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Development of novel frontotemporal lobar degeneration model mice using genome editing.

Research Project

Project/Area Number 15K09850
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Psychiatric science
Research InstitutionTokyo Metropolitan Institute of Medical Science

Principal Investigator

HOSOKAWA Masato  公益財団法人東京都医学総合研究所, 認知症・高次脳機能研究分野, 主席研究員 (00435116)

Research Collaborator ARAI tetsuaki  
Project Period (FY) 2015-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
KeywordsTDP-43 / C9orf72 / ゲノム編集 / CRISPR-Cas9 / 病態モデル / 神経変性疾患 / モデル動物 / モデルマウス / 認知症 / Tau / CRISPR/Cas9
Outline of Final Research Achievements

Frontotemporal lobar degeneration (FTLD) patients present personality changes and aphasia due to loss of neurons in the frontal and temporal lobes. Among presenile dementias, FTLD is the second most frequent disease. In most FTLD cases, specific proteins form inclusion bodies in neurons and glial cells. TDP-43 and C9orf72 knock-in (KI) mice, which have been clarified in recent years as their main component proteins, were produced by genome editing technology, and the purpose was to develop model mice of FTLD. Although C9orf72-KI mice were not obtained within this research grant period, TDP-43-KI mice were successfully produced. Next, we will investigate whether it is possible to reproduce the same pathology as that of FTLD patient's brain.

Academic Significance and Societal Importance of the Research Achievements

本研究で作出されたTDP-43-KIマウスは、これまでのTDP-43過剰発現トランスジェニックマウスとは異なり、生理的なTDP-43発現レベルを維持している世界初のマウスである。このマウスを用いてTDP-43蓄積の病理機構を解析することが可能であると考えられる。また、このマウスを用いた前頭側頭葉変性症モデルへ、TDP-43の異常凝集を抑制する候補化合物を投与することにより、疾患に適用できる新たな薬剤開発をおこなうことができると期待される。

Report

(5 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (30 results)

All 2018 2017 2016 2015 2014 Other

All Journal Article (8 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 8 results,  Open Access: 5 results,  Acknowledgement Compliant: 1 results) Presentation (16 results) (of which Int'l Joint Research: 3 results,  Invited: 1 results) Remarks (6 results)

  • [Journal Article] Clinical features of behavioral variant of frontotemporal dementia useful for predicting underlying pathological subtypes of frontotemporal lobar degeneration2018

    • Author(s)
      Kobayashi Z, Arai T, Kawakami I, Yokota O, Hosokawa M, Oshima K, Niizato K, Shiraishi A, Akiyama H, Mizusawa H
    • Journal Title

      Psychogeriatrics

      Volume: 印刷中

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Progranulin haploinsufficiency reduces amyloid beta deposition in Alzheimer’s disease model mice2018

    • Author(s)
      Hosokawa M, Tanaka Y, Arai T, Kondo H, Akiyama H, Hasegawa M
    • Journal Title

      Experimental Animals

      Volume: 67 Issue: 1 Pages: 63-70

    • DOI

      10.1538/expanim.17-0060

    • NAID

      130006339997

    • ISSN
      0007-5124, 1341-1357, 1881-7122
    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Accumulation of multiple neurodegenerative disease-related proteins in familial frontotemporal lobar degeneration associated with granulin mutation2017

    • Author(s)
      Hosokawa M, Arai T. Kondo H. Serrano GE. Beach TG. Robinson AC. Mann DM. Akiyama H. Haesgawa M
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 1513-1513

    • DOI

      10.1038/s41598-017-01587-6

    • NAID

      120007129118

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes.2017

    • Author(s)
      Tanaka Y, Suzuki G, Matsuwaki T, Hosokawa M, Serrano G, Beach TG, Yamanouchi K, Hasegawa M, Nishihara M.
    • Journal Title

      Human Molecular Genetics

      Volume: 26 Pages: 969-988

    • DOI

      10.1093/hmg/ddx011

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] iPSC-based drug repositioning identifies Src/c-Abl as a therapeutic target for ALS motor neurons2017

    • Author(s)
      Imamura K, Izumi Y, 他24名, Hosokawa M, Akiyama H, Ayaki T, Ito H, Takahashi R, Yamanaka S, Inoue H
    • Journal Title

      Science Translational Medicine

      Volume: 9 Issue: 391 Pages: 391-391

    • DOI

      10.1126/scitranslmed.aaf3962

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] The Abundance of Nonphosphorylated Tau in Mouse and Human Tauopathy Brains Revealed by the Use of Phos-Tag Method2016

    • Author(s)
      Kimura T, Hatsuta H, Masuda-Suzukake M, Hosokawa M, Ishiguro K, Akiyama H, Murayama S, Hasegawa M, Hisanaga S
    • Journal Title

      American Journal of Pathology

      Volume: 186 Issue: 2 Pages: 398-409

    • DOI

      10.1016/j.ajpath.2015.10.009

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Chorea as a clinical feature of the basophilic inclusion body disease subtype of fused-in-sarcoma-associated frontotemporal lobar degeneration.2016

    • Author(s)
      Kawakami I, Kobayashi Z, Arai T, Yokota O, Nonaka T, Aoki N, Niizato K, Oshima K, Higashi S, Katsuse O, Hosokawa M, Hasegawa M, Akiyama H.
    • Journal Title

      Acta Neuropathol Commun

      Volume: 4 Issue: 1 Pages: 36-36

    • DOI

      10.1186/s40478-016-0304-9

    • NAID

      120007135517

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] An autopsied case of corticobasal degeneration showing severe cerebral atrophy over a protracted disease course of 16 years2014

    • Author(s)
      Kondo D, Hino H, Shibuya K, Fujisawa K, Kosaka K, Hirayasu Y, Yamamoto R, Kasanuki K, Minegishi M, Sato K, Hosokawa M, Arai T, Arai H, Iseki E
    • Journal Title

      Neuropathology

      Volume: Epub ahead of print Issue: 3 Pages: 280-288

    • DOI

      10.1111/neup.12188

    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Presentation] タウのプリオン様伝播モデル2018

    • Author(s)
      細川雅人
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] タウのプリオン様伝播モデルマウスの作製2017

    • Author(s)
      細川雅人、下沢明希、鈴掛雅美、新井哲明、設楽浩志、長谷川成人
    • Organizer
      第1回伝播性タンパク研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] TDP-43 proteinopathyモデルマウスの作製2017

    • Author(s)
      細川雅人、新井哲明、野中隆、亀谷富由樹、近藤ひろみ、秋山治彦、長谷川成人
    • Organizer
      第47回日本神経精神薬理学会
    • Related Report
      2017 Research-status Report
  • [Presentation] プログラニュリンのハプロ不全はADモデルマウスにおけるAβの蓄積を減少する2017

    • Author(s)
      細川雅人、田中良法、新井哲明、近藤ひろみ、秋山治彦、長谷川成人
    • Organizer
      第36回日本認知症学会
    • Related Report
      2017 Research-status Report
  • [Presentation] TDP-43 proteinopathyモデルマウスの作製2017

    • Author(s)
      細川雅人、新井哲明、野中隆、亀谷富由樹、近藤ひろみ、秋山治彦、長谷川成人
    • Organizer
      2017年度 生命科学系学会合同年会 (ConBio2017)
    • Related Report
      2017 Research-status Report
  • [Presentation] グラニュリン変異脳における神経変性疾患関連タンパクの重複蓄積2017

    • Author(s)
      細川雅人、長谷川成人、小久保康昌
    • Organizer
      日本医療研究開発機構研究費(難治性疾患実用化研究事業)紀伊ALS/PDC診療ガイドラインの作製と臨床研究の推進班 平成28年度班会議
    • Place of Presentation
      愛知県産業労働センター(愛知県名古屋市)
    • Related Report
      2016 Research-status Report
  • [Presentation] TDP-43 proteinopathyモデルマウスの作製2017

    • Author(s)
      細川雅人、新井哲明、野中隆、亀谷富由樹、近藤ひろみ、秋山治彦、長谷川成人
    • Organizer
      第137回 日本薬学会
    • Place of Presentation
      仙台国際センター(宮城県仙台市)
    • Related Report
      2016 Research-status Report
  • [Presentation] グラニュリン変異脳における神経変性疾患関連タンパクの重複蓄積2016

    • Author(s)
      細川雅人
    • Organizer
      第1回 プログラニュリン研究会
    • Place of Presentation
      岐阜大学サテライトキャンパス(岐阜県岐阜市)
    • Related Report
      2016 Research-status Report
  • [Presentation] グラニュリン変異脳における神経変性疾患関連タンパクの重複蓄積2016

    • Author(s)
      細川雅人、新井哲明、近藤ひろみ、長谷川成人、秋山治彦
    • Organizer
      第46回 日本神経精神薬理学会
    • Place of Presentation
      ソウル(韓国)
    • Related Report
      2016 Research-status Report
  • [Presentation] Multiple accumulation of neurodegenerative disease-related proteins in familial granulin mutation brains2016

    • Author(s)
      Hosokawa M, Arai T, Kondo H, Serrano GE, Beach TG, Hasegawa M, Akiyama H
    • Organizer
      30th CINP World Congress of Neuropsychopharmacology
    • Place of Presentation
      ソウル(韓国)
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Phosphorylated tau and α-synuclein accumulation in familial granulin mutation cases2016

    • Author(s)
      Hosokawa M, Arai T, Kondo H, Serrano GE, Beach TG, Hasegawa M, Akiyama H
    • Organizer
      Alzheimer's Association International Conference 2016
    • Place of Presentation
      トロント(カナダ)
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Multiple accumulation of neurodegenerative disease-related proteins in familial granulin mutation brains2016

    • Author(s)
      Hosokawa M, Arai T, Kondo H, Serrano GE, Beach TG, Hasegawa M, Akiyama H
    • Organizer
      10th International Conference on Frontotemporal Dementias
    • Place of Presentation
      ミュンヘン(ドイツ)
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] TDP-43 proteinopathyモデルマウスの作製2016

    • Author(s)
      細川雅人、新井哲明、野中隆、亀谷富由樹、近藤ひろみ、秋山治彦、長谷川成人
    • Organizer
      第35回 日本認知症学会
    • Place of Presentation
      東京国際フォーラム(東京都千代田区)
    • Related Report
      2016 Research-status Report
  • [Presentation] グラニュリン変異例における神経変性疾患関連タンパクの重複蓄積2015

    • Author(s)
      細川雅人、新井哲明、近藤ひろみ、長谷川成人、秋山治彦
    • Organizer
      異常タンパク伝播仮説に基づく神経疾患の画期的治療法の開発 平成27年度 成果報告会
    • Place of Presentation
      東京都医学総合研究所(東京都・世田谷区)
    • Year and Date
      2015-12-17
    • Related Report
      2015 Research-status Report
  • [Presentation] プログラニュリン変異脳における神経変性疾患関連タンパク質の重複蓄積2015

    • Author(s)
      細川雅人、新井哲明、近藤ひろみ、長谷川成人、秋山治彦
    • Organizer
      第34回 日本認知症学会
    • Place of Presentation
      リンクステーションホール青森(青森県・青森市)
    • Year and Date
      2015-10-02
    • Related Report
      2015 Research-status Report
  • [Presentation] The abundance of nonphosphorylated tau among heterogeneously phosphorylated tau species in vivo in mice and human brains2015

    • Author(s)
      木村妙子、初田裕幸、鈴掛-増田雅美、細川雅人、石黒幸一、秋山治彦、村山繁雄、長谷川成人、久永眞市
    • Organizer
      第58回 日本神経化学会大会
    • Place of Presentation
      大宮ソニックシティ(埼玉県・さいたま市)
    • Year and Date
      2015-09-13
    • Related Report
      2015 Research-status Report
  • [Remarks] 東京都医学総合研究所 認知症プロジェクト

    • URL

      http://www.igakuken.or.jp/project/detail/dementia.html

    • Related Report
      2018 Annual Research Report
  • [Remarks] 公益財団法人東京都医学総合研究所 ホームページ

    • URL

      http://www.igakuken.or.jp/

    • Related Report
      2017 Research-status Report
  • [Remarks] 公益財団法人東京都医学総合研究所ホームページ

    • URL

      http://www.igakuken.or.jp/

    • Related Report
      2016 Research-status Report
  • [Remarks] 日本認知症学会 学会奨励賞(基礎研究部門)を受賞

    • URL

      http://www.igakuken.or.jp/topics/2015/1003.html

    • Related Report
      2016 Research-status Report
  • [Remarks] 公益財団法人東京都医学総合研究所

    • URL

      http://www.igakuken.or.jp/

    • Related Report
      2015 Research-status Report
  • [Remarks] 平成27年度日本認知症学会 学会奨励賞(基礎研究部門)を受賞

    • URL

      http://www.igakuken.or.jp/topics/2015/1003.html

    • Related Report
      2015 Research-status Report

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Published: 2015-04-16   Modified: 2020-03-30  

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