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Ca2+流入異常を介した核-細胞質システム破綻による細胞死メカニズムの解析

Research Project

Project/Area Number 16K09666
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurology
Research InstitutionTokyo Medical University (2018-2019)
The University of Tokyo (2016-2017)

Principal Investigator

山下 雄也  東京医科大学, 医学部, 客員研究員 (20431843)

Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Discontinued (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsADAR2 / AMPA受容体 / RNA編集 / カルパイン / 筋萎縮性側索硬化症 / 神経細胞死 / NPC / 核‐細胞質輸送 / 核膜孔複合体 / 核-細胞質輸送 / 核膜孔複合体(NPC) / 核ー細胞死輸送 / ALS / 細胞死
Outline of Annual Research Achievements

我々は、AMPA受容体を介したカルシウムイオン透過性の亢進が孤発性筋萎縮性側索硬化症(amyotrophic lateral sclerosis: ALS)の病態に繋がること、その過程でカルシウムイオン依存性プロテアーゼであるカルパインの活性化やTAR DNA-binding protein (TDP-43)の病理形成に関与することを孤発性ALSの分子病態モデルマウスである、RNA編集酵素adenosine deaminase acting on RNA 2 (ADAR2)のコンディショナルノックアウト(AR2)マウスの解析から明らかにした。
孤発性ALSの分子病態モデルであるAR2マウスでは、AMPA受容体を介したカルシウムイオン透過性の亢進で、運動ニューロンに変性・脱落が起き、その過程でローターロッドやグリップ力(行動解析)を指標とした運動機能が低下する。AR2マウスの行動解析が低下する以前に、脊髄運動ニューロンの核に核内空胞を見出し、この核の機能異常が核膜孔複合体(Nuclear pore complex: NPC)と核-細胞質輸送システムの破綻をきたし、細胞死に繋がるカスケードの一部であることを見出した。さらにAR2マウスの脊髄運動ニューロン死の指標としてコリンアセチルトランスフェラーゼ(ChAT)抗体陽性の運動ニューロン数と細胞体のサイズが相関することを見出した。また、細胞死カスケードの過程において、NPCの構成分子であるヌクレオポリンの一つNUP62がTDP-43を含む凝集体と共在することをAR2とAR2ヘテロマウスの脊髄前角領域で見出した。

Report

(4 results)
  • 2019 Annual Research Report
  • 2018 Research-status Report
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (34 results)

All 2019 2018 2017 2016 Other

All Journal Article (14 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 10 results,  Open Access: 9 results) Presentation (15 results) (of which Int'l Joint Research: 9 results,  Invited: 2 results) Remarks (5 results)

  • [Journal Article] Extracellular RNAs as Biomarkers of Sporadic Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases.2019

    • Author(s)
      Hosaka T, Yamashita T, Tamaoka A, Kwak S.
    • Journal Title

      Int J Mol Sci.

      Volume: 20 Issue: 13 Pages: 3148-3148

    • DOI

      10.3390/ijms20133148

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Impaired Nucleoporins Are Present in Sporadic Amyotrophic Lateral Sclerosis Motor Neurons that Exhibit Mislocalization of the 43-kDa TAR DNA-Binding Protein.2019

    • Author(s)
      Aizawa H, Yamashita T, Kato H, Kimura T, Kwak S
    • Journal Title

      J Clin Neurol.

      Volume: 15(1) Issue: 1 Pages: 62-67

    • DOI

      10.3988/jcn.2019.15.1.62

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] ADAR2-dependent A-to-I RNA editing in the extracellular linear and circular RNAs.2018

    • Author(s)
      Hosaka T, Yamashita T, Teramoto S, Hirose N, Tamaoka A, Kwak S
    • Journal Title

      Neurosci Res.

      Volume: 印刷中 Pages: 48-57

    • DOI

      10.1016/j.neures.2018.11.005

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cell death cascade and molecular therapy in ADAR2-deficient motor neurons of ALS.2018

    • Author(s)
      Yamashita T, Kwak S
    • Journal Title

      Neurosci Res.

      Volume: 印刷中 Pages: 4-13

    • DOI

      10.1016/j.neures.2018.06.004

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] 孤発性ALSの病態と治療-AMPA受容体阻害薬による筋萎縮性側索硬化症治療の可能性2017

    • Author(s)
      赤松恵, 山下雄也, 郭 伸
    • Journal Title

      神経治療学

      Volume: 34-2 Pages: 86-94

    • Related Report
      2017 Research-status Report 2016 Research-status Report
    • Open Access
  • [Journal Article] Altered intracellular milieu of ADAR2-deficient motor neurons in amyotrophic lateral sclerosis2017

    • Author(s)
      Yamashita T, Akamatsu M, Kwak S
    • Journal Title

      Genes

      Volume: 8(2)-60 Issue: 2 Pages: 60-60

    • DOI

      10.3390/genes8020060

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Calpain-dependent disruption of nucleo-cytoplasmic transport in ALS motor neurons.2017

    • Author(s)
      Yamashita T, Aizawa H, Teramoto S, Akamatsu M, Kwak S
    • Journal Title

      Sci Reports

      Volume: 7-39994 Issue: 1

    • DOI

      10.1038/srep39994

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Abnormal RNA editing and treatment strategy in neurological diseases; towards cure for ALS2016

    • Author(s)
      山下雄也, 郭 伸
    • Journal Title

      生化学

      Volume: 88 Issue: 5 Pages: 600-608

    • DOI

      10.14952/SEIKAGAKU.2016.880600

    • ISSN
      0037-1017
    • Year and Date
      2016-10-25
    • Related Report
      2016 Research-status Report
  • [Journal Article] 特集 認知症・神経変性疾患の克服への挑戦 Ⅲ.新たな技術開発によるチャレンジ ALSの遺伝子治療─分子病態解明から治療へ2016

    • Author(s)
      山下雄也, 郭 伸
    • Journal Title

      生体の科学

      Volume: 67 Issue: 4 Pages: 323-328

    • DOI

      10.11477/mf.2425200462

    • ISSN
      0370-9531, 1883-5503
    • Year and Date
      2016-08-15
    • Related Report
      2016 Research-status Report
  • [Journal Article] The AMPA receptor antagonist perampanel robustly rescues amyotrophic lateral sclerosis (ALS) pathology in sporadic ALS model mice.2016

    • Author(s)
      Akamatsu M, Yamashita T, Hirose N, Teramoto S, Kwak S:
    • Journal Title

      Sci Rep

      Volume: 7-28649 Issue: 1

    • DOI

      10.1038/srep28649

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Anti-TIF1-γ antibody and cancer-associated myositis2016

    • Author(s)
      Hida A, Yamashita T, Kwak.S, et al
    • Journal Title

      Neurology

      Volume: 87 Issue: 3 Pages: 299

    • DOI

      10.1212/wnl.0000000000002863

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Deficient RNA-editing enzyme ADAR2 in an amyotrophic lateral sclerosis patient with a FUSP525L mutation2016

    • Author(s)
      Aizawa H, Hideyama T, Yamashita T, Kimura T, Suzuki N, Aoki M, Kwak S
    • Journal Title

      J Clin Neurosci

      Volume: 32 Pages: 128-129

    • DOI

      10.1016/j.jocn.2015.12.039

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Phosphorylated TDP-43 becomes resistant to cleavage by calpain: a regulatory role for phosphorylation in TDP-43 pathology of ALS/FTLD.2016

    • Author(s)
      Yamashita T, Teramoto S, Kwak S
    • Journal Title

      Neurosci Res

      Volume: 未定 Pages: 63-69

    • DOI

      10.1016/j.neures.2015.12.006

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 筋萎縮性側索硬化症-孤発性ALSモデルマウスを用いたALSの遺伝子治療法開発2016

    • Author(s)
      山下雄也, 郭 伸
    • Journal Title

      遺伝子医学 MOOK

      Volume: 30 Pages: 257-263

    • Related Report
      2016 Research-status Report
  • [Presentation] ALSにおいて発現が低下するADAR2遺伝子の発現をヒト脊髄運動神経にて制御しうる転写因子の探索2019

    • Author(s)
      廣瀬 直毅,寺本さやか,山下雄也,郭 伸
    • Organizer
      第42回日本神経科学大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] AMPA受容体サブユニット特異的RNAアプタマーによるALSモデルマウス(AR2)におけるALS病態の改善効果.2019

    • Author(s)
      赤松 恵, 山下雄也, 寺本さやか, Huang Zhen, 戸田達史, Niu Li,郭 伸
    • Organizer
      第42回日本神経科学大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Development of ALS therapy using AMPA receptor RNA aptamers.2018

    • Author(s)
      Akamatsu M, Yamashita T, Teramoto S, Huang, Z, Niu L, Kwak S
    • Organizer
      4th EAN Congress
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] RNA aptamer as a potential drug candidate for ALS - rescue of clinicopathologic ALS phenotype in model mice.2018

    • Author(s)
      Akamatsu M, Yamashita T, Teramoto S, Huang, Z, Niu L, Kwak S
    • Organizer
      Neurobiology of Disease
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] ADAR2-dependent A-to-I RNA editing in the extracellular linear and circular RNAs.2018

    • Author(s)
      Hosaka T, Yamashita T, Teramoto S, Hirose N, Tamaoka A, Kwak S
    • Organizer
      Neurobiology of Disease
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] ADAR2-mediated RNA editing of extracellular liner and circular RNAs: a potential biomarker of amyotrophic lateral sclerosis.2018

    • Author(s)
      Hosaka T, Yamashita T, Teramoto S, Hirose N, Tamaoka A, Kwak S
    • Organizer
      The 49th Annual Meeting Society for Neuroscience
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Target therapy for ALS with RNA aptamers - rescue of ALS phenotype resulting from loss of motor neurons with TDP-43 pathology in ALS model mice.2018

    • Author(s)
      Akamatsu M, Yamashita T, Teramoto S, Huang, Z, Niu L, Kwak S
    • Organizer
      The 49th Annual Meeting Society for Neuroscience
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] ADAR2-mediated A-to-I sites in extracellular RNAs as a biomarker of amyotrophic lateral sclerosis2018

    • Author(s)
      保坂孝史, 山下雄也, 寺本さやか, 廣瀬直樹, 玉岡晃, 郭伸
    • Organizer
      The 59th Annual Meeting of the Japanese Society of Neurology
    • Related Report
      2018 Research-status Report
  • [Presentation] ALSにおいて発現が低下するADAR2遺伝子の発現制御メカニズムのヒト運動ニューロン特異性,2018

    • Author(s)
      廣瀬直毅,寺本さやか,山下雄也,郭伸
    • Organizer
      第41回日本神経科学学会
    • Related Report
      2018 Research-status Report
  • [Presentation] SEARCH FOR ALS-ASSOCIATED EXTRACELLULAR RNA AS A BIOMARKER2017

    • Author(s)
      1.Takashi Hosaka, Takenari Yamashita, Naoki Hirose, Sayaka Teramoto, Akira Tamaoka, Shin Kwak
    • Organizer
      WCN2017: XXIII World Congress of Neurology
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] ROBUST BENEFICIAL EFFECTS OF A NON-COMPETITIVE AMPA RECEPTOR ANTAGONIST IN AN ALS MOUSE MODEL.2016

    • Author(s)
      Megumi Akamatsu, Takenari Yamashita, Sayaka Teramoto, Shin Kwak
    • Organizer
      The 27th International Symposium on ALS/MND .
    • Place of Presentation
      Convention Centre Dublin (Dublin Ireland)
    • Year and Date
      2016-12-08
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] A selective non-competitive AMPA receptor antagonist as a potential drug for sporadic amyotrophic lateral sclerosis (ALS) -rescue of motor dysfunctions and loss of motor neurons with TDP-43 pathology in ALS model mice.2016

    • Author(s)
      Megumi Akamatsu, Takenari Yamashita, Takashi Hosaka, Naoki Hirose, Sayaka Teramoto, Shin Kwak
    • Organizer
      Society for Neuroscience 2016.
    • Place of Presentation
      San Diego Convention Center(San Diego USA)
    • Year and Date
      2016-11-13
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Death of motor neurons caused by failure of GluA2 RNA editing was robustly rescued by a selective AMPA receptor antagonist in the mechanistic ALS model mice: a potential drug for sporadic amyotrophic lateral scleroses(ALS).2016

    • Author(s)
      Megumi Akamatsu, Takenari Yamashita, Takashi Hosaka, Naoki Hirose, Sayaka Teramoto, Shin Kwak
    • Organizer
      【4th RNA Metabolism in Neurological Disease】11th Brain Research Conference.
    • Place of Presentation
      Paradise Point(San Diego USA)
    • Year and Date
      2016-11-10
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 孤発性筋萎縮性側索硬化症の病因に基づいた特異治療法の確立.2016

    • Author(s)
      山下雄也, 赤松恵、寺本さやか、村松慎一, 相澤仁志, 郭伸
    • Organizer
      2015年度IBCグラント研究奨励金報告会
    • Place of Presentation
      中央大学駿河台記念館610教室(東京都文京区)
    • Year and Date
      2016-11-06
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] 筋萎縮性側索硬化症の分子標的治療.2016

    • Author(s)
      郭 伸, 山下 雄也, 赤松 恵, 寺本 さやか
    • Organizer
      第34回日本神経治療学会】特別プログラム「シンポジウム3」
    • Place of Presentation
      米子コンベンションセンター(鳥取県米子市)
    • Year and Date
      2016-11-03
    • Related Report
      2016 Research-status Report
    • Invited
  • [Remarks] 東京医科大学 郭研究室のホームページ

    • URL

      http://square.umin.ac.jp/teamkwak/

    • Related Report
      2019 Annual Research Report
  • [Remarks]

    • URL

      http://square.umin.ac.jp/teamkwak/

    • Related Report
      2018 Research-status Report
  • [Remarks] 東京大学大学院医学系研究科 郭 研究室

    • URL

      http://square.umin.ac.jp/teamkwak/

    • Related Report
      2017 Research-status Report
  • [Remarks] 筋萎縮性側索硬化症(ALS)の細胞死を引き起こすメカニズムを更に解明

    • URL

      http://www.m.u-tokyo.ac.jp/news/admin/release_20170103.pdf

    • Related Report
      2016 Research-status Report
  • [Remarks] 経口AMPA受容体拮抗剤による筋萎縮性側索硬化症(ALS)の治療法確立

    • URL

      http://www.m.u-tokyo.ac.jp/news/admin/release_20160628.pdf

    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2021-01-27  

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