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Establishment of RNA-based Biomarkers for ALS

Research Project

Project/Area Number 17K09766
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurology
Research InstitutionJikei University School of Medicine

Principal Investigator

Okano Hirotaka James  東京慈恵会医科大学, 医学部, 教授 (90338020)

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: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
KeywordsALS / TDP-43 / 選択的スプライシング / RNA結合タンパク質 / 神経変性疾患 / バイオマーカー / RNA代謝
Outline of Final Research Achievements

We cloned and analyzed the promoter region of the TARDBP gene. TARDBP upstream sequences luciferase constructs were generated and their promoter activity was experimentally assessed. The upstream region predictably exhibited promoter activity and identified putative cis-acting elements, including the i-motif, was relevant for the regulation of TDP-43 expression. The cellular abundance of TDP-43 is strictly controlled, and its constancy is critically important for motor neuron survival. A machinery serving to maintain a constant level of TDP-43 is autoregulation via control of mRNA stability, a negative feedback system. We showed that TDP-43 negatively regulates the TARDBP promoter and, surprisingly, that disease-causing TDP-43 mutants lacked this regulatory activity. These results allowed the elucidation of a novel transcriptional autoregulatory mechanism of TDP-43 and quantification of the transcriptional activity could be a good biomarker to monitor the functional activity of TDP-43.

Academic Significance and Societal Importance of the Research Achievements

ALSは50~60代を中心とした成人の呼吸機能を含む運動機能を全廃に至らしめる最も悲惨な神経変性疾患の一つであるが、その発症原因はいまだ不明である。これまで多くの薬剤の臨床試験が行われてきたが、有効な治療薬の開発には至っていない。もしALSの発症早期に薬剤を投与し効果の判定ができれば、臨床試験で脱落した薬剤でさえ有効性が認められる可能性がある。しかし、ALSの早期診断を可能にするバイオマーカーが存在しないため早期治療介入は極めて難しい。優れたモデル動物が存在しない上、早期診断バイオマーカーが不在であることこそがALSの新規治療法開発を阻む原因であり、本計画で解決すべき課題であると考える。

Report

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

    (14 results)

All 2019 2018 2017 Other

All Int'l Joint Research (2 results) Journal Article (9 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 9 results,  Open Access: 7 results) Presentation (2 results) (of which Int'l Joint Research: 2 results,  Invited: 2 results) Book (1 results)

  • [Int'l Joint Research] Baylaor College of Medicine(米国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] The Rockefeller University(米国)

    • Related Report
      2017 Research-status Report
  • [Journal Article] In vivo regeneration of interspecies chimeric kidneys using a nephron progenitor cell replacement system2019

    • Author(s)
      Fujimoto Toshinari、Yamanaka Shuichiro、Tajiri Susumu、Takamura Tsuyoshi、Saito Yatsumu、Matsumoto Kei、Takase Kentaro、Fukunaga Shohei、Okano Hirotaka James、Yokoo Takashi
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 6965-6965

    • DOI

      10.1038/s41598-019-43482-2

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Anatomical and Surgical Evaluation of the Common Marmoset as an Animal Model in Hearing Research.2019

    • Author(s)
      Kurihara S, Fujioka M, Hata J, Yoshida T, Hirabayashi M, Yamamoto Y, Ogawa K, Kojima H, Okano HJ.
    • Journal Title

      Frontiers in Neuroanatomy

      Volume: 13 Pages: 60-60

    • DOI

      10.3389/fnana.2019.00060

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Neurite orientation dispersion and density imaging for evaluating the severity of neonatal hypoxic-ischemic encephalopathy in rats2019

    • Author(s)
      Ohki Akiko、Saito Shigeyoshi、Hata Junichi、Okano Hirotaka James、Higuchi Takahiro、Fukuchi Kazuki
    • Journal Title

      Magnetic Resonance Imaging

      Volume: 62 Pages: 214-219

    • DOI

      10.1016/j.mri.2019.07.013

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Elavl3 regulates neuronal polarity through the alternative splicing of an embryo-specific exon in AnkyrinG.2018

    • Author(s)
      Ogawa Y, Yamaguchi J, Yano M, Uchiyama Y, Okano HJ
    • Journal Title

      Neurosci Res.

      Volume: - Pages: 13-20

    • DOI

      10.1016/j.neures.2018.03.008

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Regenerative potential of induced pluripotent stem cells derived from patients undergoing haemodialysis in kidney regeneration2018

    • Author(s)
      Tajiri Susumu、Yamanaka Shuichiro、Fujimoto Toshinari、Matsumoto Kei、Taguchi Atsuhiro、Nishinakamura Ryuichi、Okano Hirotaka James、Yokoo Takashi
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 1-12

    • DOI

      10.1038/s41598-018-33256-7

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Loss of DDHD2, whose mutation causes spastic paraplegia, promotes reactive oxygen species generation and apoptosis2018

    • Author(s)
      Maruyama Tomohiro、Baba Takashi、Maemoto Yuki、Hara-Miyauchi Chikako、Hasegawa-Ogawa Minami、Okano Hirotaka James、Enda Yuki、Matsumoto Kei、Arimitsu Nagisa、Nakao Kazuki、Hamamoto Hiroshi、Sekimizu Kazuhisa、Ohto-Nakanishi Takayo、Nakanishi Hiroki、Tokuyama Takeshi、Yanagi Shigeru、Tagaya Mitsuo、Tani Katsuko
    • Journal Title

      Cell Death & Disease

      Volume: 9 Issue: 8 Pages: 797-811

    • DOI

      10.1038/s41419-018-0815-3

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Elavl3 is essential for the maintenance of Purkinje neuron axons2018

    • Author(s)
      Ogawa Yuki、Kakumoto Kyoko、Yoshida Tetsu、Kuwako Ken-ichiro、Miyazaki Taisuke、Yamaguchi Junji、Konno Ayumu、Hata Junichi、Uchiyama Yasuo、Hirai Hirokazu、Watanabe Masahiko、Darnell Robert B.、Okano Hideyuki、Okano Hirotaka James
    • Journal Title

      Sci Rep.

      Volume: 8 Issue: 1 Pages: 2722-2722

    • DOI

      10.1038/s41598-018-21130-5

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A Surgical Procedure for the Administration of Drugs to the Inner Ear in a Non-Human Primate Common Marmoset (Callithrix jacchus).2018

    • Author(s)
      Kurihara S, Fujioka M, Yoshida T, Koizumi M, Ogawa K, Kojima H, Okano HJ.
    • Journal Title

      Journal of Visualized Experiments

      Volume: 132 Issue: 132 Pages: 132-132

    • DOI

      10.3791/56574

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Generation of interspecies limited chimeric nephrons using a conditional nephron progenitor cell replacement system.2017

    • Author(s)
      Yamanaka S, Tajiri S, Fujimoto T, Matsumoto K, Fukunaga S, Kim BS, Okano HJ, Yokoo T.
    • Journal Title

      Nature Communications

      Volume: 8 Issue: 1 Pages: 1719-1732

    • DOI

      10.1038/s41467-017-01922-5

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Pathophysiological studies of familial Parkinson’s Disease PARK17 using iPSC technology2019

    • Author(s)
      Hirotaka James Okano
    • Organizer
      BRIMS International Neuroscience Symposium 2019 [Neurodegenerative Diseases & Brain Ageing]
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Pathophysiological consequences of Retromer dysfunction in Neurological Disorder2019

    • Author(s)
      Hirotaka James Okano
    • Organizer
      The 5th International Forum for Lysosomal Storage Diseases
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Book] The 3-Dimensional Atlas of the Marmoset Brain: Reconstructible in Stereotaxic Coordinates (Brain Science).2019

    • Author(s)
      Iriki A, Okano HJ, Sasaki E, Okano H.
    • Total Pages
      399
    • Publisher
      Springer
    • ISBN
      9784431566106
    • Related Report
      2019 Annual Research Report 2017 Research-status Report

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Published: 2017-04-28   Modified: 2022-02-21  

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