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Investigation of cellular/molecular pathophysiology of brain disorders using human brain organoids established from iPS cells

Research Project

Project/Area Number 16K06996
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurophysiology / General neuroscience
Research InstitutionKumamoto University

Principal Investigator

Numakawa Tadahiro  熊本大学, 発生医学研究所, 特定事業研究員 (40425690)

Research Collaborator ODAKA HARUKI  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
KeywordsiPS細胞 / 大脳皮質 / 脳疾患 / 神経細胞 / オルガノイド / iPS / 神経科学 / 脳神経疾患
Outline of Final Research Achievements

Although studies using neurons obtained from animals including rats or mice are very useful to examine the cellular/molecular basis of brain disorders, models using human neurons established from iPSCs are much more suitable for investigating the pathophysiology of brain disease. In this study, dissociated human neurons and brain organoids made using iPSCs (healthy, maple syrup urine disease, propionic academia, and adrenoleukodystrophy) were established. Interestingly, disease human neurons (from iPSC of maple syrup urine disease or propionic academia) showed a significant decrease in the system of neurotransmitter release. Furthermore, it was revealed that brain organoids of maple syrup urine disease exhibited an immaturity in the neuronal differentiation.

Academic Significance and Societal Importance of the Research Achievements

これまでの脳研究では、生きたヒト脳を使用することは極めて困難であったため、動物個体レベルもしくは動物脳より分散させた初代培養ニューロンを用いたアプローチが主であった。本研究では、これまでの動物を用いた研究の弱点を克服するiPS細胞由来のヒトニューロンを用いて、メープルシロップ尿症、副腎白質ジストロフィー、およびプロピオン酸血症などの有効な治療法がみつかっていない疾患において、細胞・分子レベルでの病態解析に成功した。特に、メープルシロップ尿症やプロピオン酸血症では、機能的ニューロンにおいて、それぞれ固有の脆弱性を発見し、これが今後の病態解明および新規薬剤スクリーニングに役立つ可能性を示した。

Report

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

    (11 results)

All 2018 2017 2016

All Journal Article (8 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 8 results,  Open Access: 5 results,  Acknowledgement Compliant: 2 results) Presentation (3 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Basic fibroblast growth factor increased glucocorticoid receptors in cortical neurons through MAP kinase pathway2018

    • Author(s)
      Numakawa Tadahiro、Odaka Haruki、Adachi Naoki、Chiba Shuichi、Ooshima Yoshiko、Matsuno Hitomi、Nakajima Shingo、Yoshimura Aya、Fumimoto Kazuhiro、Hirai Yohei、Kunugi Hiroshi
    • Journal Title

      Neurochemistry International

      Volume: 118 Pages: 217

    • DOI

      10.1016/j.neuint.2018.06.009

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Actions of Brain-Derived Neurotrophin Factor in the Neurogenesis and Neuronal Function, and Its Involvement in the Pathophysiology of Brain Diseases2018

    • Author(s)
      Numakawa Tadahiro、Odaka Haruki、Adachi Naoki
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 19 Issue: 11 Pages: 3650-3650

    • DOI

      10.3390/ijms19113650

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Sox2 promoter-driven CD63-GFP transgenic rat model allows tracking of neural stem cell-derived extracellular vesicles2018

    • Author(s)
      Yoshimura A., Adachi N., Matsuno H., Kawamata M., Yoshioka Y., Kikuchi H., Odaka H., Numakawa T., Kunugi H., Ochiya T.* & Tamai Y.
    • Journal Title

      Disease Models & Mechanisms

      Volume: 11 Issue: 1 Pages: 028779-028779

    • DOI

      10.1242/dmm.028779

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Actions of Brain-Derived Neurotrophic Factor and Glucocorticoid Stress in Neurogenesis.2017

    • Author(s)
      Numakawa T.*, Odaka H. & Adachi N.
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 18 Issue: 11 Pages: 2312-2312

    • DOI

      10.3390/ijms18112312

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impact of glucocorticoid on neurogenesis.2017

    • Author(s)
      Odaka H., Adachi N. & Numakawa T.
    • Journal Title

      Neural Regeneration Research

      Volume: 12 Issue: 7 Pages: 1028-1035

    • DOI

      10.4103/1673-5374.211174

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Generation of a novel transgenic rat model for tracing extracellular vesicles in body fluids2016

    • Author(s)
      Yoshimura A, Kawamata M, Yoshioka Y, Katsuda T, Kikuchi H, Nagai Y, Adachi N, Numakawa T, Kunugi H, Ochiya T, Tamai Y.
    • Journal Title

      Scientific Reports

      Volume: 6 Issue: 1 Pages: 31172-31172

    • DOI

      10.1038/srep31172

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Chronic glucocorticoid exposure suppressed the differentiation and survival of embryonic neural stem/progenitor cells: Possible involvement of ERK and PI3K/Akt signaling in the neuronal differentiation2016

    • Author(s)
      Odaka H, Numakawa T, Yoshimura A, Nakajima S, Adachi N, Ooshima Y, Inoue T, Kunugi H.
    • Journal Title

      Neuroscience Research

      Volume: 113 Pages: 28

    • DOI

      10.1016/j.neures.2016.07.002

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Negative regulation of microRNA-132 in expression of synaptic proteins in neuronal differentiation of embryonic neural stem cells2016

    • Author(s)
      Aya Yoshimura, Tadahiro Numakawa, Haruki Odaka, Naoki Adachi, Yoshitaka Tamai, Hiroshi Kunugi
    • Journal Title

      Neurochemistry International

      Volume: 97 Pages: 26

    • DOI

      10.1016/j.neuint.2016.04.013

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] SIALIDOSIS NEURONS FROM PATIENT-DERIVED INDUCED PLURIPOTENT STEM CELL EXHIBIT SYNAPTIC DYSFUNCTION2018

    • Author(s)
      Haruki Odaka, Tadahiro Numakawa, Minami Soga, Jun Kido, Ryutaro Kajihara, Toshika Okumiya, Hirokazu Furuya, Takafumi Inoue, Takumi Era
    • Organizer
      ISSCR 2018 - The International Society of Stem Cell Research Annual Meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ゴーシェー病II 型患者由来のiPS 細胞を使用した薬剤スクリーニングシステムの開発2017

    • Author(s)
      城戸 淳、沼川 忠広、松本 志郎、小高 陽樹、曽我 美南、梶原 隆太郎、 遠藤 文夫、中村 公俊、江良 択実
    • Organizer
      第59回日本先天性代謝異常学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] シアリドーシス患者iPS 細胞を用いた神経障害の病理学的解析2017

    • Author(s)
      小髙 陽樹、沼川 忠広、曽我 美南、城戸 淳、梶原 隆太郎、奥宮 敏可、古谷博和、井上 貴文、江良 択実
    • Organizer
      第59回日本先天性代謝異常学会総会
    • Related Report
      2017 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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