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Discovery of novel target and disease modifying therapy for ALS/FTLD using neuro-specific transcriptome analysis

Research Project

Project/Area Number 17K09753
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurology
Research InstitutionNagoya University

Principal Investigator

IGUCHI YOHEI  名古屋大学, 医学部附属病院, 助教 (80790659)

Co-Investigator(Kenkyū-buntansha) 勝野 雅央  名古屋大学, 医学系研究科, 教授 (50402566)
佐橋 健太郎  名古屋大学, 医学部附属病院, 病院助教 (90710103)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsALS / FTLD / TDP-43 / TBK1 / 筋萎縮性側索硬化症 / 前頭側頭葉変性症 / polysome解析
Outline of Final Research Achievements

ALS and FTLD are progressive neurodegenerative diseases and the causes are unknown. The genetic and neuropathological studies suggest that loss of functions of TDP-43 or TBK1 are related to the neurodegeneration. We established a novel transgenic mouse, in which GFP-tagged ribosomal protein (RPL10a) and Cre are expressed under synapsin promotor. This mouse allows us to perform neuron-specific polysome (mRNA-ribosome complex) in the conditional TDP-43/TBK1 knockout mice. We validated the expression profile of GFP-RPL10a of the transgenic mouse and analyzed the neuron-specific transcriptome data of the conditional knockout mice.

Academic Significance and Societal Importance of the Research Achievements

ALSとFTLDは上位・下位運動ニューロンや前頭側頭葉皮質のニューロンが選択的に変性する原因不明の神経変性疾患である。これらの疾患における神経変性病態を解明するにはニューロン特異的な解析が必須であるが、モデル動物において変性過程にあるニューロンの単離は非常に困難である。この問題を解決するために、Syn-Ribotag-Creマウスを作成した。このマウスと各floxマウスを交配することで特定の遺伝子をノックアウトしたニューロン特異的な遺伝子発現解析が可能となった。今後多くの神経変性疾患の病態解明に利用することができるため研究を発展させていきたい。

Report

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

    (14 results)

All 2020 2019 2018 2017

All Journal Article (5 results) (of which Peer Reviewed: 5 results,  Open Access: 2 results) Presentation (9 results) (of which Int'l Joint Research: 3 results,  Invited: 2 results)

  • [Journal Article] Characteristic Features of FUS Inclusions in Spinal Motor Neurons of Sporadic Amyotrophic Lateral Sclerosis.2020

    • Author(s)
      Ikenaka K, Ishigaki S, Iguchi Y, Kawai K, Fujioka Y, Yokoi S, Abdelhamid RF, Nagano S, Mochizuki H, Katsuno M, Sobue G.
    • Journal Title

      J Neuropathol Exp Neurol

      Volume: 79 Issue: 4 Pages: 370-377

    • DOI

      10.1093/jnen/nlaa003

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets2019

    • Author(s)
      Araki Kunihiko、(他10名)、Ishigaki Shinsuke、Nakamichi Yoko、Tsunekawa Shin、Seino Yusuke、Yamamoto Akiko、Takayama Yasunori、Hidaka Shihomi、Tominaga Makoto、Ohara-Imaizumi Mica、Suzuki Atsushi、Ishiguro Hiroshi、Enomoto Atsushi、Yoshida Mari、Arima Hiroshi、Muramatsu Shin-ichi、Sobue Gen、Katsuno Masahisa
    • Journal Title

      Journal of Clinical Investigation

      Volume: 129 Issue: 9 Pages: 3578-3593

    • DOI

      10.1172/jci124481

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Elevated serum creatine kinase in the early stage of sporadic amyotrophic lateral sclerosis.2019

    • Author(s)
      Ito D, Hashizume A, Hijikata Y, Yamada S, Iguchi Y, Iida M, Kishimoto Y, Moriyoshi H, Hirakawa A, Katsuno M.
    • Journal Title

      J Neurol.

      Volume: 266 Issue: 12 Pages: 2952-2961

    • DOI

      10.1007/s00415-019-09507-6

    • NAID

      120006786260

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Preclinical progression of neurodegenerative diseases.2018

    • Author(s)
      Katsuno M, Sahashi K, Iguchi Y, Hashizume A
    • Journal Title

      Nagoya J Med Sci

      Volume: 80 Pages: 289-298

    • NAID

      120006502462

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Altered tau isoform ratio caused by loss of Fus and Sfpq function leads to FTLD-like phenotypes2017

    • Author(s)
      Ishigaki S, Fujioka Y, Okada Y, Riku Y, Udagawa T, Honda D, Yokoi S, Endo K, Ikenaka K, Takagi S, Iguchi Y, Sahara N, Takashima A, Okano H, Yoshida M, Warita H, Aoki M, Watanabe H, Okado H, Katsuno H, Sobue G.
    • Journal Title

      Cell Reports

      Volume: 18 Issue: 5 Pages: 1118-1131

    • DOI

      10.1016/j.celrep.2017.01.013

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] TDP-43凝集におけるエンドソームの関わり2019

    • Author(s)
      井口洋平、高橋裕平、李佳益、荒木邦彦、井汲一尋、勝野雅央
    • Organizer
      第60回日本神経学会学術大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Filamin-A as a novel driver for progressive supra nuclear palsy2019

    • Author(s)
      Koyo Tsujikawa, kohei Hamanaka, Mari Yoshida, Kentaro Sahashi, Satoko Miyatake, Satomi Mihashi, Yohei Iguchi, Yuichi Riku, Shinsuke Ishigaki, Gen Sobue, Naomichi Matsumoto, Masahisa Katsuno
    • Organizer
      第60回日本神経学会学術大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Elevation of serum creatine kinase before the disease onset of amyotrophic lateral sclerosis2019

    • Author(s)
      Daisuke Ito, Atsushi Hashizume, Yasuhiro Hijikata, Shinichiro Yamada, Yoshiyuki Kishimoto, Hideyuki Moriyoshi, Yohei Iguchi, Madoka Iida, Masahisa Katsuno
    • Organizer
      第60回日本神経学会学術大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Role of late endosome in the formation of TDP-43 cytoplasmic aggregation2019

    • Author(s)
      Yuhei takahashi, Yohei Iguchi, Masahisa Katsuno
    • Organizer
      第42回日本神経科学大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Exosome pathway: a key for clearance of pathological TDP-432018

    • Author(s)
      Yohei Iguchi
    • Organizer
      第59回日本神経学会総会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Hereditary leukoencephalopathy with brain stem and spinal cord involvement2018

    • Author(s)
      井口 洋平, 熱田 直樹, 勝野 雅央
    • Organizer
      第59回日本神経学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Emerging roles of exosomes in TDP-43 proteinopathy2017

    • Author(s)
      Yohei Iguchi
    • Organizer
      第60回日本神経化学会大会
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Exosome secretion is a key pathway for clearance of pathological TDP-432017

    • Author(s)
      Yohei Iguchi
    • Organizer
      第40回日本神経科学大会
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] THE ROLE OF TDP-43 SECRETION IN ASSOCIATION WITH EXOSOMES2017

    • Author(s)
      Yohei Iguchi1, 2, Lara Eid1, Martin Parent1, Yuichi Riku2, Kaori Kawai, Mari Yoshida, Masahisa Katsuno, Gen Sobue, Jean-Pierre Julien
    • Organizer
      XXIII World Congress of Neurology
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research

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Published: 2017-04-28   Modified: 2021-02-19  

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