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ミクログリアの毒性転換の制御による神経変性疾患の新規治療法開発

Publicly Offered Research

Project AreaBrain Environment
Project/Area Number 24111520
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionNagoya University

Principal Investigator

竹内 英之  名古屋大学, 環境医学研究所, 助教 (30362213)

Project Period (FY) 2012-04-01 – 2014-03-31
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000)
Fiscal Year 2013: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2012: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Keywordsミクログリア / 神経変性疾患 / 毒性転換 / 脳神経疾患 / ニューロン
Research Abstract

近年、神経変性疾患において、ニューロンのみの機序による自滅的な細胞死(自律性ニューロン死)の他に、ニューロンの周囲環境であるグリア細胞、とくにミクログリアが異常に活性化することでニューロン死をきたす(非自律性ニューロン死)機序が病態進展に大きく関与していることが明らかとなった。本来は神経保護的な役割を果たしている生理的なミクログリアが、変性ニューロンなどからの放出因子に対する応答反応として、神経保護的な役割から神経傷害的な役割へと「毒性転換」を来すことが、神経変性疾患の病態の進展因子である証拠が蓄積している。さらに、最近の知見として、多くの神経変性疾患において、原因となる変異タンパクや異常シグナルのプリオン様の細胞間伝播による病状進展も報告されており、病変細胞から分泌される変異タンパクやmiRNAを含有するエクソソームによる細胞間連絡を介する伝播形式が、その機序の一つとして示唆されている。
そこで、本研究では、ミクログリアの毒性転換の詳細なメカニズムを明らかにし、神経変性疾患の病態機序の解明や新たな診断・治療戦略の展開への基盤を確立することを目的として、検討を行った。マウス初代培養ニューロンおよびミクログリアを用いた、cDNAおよびmiRNAマイクロアレイ法およびサイトカイン/ケモカイン蛍光ビーズアレイ法による網羅的解析とニューロン・ミクログリア共培養系での確認実験を通じて、変性ニューロン由来のミクログリア毒性転換制御因子の候補因子としてIL-34, CX3CL1, FGF-2等の因子を、また、ミクログリア自体のミクログリア毒性転換制御の候補因子として、数種類のmiRNAおよびサイトカインを絞り込むことに成功した。
今後、得られた候補因子による神経外環境の制御・正常化を利用した神経変性疾患モデル動物に対する治療効果を検証していく予定である。

Current Status of Research Progress
Reason

25年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

25年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • Research Products

    (27 results)

All 2014 2013 2012 2011 Other

All Journal Article (14 results) (of which Peer Reviewed: 14 results,  Open Access: 2 results) Presentation (11 results) (of which Invited: 2 results) Book (1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] FGF-2 released from degenerating neurons exerts microglial-induced neuroprotection via FGFR3-ERK signaling pathway.2014

    • Author(s)
      Mariko Noda, Kento Takii, Bijay Parajuli, Jun Kawanokuchi, Yoshifumi Sonobe, Hideyuki Takeuchi, Tetsuya Mizuno, Akio Suzumura
    • Journal Title

      Journal of Neuroinflammation

      Volume: 11(1) Issue: 1 Pages: 76-76

    • DOI

      10.1186/1742-2094-11-76

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Evidence for Aberrant Astrocyte Hemichannel Activity in Juvenile Neuronal Ceroid Lipofuscinosis (JNCL).2014

    • Author(s)
      Maria Burkovetskaya, Nikolay Karpuk, Juan Xiong, Megan Bosch, Michael D Boska, Hideyuki Takeuchi, Akio Suzumura, Tammy Kielian
    • Journal Title

      PLoS ONE

      Volume: 9(4) Issue: 4 Pages: e95023-e95023

    • DOI

      10.1371/journal.pone.0095023

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Midkine and multiple sclerosis.2014

    • Author(s)
      Hideyuki Takeuchi
    • Journal Title

      British Journal of Pharmacology

      Volume: 171(4) Issue: 4 Pages: 931-935

    • DOI

      10.1111/bph.12499

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Sirtuin 1 attenuates oxidative stress via upregulation of superoxide dismutase 2 and catalase in astrocytes2014

    • Author(s)
      Yi Cheng, Hideyuki Takeuchi, Yoshifumi Sonobe, Shijie Jin, Yue Wang, Hiroshi Horiuchi, Bijay Parajuli, Jun Kawanokuchi, Tetsuya Mizuno, Akio Suzumura
    • Journal Title

      Journal of neuroimmunology

      Volume: 269(1-2) Issue: 1-2 Pages: 38-43

    • DOI

      10.1016/j.jneuroim.2014.02.001

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fingolimod phosphate promotes the neuroprotective effects of microglia.2013

    • Author(s)
      Hiromi Noda, Hideyuki Takeuchi, Tetsuya Mizuno, Akio Suzumura
    • Journal Title

      Journal of neuroimmunology

      Volume: 256(1-2) Issue: 1-2 Pages: 13-18

    • DOI

      10.1016/j.jneuroim.2012.12.005

    • Related Report
      2013 Annual Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ablation of Keratan Sulfate Accelerates Early Phase Pathogenesis of ALS.2013

    • Author(s)
      Kenichi Hirano, Tomohiro Ohgomori, Kazuyoshi Kobayashi, Fumiaki Tanaka, Tomohiro Matsumoto, Takamitsu Natori, Yukihiro Matsuyama, Kenji Uchimura, Kazuma Sakamoto, Hideyuki Takeuchi, Akihiro Hirakawa, Akio Suzumura, Gen Sobue, Naoki Ishiguro, Shiro Imagama, Kenji Kadomatsu
    • Journal Title

      PLoS ONE

      Volume: 8(6) Issue: 6 Pages: e66969-e66969

    • DOI

      10.1371/journal.pone.0066969

    • NAID

      120005946841

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Minocycline selectively inhibits M1 polarization of microglia2013

    • Author(s)
      Kazuyoshi Kobayashi
    • Journal Title

      Cell Death and Disease

      Volume: 4 Issue: 3 Pages: e525-e525

    • DOI

      10.1038/cddis.2013.54

    • Related Report
      2013 Annual Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Oligomeric amyloid β induces IL-1β processing via production of ROS: implication in Alzheimer's disease.2013

    • Author(s)
      B Parajuli, Y Sonobe, H Horiuchi, H Takeuchi, T Mizuno, A Suzumura
    • Journal Title

      Cell Death & Disease

      Volume: 4 Issue: 12 Pages: e975-e975

    • DOI

      10.1038/cddis.2013.503

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Fingolimod Phosphate Attenuates Oligomeric Amyloid β-Induced Neurotoxicity via Increased Brain-Derived Neurotrophic Factor Expression in Neurons.2013

    • Author(s)
      Yukiko Doi, Hideyuki Takeuchi, Hiroshi Horiuchi, Taketo Hanyu, Jun Kawanokuchi, Shijie Jin, Bijay Parajuli, Yoshifumi Sonobe, Tetsuya Mizuno, Akio Suzumura
    • Journal Title

      PLoS ONE

      Volume: 8(4) Issue: 4 Pages: e61988-e61988

    • DOI

      10.1371/journal.pone.0061988

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] GM-CSF increases LPS-induced production of proinflammatory mediators via upregulation of TLR4 and CD14 in murine microglia.2013

    • Author(s)
      Bijay Parajuli, Yoshifumi Sonobe, Jun Kawanokuchi, Yukiko Doi, Mariko Noda, Hideyuki Takeuchi, Tetsuya Mizuno, Akio Suzumura
    • Journal Title

      Journal of Neuroinflammation

      Volume: 9(1) Issue: 1 Pages: 268-268

    • DOI

      10.1186/1742-2094-9-268

    • Related Report
      2013 Annual Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TGF-β induced by interleukin-34-stimulated microglia regulates microglial proliferation and attenuates oligomeric amyloid β neurotoxicity2012

    • Author(s)
      Ma D, Doi Y, Jin S, Li E, Sonobe Y, Takeuchi H, Mizuno T, Suzumura A
    • Journal Title

      Neuroscience Letters

      Volume: 529(1) Issue: 1 Pages: 86-91

    • DOI

      10.1016/j.neulet.2012.08.071

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The neuroprotective effects of milk fat globule-EGF factor 8 against oligomeric amyloid β toxicity.2012

    • Author(s)
      Li E, Noda M, Doi Y, Parajuli B, Kawanokuchi J, Sonobe Y, Takeuchi H, Mizuno T, Suzumura A.
    • Journal Title

      Journal of Neuroinflammation

      Volume: 9 Issue: 1 Pages: 148-148

    • DOI

      10.1186/1742-2094-9-148

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Midkine inhibits inducible regulatory T cell differentiation by suppressing the development of tolerogenic dendritic cells2012

    • Author(s)
      SONOBE Yoshifumi
    • Journal Title

      Journal of Immunology

      Volume: 188(6) Issue: 6 Pages: 2602-2611

    • DOI

      10.4049/jimmunol.1102346

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Immunoglobulin G_1 immune complex upregulates interferon-γ induced nitrie oxide production via ERK1/2 activation in murine microglia2011

    • Author(s)
      PARAJULI Bijay
    • Journal Title

      Journal of Neuroimmunology

      Volume: 244(1-2) Issue: 1-2 Pages: 57-62

    • DOI

      10.1016/j.jneuroim.2012.01.004

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Presentation] FTY720 has the effects of anti-neuroinflammation and neuroprotection on microglia.2012

    • Author(s)
      Noda H (Takeuchi H)
    • Organizer
      第41回日本免疫学会学術集会
    • Place of Presentation
      神戸
    • Year and Date
      2012-12-05
    • Related Report
      2012 Annual Research Report
  • [Presentation] FTY720 has the effects of anti-neuroinflammation and neuroprotection on microglia.2012

    • Author(s)
      Noda H (Takeuchi H)
    • Organizer
      11th International Congress of Neuroimmunology
    • Place of Presentation
      Boston, USA
    • Year and Date
      2012-11-04
    • Related Report
      2012 Annual Research Report
  • [Presentation] FTY720 はミクログリアの炎症作用を抑え神経保護作用を上昇させる2012

    • Author(s)
      野田裕美(竹内英之)
    • Organizer
      第24回神経免疫学会学術集会
    • Place of Presentation
      軽井沢
    • Year and Date
      2012-09-19
    • Related Report
      2012 Annual Research Report
  • [Presentation] GM-CSF increases proinflammatory cytokineproduction via upregulation of TLR4 and CD14 in microglia.2012

    • Author(s)
      Parajuli B (竹内英之)
    • Organizer
      第24回神経免疫学会学術集会
    • Place of Presentation
      軽井沢
    • Year and Date
      2012-09-19
    • Related Report
      2012 Annual Research Report
  • [Presentation] Roles of glial calls in neuroinflammation and neurodegeneration.

    • Author(s)
      TAKEUCHI Hideyuki
    • Organizer
      12th MS Workshop
    • Place of Presentation
      福岡
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] フィンゴリモドの神経保護作用

    • Author(s)
      竹内英之
    • Organizer
      第18回グリア研究会
    • Place of Presentation
      仙台
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] FTY720はBDNFの発現上昇を介してアミロイドβによる神経細胞死を抑制する

    • Author(s)
      竹内英之, 土井由紀子, 薗部佳史, 水野哲也, 錫村明生
    • Organizer
      第54回日本神経学会総会
    • Place of Presentation
      東京
    • Related Report
      2013 Annual Research Report
  • [Presentation] 脳移行性CpGのアルツハイマー病モデルマウスの認知機能障害に対する有用性の検討

    • Author(s)
      水野哲也, 土井由紀子, 竹内英之, 錫村明生
    • Organizer
      第54回日本神経学会総会
    • Place of Presentation
      東京
    • Related Report
      2013 Annual Research Report
  • [Presentation] Fingolimod protects axonal damage in experimental autoimmune encephalomyelitis

    • Author(s)
      JIN Shijie, TAKEUCHI Hideyuki, MIZUNO Tetsuya, SUZUMURA Akio
    • Organizer
      PACTRIMS2013, Annual Meeting of Pan-Asian Committee for Treatment and Research in Multiple Sclerosis
    • Place of Presentation
      京都
    • Related Report
      2013 Annual Research Report
  • [Presentation] Fingolimodの神経保護作用

    • Author(s)
      竹内英之, 金 世杰, 土井由紀子, 堀内 浩, 川ノ口潤, 水野哲也, 錫村明生
    • Organizer
      第25回日本神経免疫学会学術集会
    • Place of Presentation
      下関
    • Related Report
      2013 Annual Research Report
  • [Presentation] 可溶性Aβオリゴマーによるミクログリアの神経傷害作用

    • Author(s)
      PARAJULI Bijay, 水野哲也, 竹内英之, 錫村明生
    • Organizer
      第25回日本神経免疫学会学術集会
    • Place of Presentation
      下関
    • Related Report
      2013 Annual Research Report
  • [Book] Midkine: From Embryogenesis to Pathogenesis and Therapy2012

    • Author(s)
      Takeuchi H
    • Total Pages
      335
    • Publisher
      Springer
    • Related Report
      2012 Annual Research Report
  • [Patent(Industrial Property Rights)] 特願2013-2431302013

    • Inventor(s)
      竹内英之、錫村明生
    • Industrial Property Rights Holder
      竹内英之、錫村明生
    • Industrial Property Rights Type
      特許
    • Filing Date
      2013-11-25
    • Related Report
      2013 Annual Research Report

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Published: 2013-05-15   Modified: 2019-07-29  

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