura A., Kittaka D., Watanabe H. & Harada T.
    • Journal Title

      Journal of Neuroscience

      Volume: 32 Pages: 264-274

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Glia- and neuron-specific functions of TrkB signalling during retinal degeneration and regeneration2011

    • Author(s)
      Harada C., Guo X., Namekata K., Kimura A., Nakamura K., Tanaka K., Parada L.F. & Harada T
    • Journal Title

      Nature Communications

      Volume: 2 Pages: 189-189

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Spermidine alleviates severity of murine experimental autoimmune encephalomyelitis2011

    • Author(s)
      Guo X., Harada C., Namekata K., Kimura A., Mitamura Y., Yoshida H., Matsumuto Y. & Harada T
    • Journal Title

      Investigative Ophthalmology & Visual Science

      Volume: 52 Pages: 2696-2703

    • Related Report
      2012 Final Research Report 2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Spermidine投与による実験的自己免疫性脳脊髄炎の軽症化2011

    • Author(s)
      郭 暁麗、原田知加子、行方和彦、木村敦子、三田村佳典、吉田 寛、松本 陽、原田高幸
    • Journal Title

      日眼会誌

      Volume: 115(8) Pages: 729-729

    • Related Report
      2012 Final Research Report
  • [Journal Article] 網膜の変性と再生過程におけるグリアおよび神経特異的なTrkBシグナルの機能解析2011

    • Author(s)
      原田知加子、郭 暁麗、行方和彦、木村敦子、中村和昭、田中光一、Luis F. Parada、原田高幸
    • Journal Title

      日眼会誌

      Volume: 115(7) Pages: 637-637

    • Related Report
      2012 Final Research Report
  • [Journal Article] TLR-ASK1-p38経路による神経炎症と脱髄症状の制御2011

    • Author(s)
      郭 暁麗、原田知加子、行方和彦、松沢 厚、Monsterrat Camps、Hong Ji、Dominique Swinnen、Catherine Jorand-Lebrun、Mathilde Muzerelle、Pierre-Alain Vitte、Thomas Ruckle、木村敦子、神山邦子、松本 陽、一條秀憲、原田高幸
    • Journal Title

      日眼会誌

      Volume: 115(5) Pages: 485-485

    • Related Report
      2012 Final Research Report
  • [Journal Article] Glia- and neuron-specific functions of TrkB signaling during retinal degeneration and regeneration2011

    • Author(s)
      Harada, C.
    • Journal Title

      Nature Communications

      Volume: 2 Issue: 1 Pages: 1-9

    • DOI

      10.1038/ncomms1190

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Dock3 attenuates neural cell death due to NMDA neurotoxicity and oxidative stress in a mouse model of normal tension glaucoma

    • Author(s)
      Namekata, K., Kimura, A., Kawamura, K., Guo, X., Harada, C., Tanaka, K. and Harada, T
    • Journal Title

      Cell Death and Differentiation

      Volume: (in press)

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Presentation] The role of Dock3 in axon regeneration following optic nerve injury2012

    • Author(s)
      Namekata K., Harada C., Guo X., Kimura A. & Harada T
    • Organizer
      Poster session: Retinal cell biology XX International Congress of Eye Research (ISER 2012)
    • Place of Presentation
      Berlin, Germany
    • Year and Date
      2012-07-24
    • Related Report
      2012 Final Research Report
  • [Presentation] ASK1 inhibition ameliorates optic neuritis by modulating glial innate immunity2012

    • Author(s)
      Guo X., Harada C., Namekata K., Kimura A. & Harada T
    • Organizer
      Oral session: Macrophages and microglial regulation of ocular inflammation XX International Congress of Eye Research (ISER2012)
    • Place of Presentation
      Berlin, Germany
    • Year and Date
      2012-07-23
    • Related Report
      2012 Final Research Report
  • [Presentation] Glia- and neuron-specific functions of TrkB signaling during retinal degeneration and regeneration2011

    • Author(s)
      Harada T., Guo X., Namekata K., Parada L.F. & Harada C
    • Organizer
      8^<th> World Congress of Neuroscience, International Brain Research Organization (IBRO)
    • Place of Presentation
      Florence, Italy
    • Year and Date
      2011-07-18
    • Related Report
      2012 Final Research Report
  • [Presentation] ASK1 deficiency attenuates neural cell death in a mouse model of normal tension glaucoma2011

    • Author(s)
      Harada T., Namekata K, Guo X., Tanaka K, Ichijo H., Harada C
    • Organizer
      The 26th Asia Pacific Academy of Ophthalmology (APAO) Congress
    • Place of Presentation
      Sydney, Australia
    • Year and Date
      2011-03-22
    • Related Report
      2012 Final Research Report
  • [Presentation] Optic nerve regeneration is enhanced in Dock3 overexpressing transgenic mice2011

    • Author(s)
      Namekata K., Harada C., Guo X., Harada T
    • Organizer
      The 26th Asia Pacific Academy of Ophthalmology (APAO) Congress
    • Place of Presentation
      Sydney, Australia
    • Year and Date
      2011-03-22
    • Related Report
      2012 Final Research Report
  • [Presentation] ASK1 inhibition ameliorates optic neuritis by modulating glial innate immunity2011

    • Author(s)
      Guo X., Harada C., Nakamura K., Kimura A., Ichijo H., Harada T
    • Organizer
      The 26th Asia Pacific Academy of Ophthalmology (APAO) Congress
    • Place of Presentation
      Sydney, Australia
    • Year and Date
      2011-03-22
    • Related Report
      2012 Final Research Report
  • [Presentation] The role of Dock3 in axon regeneration following optic nerve injury

    • Author(s)
      Kazuhiko Namekata, Chikako Harada, Xiaoli Guo, Atsuko Kimura, Takayuki Harada
    • Organizer
      XX International Congress of Eye Research (ISER 2012)
    • Place of Presentation
      Berin, Germany
    • Related Report
      2012 Annual Research Report
  • [Presentation] ASK1 inhibition ameliorates optic neuritis by modulating glial innate immunity

    • Author(s)
      Xiaoli Guo, Chikako Harada, Kazuhiko Namekata, Atsuko Kimura, Takayuki Harada
    • Organizer
      XX International Congress of Eye Research (ISER 2012)
    • Place of Presentation
      Berin, Germany
    • Related Report
      2012 Annual Research Report
  • [Remarks] 視覚病態プロジェクトの研究紹介

    • URL

      http://www.igakuken.or.jp/retina/

    • Related Report
      2012 Final Research Report
  • [Remarks] 視覚病態プロジェクトの研究紹介

    • URL

      http://www.igakuken.or.jp/retina/

    • Related Report
      2012 Annual Research Report
  • [Patent(Industrial Property Rights)] Dock8を含む神経炎症又は脱髄疾患の予防又は治療用医薬組成物2013

    • Inventor(s)
      原田高幸、行方和彦、郭 暁麗
    • Industrial Property Rights Holder
      原田高幸、行方和彦、郭 暁麗
    • Industrial Property Number
      2013-026753
    • Filing Date
      2013-02-18
    • Related Report
      2012 Final Research Report
  • [Patent(Industrial Property Rights)] Dock8を含む神経炎症又は脱髄疾患の予防又は治療用医薬組成物2013

    • Inventor(s)
      原田高幸、行方和彦、郭 暁麗
    • Industrial Property Rights Holder
      原田高幸、行方和彦、郭 暁麗
    • Industrial Property Rights Type
      特許
    • Filing Date
      2013-02-18
    • Related Report
      2012 Annual Research Report

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Published: 2011-08-05   Modified: 2019-07-29  

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