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Elucidating pathomechanism of ALS through the abnormality in astrocytes

Research Project

Project/Area Number 26293208
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Neurology
Research InstitutionNagoya University

Principal Investigator

YAMANAKA Koji  名古屋大学, 環境医学研究所, 教授 (80446533)

Co-Investigator(Kenkyū-buntansha) 小峯 起  名古屋大学, 環境医学研究所, 助教 (00456211)
高橋 英機  国立研究開発法人理化学研究所, 脳科学総合研究センター, 支援ユニットリーダー (40446521)
三澤 日出巳  慶應義塾大学, 薬学部(芝共立), 教授 (80219617)
内匠 透  国立研究開発法人理化学研究所, 脳科学総合研究センター, チームリーダー (00222092)
Co-Investigator(Renkei-kenkyūsha) Suzumura Akio  名古屋大学, 環境医学研究所, 教授 (50196896)
Takeuchi Hideyuki  横浜市立大学, 医学部, 准教授 (30362213)
Takahashi Ryosuke  京都大学, 医学研究科, 教授 (90216771)
Yamashita Hirofumi  京都大学, 医学研究科, 講師 (60402913)
Research Collaborator Endo Fumito  名古屋大学, 環境医学研究所, 特任助教
Watanabe Seiji  名古屋大学, 環境医学研究所, 助教
Project Period (FY) 2014-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥16,250,000 (Direct Cost: ¥12,500,000、Indirect Cost: ¥3,750,000)
Fiscal Year 2017: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2016: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2015: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2014: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Keywords神経変性疾患 / アストロサイト / ALS
Outline of Final Research Achievements

Using model mice for amyotrophic lateral sclerosis (ALS), we identified cytokine TGF-β1 as a detrimental factor for ALS by interfering a neuroprotective environment mediated by glial cells. TGF-β1 was abnormally upregulated in astrocytes of human ALS and a mouse model for ALS. Administrating TGF-β1 inhibitor slowed disease progression in ALS mice, indicating TGF-β1 as a potential therapeutic target for ALS. In addition, we elucidated a novel role of innate immune adaptor TRIF in eliminating abnormally activated astrocytes through inducing apoptosis.

Report

(5 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • Research Products

    (46 results)

All 2018 2017 2016 2015 2014 Other

All Int'l Joint Research (2 results) Journal Article (14 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 14 results,  Open Access: 10 results,  Acknowledgement Compliant: 8 results) Presentation (21 results) (of which Int'l Joint Research: 5 results,  Invited: 14 results) Book (1 results) Remarks (8 results)

  • [Int'l Joint Research] スタンフォード大学(米国)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] スタンフォード大学/カリフォルニア大学サンディエゴ校(米国)

    • Related Report
      2015 Annual Research Report
  • [Journal Article] Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes2018

    • Author(s)
      Komine Okiru、Yamashita Hirofumi、Fujimori-Tonou Noriko、Koike Masato、Jin Shijie、Moriwaki Yasuhiro、Endo Fumito、Watanabe Seiji、Uematsu Satoshi、Akira Shizuo、Uchiyama Yasuo、Takahashi Ryosuke、Misawa Hidemi、Yamanaka Koji
    • Journal Title

      Cell Death & Differentiation

      Volume: 印刷中 Issue: 12 Pages: 2130-2146

    • DOI

      10.1038/s41418-018-0098-3

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The multi-dimensional roles of astrocytes in ALS2018

    • Author(s)
      Yamanaka Koji、Komine Okiru
    • Journal Title

      Neuroscience Research

      Volume: 126 Pages: 31-38

    • DOI

      10.1016/j.neures.2017.09.011

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] TDP-43 accelerates age-dependent degeneration of interneurons2017

    • Author(s)
      Tsuiji Hitomi、Inoue Ikuyo、Takeuchi Mari、Furuya Asako、Yamakage Yuko、Watanabe Seiji、Koike Masato、Hattori Mitsuharu、Yamanaka Koji
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 14972-14972

    • DOI

      10.1038/s41598-017-14966-w

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dissociation of blood-brain barrier disruption and disease manifestation in an aquaporin-4-deficient mouse model of amyotrophic lateral sclerosis2017

    • Author(s)
      Watanabe-Matsumoto Saori et al.
    • Journal Title

      Neuroscience Research

      Volume: in press Pages: 48-57

    • DOI

      10.1016/j.neures.2017.11.001

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Immunochemical characterization on pathological oligomers of mutant Cu/Zn-superoxide dismutase in amyotrophic lateral sclerosis2017

    • Author(s)
      Eiichi Tokuda, Itsuki Anzai, Takao Nomura, Keisuke Toichi, Masahiko Watanabe, Shinji Ohara, Seiji Watanabe, Koji Yamanaka, Yuta Morisaki, Hidemi Misawa, and Yoshiaki Furukawa
    • Journal Title

      Molecular Neurodegeneration

      Volume: 12 Issue: 1 Pages: 2-2

    • DOI

      10.1186/s13024-016-0145-9

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS.2016

    • Author(s)
      Watanabe S, Ilieva H, Tamada H, Nomura H, Komine O, Endo F, Jin S, Mancias P, Kiyama H, *Yamanaka K.
    • Journal Title

      EMBO Molecular Medicine

      Volume: 8 Issue: 12 Pages: 1421-1437

    • DOI

      10.15252/emmm.201606403

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Selective expression of osteopontin in ALS-resistant motor neurons is a critical determinant of late phase neurodegeneration mediated by matrix metalloproteinase-9.2016

    • Author(s)
      Morisaki Y, Niikura M, Watanabe M, Onishi K, Tanabe S, Moriwaki Y, Okuda T, Ohara S, Murayama S, Takao M, Uchida S, Yamanaka K, *Misawa H.
    • Journal Title

      Scientific Reports

      Volume: 6 Issue: 1 Pages: 27354-27354

    • DOI

      10.1038/srep27354

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Neuroinflammation in motor neuron disease.2016

    • Author(s)
      Endo F, Komine O, Yamanaka K.
    • Journal Title

      Clinical and Experimental Neuroimmunology

      Volume: 7 Issue: 2 Pages: 126-138

    • DOI

      10.1111/cen3.12309

    • NAID

      120005672307

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Neuregulin 1 confers neuroprotection in SOD1-linked amyotrophic lateral sclerosis mice via restoration of C-boutons of spinal motor neurons.2016

    • Author(s)
      Lasiene J, Komine O, Fujimori-Tonou N, Powers B, Endo F, Watanabe S, Shijie J, Ravits J, Horner P, Misawa H, Yamanaka K
    • Journal Title

      Acta Neuropathologica Communications

      Volume: 4 Issue: 1 Pages: 15-15

    • DOI

      10.1186/s40478-016-0286-7

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Neuroinflammation in Alzheimer’s disease.2015

    • Author(s)
      Heneka MT et al.
    • Journal Title

      Lancet Neurology

      Volume: 14 Issue: 4 Pages: 388-405

    • DOI

      10.1016/s1474-4422(15)70016-5

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Mahogunin ring finger 1 confers cytoprotection against mutant SOD1 aggresomes and is defective in an ALS mouse model.2015

    • Author(s)
      Chhangani D, Endo F, Amanullah A, Upadhyay A, Watanabe S, Mishra R, Yamanaka K, Mishra A
    • Journal Title

      Neurobiology of Disease

      Volume: 86 Pages: 16-16

    • DOI

      10.1016/j.nbd.2015.11.017

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Astrocyte-Derived TGF-β1 Accelerates Disease Progression in ALS Mice by Interfering with the Neuroprotective Functions of Microglia and T Cells.2015

    • Author(s)
      Endo F, Komine O, Fujimori-Tonou N, Katsuno M, Jin S, Watanabe S, Sobue G, Dezawa M, Wyss-Coray T, Yamanaka K
    • Journal Title

      Cell Reports

      Volume: 11 Issue: 4 Pages: 592-604

    • DOI

      10.1016/j.celrep.2015.03.053

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] SIRT1 overexpression ameliorates a mouse model of SOD1-linked amyotrophic lateral sclerosis via HSF1/HSP70i chaperone system.2014

    • Author(s)
      Watanabe S, Ageta-Ishihara N, Nagatsu S, Takao K, Komine O, Endo F, Miyakawa T, Misawa H, Takahashi R, Kinoshita M, Yamanaka K.
    • Journal Title

      Mol Brain

      Volume: 7 Issue: 1 Pages: 62-62

    • DOI

      10.1186/s13041-014-0062-1

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Cystatin C protects neuronal cells against mutant copper-zinc superoxide dismutase-mediated toxicity.2014

    • Author(s)
      WATANABE Seiji, HAYAKAWA Tomoyo, Wakasugi Keisuke, YAMANAKA Koji
    • Journal Title

      Cell Death & Disease

      Volume: 5 Issue: 10 Pages: e1497-e1497

    • DOI

      10.1038/cddis.2014.459

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] ALSにおける細胞群特異性病態と治療への展開2017

    • Author(s)
      山中宏二
    • Organizer
      第39回日本生物学的精神医学会, 第47回日本神経精神薬理学会合同年会シンポジウム
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 筋萎縮性側索硬化症におけるグリア細胞・神経炎症の役割2017

    • Author(s)
      山中宏二
    • Organizer
      千里ライフサイエンスセミナー,神経変性疾患の最前線(グリア細胞と神経疾患)
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 免疫学的視点からみた神経変性疾患の分子病態2017

    • Author(s)
      山中宏二
    • Organizer
      第29回日本神経免疫学会学術集会シンポジウム
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 運動神経変性におけるグリア細胞・神経炎症の役割2017

    • Author(s)
      山中宏二
    • Organizer
      2017年度生命科学系学会合同年次大会(ConBio2017)ワークショップ
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Innate immune adaptor TRIF slows disease progression of ALS mice by eliminating aberrantly activated astrocytes.2017

    • Author(s)
      Komine O, Yamashita H. Fujimori-Tonou N, Uematsu S, Akira S, Yamanaka K.
    • Organizer
      28th International symposium on ALS/MND
    • Related Report
      2017 Annual Research Report
  • [Presentation] Astrocyte-derived extracellular vesicles contribute to the propagation of pathogenic protein in ALS.2017

    • Author(s)
      Endo F, Yamanaka K
    • Organizer
      28th international Symposium on ALS/MND
    • Related Report
      2017 Annual Research Report
  • [Presentation] Neuregulin 1 confers neuroprotection in SOD1-linked ALS mice via restoration of C-boutons of spinal motor neurons.2016

    • Author(s)
      Komine O, Lasiene J, Fujimori-Tonou N, Powers B, Endo F, Watanabe S, Jin S, Ravits J, Horner P, Misawa H, Yamanaka K.
    • Organizer
      The 27th International Symposium on ALS/MND
    • Place of Presentation
      ダブリン
    • Year and Date
      2016-12-07
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Active role of neuroinflammation in motor neuron disease.2016

    • Author(s)
      Yamanaka Koji
    • Organizer
      The 2nd IMCR Symposium on Endocrine and Metabolism: International Frontiers in Homeostatic Regulation Research,
    • Place of Presentation
      群馬
    • Year and Date
      2016-11-10
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Dysregulation of TGF-β signaling facilitates motor neurodegeneration of ALS mice.2016

    • Author(s)
      遠藤史人、山中宏二
    • Organizer
      第39回日本神経科学大会
    • Place of Presentation
      横浜
    • Year and Date
      2016-07-20
    • Related Report
      2016 Annual Research Report
  • [Presentation] グリア細胞からみた神経変性疾患2016

    • Author(s)
      山中宏二
    • Organizer
      第39回日本神経科学大会
    • Place of Presentation
      横浜
    • Year and Date
      2016-07-20
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Dysregulation of neuronal TGF-β signaling contributes to neurodegeneration in mutant SOD1 mice.2016

    • Author(s)
      遠藤史人、宮﨑 朗、山中宏二
    • Organizer
      第57回日本神経学会学術大会
    • Place of Presentation
      神戸
    • Year and Date
      2016-05-18
    • Related Report
      2016 Annual Research Report
  • [Presentation] Astrocyte-derived TGF-β1 accelerates disease progression in ALS mice by interfering with neuroprotective functions of microglia and T cells.2015

    • Author(s)
      Endo Fumito, et al.
    • Organizer
      26th International Symposium on ALS/MND
    • Place of Presentation
      オーランド、米国
    • Year and Date
      2015-12-11
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] グリア細胞からみた運動神経変性機序2015

    • Author(s)
      山中 宏二
    • Organizer
      第34回日本認知症学会学術集会
    • Place of Presentation
      青森
    • Year and Date
      2015-10-03
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] The active roles of glial cells in motor neuron disease.2015

    • Author(s)
      Yamanaka Koji
    • Organizer
      The10th Annual GEO-PD (Genetic Epidemiology of Parkinson’s Disease)
    • Place of Presentation
      東京
    • Year and Date
      2015-10-02
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] The role of astrocyte-derived TGF-β in motor neuron disease.2015

    • Author(s)
      Yamanaka Koji
    • Organizer
      25th International Society for Neurochemistry Biennial Meeting, symposium
    • Place of Presentation
      ケアンズ、豪州
    • Year and Date
      2015-08-23
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Pathomechanisms and therapeutic directions common to motor neuron diseases.2015

    • Author(s)
      山中 宏二
    • Organizer
      第56回日本神経学会学術大会 シンポジウム
    • Place of Presentation
      新潟
    • Year and Date
      2015-05-22
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] ALS mice by interfering with neuroprotective functions of microglia and T cells2014

    • Author(s)
      Fumito Endo et al.
    • Organizer
      25th International symposium on ALS/MND
    • Place of Presentation
      ブリュッセル(ベルギー)
    • Year and Date
      2014-12-06 – 2014-12-08
    • Related Report
      2014 Annual Research Report
  • [Presentation] Astrocyte-derived TGF-β1 accelerates disease progression in ALS mice by interfering with neuroprotective functions of microglia and T cells2014

    • Author(s)
      Fumito Endo et al.
    • Organizer
      9th Brain Research Conference-Neuroprotection
    • Place of Presentation
      ワシントンD.C.(米国)
    • Year and Date
      2014-11-13 – 2014-11-14
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] 神経変性疾患ALSにおける自然免疫機構の役割2014

    • Author(s)
      山中宏二
    • Organizer
      第37回日本神経科学大会
    • Place of Presentation
      パシフィコ横浜(横浜)
    • Year and Date
      2014-09-11 – 2014-09-13
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] 筋萎縮性側索硬化症における神経炎症2014

    • Author(s)
      遠藤史人、山中宏二
    • Organizer
      第55回日本神経学会学術大会
    • Place of Presentation
      福岡国際会議場(福岡)
    • Year and Date
      2014-05-24
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] 筋萎縮性側索硬化症における細胞群特異的病態の解明2014

    • Author(s)
      山中宏二
    • Organizer
      第55回日本神経学会学術大会
    • Place of Presentation
      福岡国際会議場(福岡)
    • Year and Date
      2014-05-23
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Book] 遺伝子医学MOOK26 脳内環境ー維持機構と破綻がもたらす疾患研究2014

    • Author(s)
      小峯起、山中宏二
    • Publisher
      メディカルドゥ
    • Related Report
      2014 Annual Research Report
  • [Remarks] 名古屋大学環境医学研究所

    • URL

      http://www.riem.nagoya-u.ac.jp/byoutai_shinkei.html

    • Related Report
      2017 Annual Research Report
  • [Remarks] 名古屋大学環境医学研究所 病態神経科学分野HP

    • URL

      http://www.riem.nagoya-u.ac.jp/4/mnd/index.html

    • Related Report
      2017 Annual Research Report
  • [Remarks] 山中宏二 研究室(名古屋大学環境医学研究所病態神経科学分野)

    • URL

      http://www.riem.nagoya-u.ac.jp/4/mnd/index.html

    • Related Report
      2016 Annual Research Report
  • [Remarks] 名古屋大学 環境医学研究所

    • URL

      http://www.riem.nagoya-u.ac.jp/index.html

    • Related Report
      2016 Annual Research Report
  • [Remarks] 山中宏二研究室 名古屋大学 環境医学研究所 病態神経科学分野

    • URL

      http://www.riem.nagoya-u.ac.jp/4/mnd/index.html

    • Related Report
      2015 Annual Research Report
  • [Remarks] 名古屋大学プレスリリース:神経難病 ALS の進行にグリア細胞由来の TGF-β1 が関与

    • URL

      http://www.nagoya-u.ac.jp/about-nu/public-relations/researchinfo/upload_images/20150417_riem.pdf

    • Related Report
      2015 Annual Research Report
  • [Remarks] ALS Research Forum (April 24, 2015)

    • URL

      http://www.alsresearchforum.org/in-als-astrocyte-tgf-1-pulls-rug-from-under-motor-neurons/

    • Related Report
      2015 Annual Research Report
  • [Remarks] 山中宏二研究室 名古屋大学環境医学研究所 病態神経科学分野

    • URL

      http://www.riem.nagoya-u.ac.jp/4/mnd/index.html

    • Related Report
      2014 Annual Research Report

URL: 

Published: 2014-04-04   Modified: 2019-03-29  

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