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Establishment of TDP-43 C-terminal deficient mice using zinc finger nuclease and application to the model for amyotrophic lateral sclerosis

Research Project

Project/Area Number 25461271
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurology
Research InstitutionKitasato University (2014-2015)
Niigata University (2013)

Principal Investigator

SATO TOSHIYA  北里大学, 医学部, 教授 (90359703)

Co-Investigator(Kenkyū-buntansha) KODERA YOSHIO  北里大学, 理学部, 准教授 (60265733)
Co-Investigator(Renkei-kenkyūsha) ONODERA OSAMU  新潟大学, 脳研究所, 教授 (20303167)
Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsALS / TDP-43 / 疾患モデル / 脳神経疾患 / 発生・分化
Outline of Final Research Achievements

To investigate the physiological functions of the C-terminal region (CTR) of TDP-43, we established eight lines of CTR deficient mice using zinc finger nuclease. Mutant TDP-43 mice carrying a deletion within 6 amino acids in the middle of CTR (A) appeared normal even in the homozygote, whereas homozygous mice carrying a large deletion of the N- (B; 262-348) or C-terminal (C; 345-414) half of CTR showed embryonic lethality. In the brains of heterozygous B or C mice, a comparable level of the truncated protein corresponding to the large deletion was observed only in B mice. The truncated TDP-43 was exclusively in the cytoplasm fraction, thus it could not show physiological function in the nucleus. These results show N-terminal half of CTR is essential for maintaining nuclear function of TDP-43, whereas C-terminal half of CTR is important for the protein stability.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Research-status Report
  • 2013 Research-status Report
  • Research Products

    (11 results)

All 2015 2014 Other

All Journal Article (1 results) Presentation (10 results) (of which Invited: 2 results)

  • [Journal Article] TDP-43の生理的機能とALS病態における意義2015

    • Author(s)
      佐藤俊哉
    • Journal Title

      北里医学

      Volume: 45 Pages: 79-85

    • NAID

      40020708358

    • Related Report
      2015 Annual Research Report
  • [Presentation] TDP-43 C-terminal deficient mice exhibit a loss-of-function phenotype with up-regulated Tardbp mRNA.2015

    • Author(s)
      佐藤俊哉,小田佳奈子,酒井清子,西澤正豊,笹岡俊邦,小野寺理,横山峯介.
    • Organizer
      第5回新潟大学脳研究所共同研究拠点国際シンポジウム
    • Place of Presentation
      新潟大学脳研究所(新潟県・新潟市)
    • Year and Date
      2015-03-05 – 2015-03-06
    • Related Report
      2014 Research-status Report
  • [Presentation] 神経変性疾患モデルの開発を成功に導くために2015

    • Author(s)
      佐藤俊哉.
    • Organizer
      東海医学会例会
    • Place of Presentation
      東海大学医学部(神奈川県・伊勢原市)
    • Year and Date
      2015-02-12
    • Related Report
      2014 Research-status Report
    • Invited
  • [Presentation] 神経変性疾患モデルの開発を志して2014

    • Author(s)
      佐藤俊哉.
    • Organizer
      第31回動物生殖工学研究会
    • Place of Presentation
      北里本館(東京都・港区)
    • Year and Date
      2014-12-06
    • Related Report
      2014 Research-status Report
    • Invited
  • [Presentation] 人工ヌクレアーゼ技術による内在性TDP-43遺伝子改変と筋萎縮性側索硬化症モデルへの応用2014

    • Author(s)
      佐藤俊哉,小田佳奈子,酒井清子,西澤正豊,小野寺理,横山峯介,笹岡俊邦.
    • Organizer
      第44回新潟神経学夏期セミナー
    • Place of Presentation
      新潟大学脳研究所(新潟県・新潟市)
    • Year and Date
      2014-07-31 – 2014-08-02
    • Related Report
      2014 Research-status Report
  • [Presentation] 人工ヌクレアーゼ技術による内在性TDP-43遺伝子改変と筋萎縮性側索硬化症モデルへの応用2014

    • Author(s)
      佐藤俊哉,小田佳奈子,酒井清子,西澤正豊,小野寺理,横山峯介,笹岡俊邦.
    • Organizer
      第55回新潟生化学懇話会
    • Place of Presentation
      長岡技術科学大学 (新潟県・長岡市)
    • Year and Date
      2014-06-28
    • Related Report
      2014 Research-status Report
  • [Presentation] 人工制限酵素による内在性TDP-43遺伝子改変と筋萎縮性側索硬化症モデルへの応用

    • Author(s)
      佐藤俊哉,小田佳奈子,酒井清子,廣川祥子,永田史也,前田宜俊,藤澤信義,西澤正豊,小野寺理,横山峯介.
    • Organizer
      第54回日本神経学会学術大会
    • Place of Presentation
      東京国際フォーラム(東京都)
    • Related Report
      2013 Research-status Report
  • [Presentation] 人工制限酵素による内在性TDP-43遺伝子改変と筋萎縮性側索硬化症モデルへの応用

    • Author(s)
      佐藤俊哉,小田佳奈子,酒井清子,笹岡俊邦,西澤正豊,小野寺理,横山峯介.
    • Organizer
      第43回新潟神経学夏期セミナー
    • Place of Presentation
      新潟大学脳研究所統合脳機能研究センター(新潟県)
    • Related Report
      2013 Research-status Report
  • [Presentation] 人工制限酵素による内在性TDP-43遺伝子改変と筋萎縮性側索硬化症モデルへの応用

    • Author(s)
      佐藤俊哉,小田佳奈子,酒井清子,笹岡俊邦,西澤正豊,小野寺理,横山峯介.
    • Organizer
      第4回新潟大学脳研究所共同研究拠点国際シンポジウム
    • Place of Presentation
      新潟大学脳研究所統合脳機能研究センター(新潟県)
    • Related Report
      2013 Research-status Report
  • [Presentation] 人工制限酵素による内在性TDP-43遺伝子改変と筋萎縮性側索硬化症モデルへの応用

    • Author(s)
      佐藤俊哉,小田佳奈子,酒井清子,笹岡俊邦,横山峯介.
    • Organizer
      第2回新潟大学医学系基礎・臨床研究交流会
    • Place of Presentation
      新潟大学医学部大講義室(新潟県)
    • Related Report
      2013 Research-status Report
  • [Presentation] Analysis of the physiological function of TDP-43 using the C-terminal deficient mice established by zinc finger nuclease

    • Author(s)
      佐藤俊哉,小田佳奈子,酒井清子,西澤正豊,笹岡俊邦,小野寺理,横山峯介.
    • Organizer
      第36回日本分子生物学会年会
    • Place of Presentation
      神戸国際展示場(神戸)
    • Related Report
      2013 Research-status Report

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Published: 2014-07-25   Modified: 2019-07-29  

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