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Identifying drug targets for neuropsychiatric and neurodevelopmental disorders via brain transcriptome

Research Project

Project/Area Number 21K07820
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionKobe University

Principal Investigator

NOMURA Jun  神戸大学, 医学研究科, 学内講師 (70406528)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Keywords神経発達症 / 疾患モデル / 染色体操作 / コピー数多型/CNV / 自閉症 / 統合失調症 / 電気生理 / オルガノイド / コピー数変異 / ヒトES細胞 / 幹細胞生物学 / 神経生理 / シングルセル解析 / コピー数多型 / 神経発達 / 神経発達障害 / 精神疾患 / 次世代シーケンサー
Outline of Research at the Start

染色体レベルの変異はヒト遺伝学研究から様々な疾患との相関が示唆されている.このうち,1q21.1は,「コピー数の違い」が「異なる精神疾患」と相関するユニークな領域である(欠失:統合失調症,重複:自閉症).すなわち,本領域を研究対象とするメリットは,『多因子が発症に関与する統合失調症と自閉症の違いを一因子(コピー数)からシンプルに比較・考察する事が可能』という点にある.本研究は,申請者らがヒトES細胞を基に作製した1q21.1領域の欠失/重複モデル細胞を基に,脳オルガノイドを作製する事で,『脳内全細胞を対象とした統合失調症と自閉症のバイオマーカーの同定』を試みる.

Outline of Final Research Achievements

Chromosome 1q21.1 is a region containing approximately 1 Mb and 8 genes, and has been reported to be associated with schizophrenia, attention deficit hyperactivity disorder (ADHD), and autism. In this study, we generated human embryonic stem (ES) cells with a deletion of 1q21.1 (1q21.1del) and a duplication of 1q21.1 (1q21.1dup) as disease models of this chromosomal region and analyzed their phenotypes. dup cells showed a tendency toward anti-neuronal differentiation, i.e., a strong retention of stem cell characteristics. In addition, electrophysiological characteristics of these showed a marked increase in spike and burst frequency in both types of neurons compared to control cells.

Academic Significance and Societal Importance of the Research Achievements

1q21.1染色体領域は,統合失調症,ADHD,自閉症等様々な精神疾患,神経発達症との相関が示唆されているにもかかわらず,疾患に至るメカニズムが不明であった.今回,疾患の基盤と考えられる脳内神経細胞および神経幹細胞の表現型を明らかにすべく,(1q21.1欠失および重複)細胞モデルを作製,モデルを用いた疾患表現型解析を実施した.神経幹細胞では1q21.1欠失で易神経分化,1q21.1重複では抗神経分化特性と真逆の表現型を認めた一方,電気生理特性はともに発火頻度が高いという結果が得られた.細胞モデルというシンプルなモデルのメリットを生かし,1q21.1領域が直接関与する疾患表現型を明らかとした.

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (18 results)

All 2023 2022 2021

All Journal Article (8 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 5 results,  Open Access: 6 results) Presentation (10 results) (of which Int'l Joint Research: 2 results,  Invited: 3 results)

  • [Journal Article] Germ‐cell‐specific transcriptome analysis illuminates the chromatin and ubiquitin pathway in autism spectrum disorders2023

    • Author(s)
      Furukawa Sawako、Nomura Jun、Hanafusa Hiroaki、Maegawa Hiroko、Takumi Toru
    • Journal Title

      Autism Research

      Volume: 16 Issue: 6 Pages: 1101-1110

    • DOI

      10.1002/aur.2939

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Germ-cell-specific transcriptome analysis illuminates the chromatin and ubiquitin pathway in autism spectrum disorders2023

    • Author(s)
      Furukawa S, Nomura J, Hanafusa H, Maegawa H, Takumi T.
    • Journal Title

      Autism Research

      Volume: -

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] A common pathologic mechanism across cellular origins underlies systemic immune dysregulation in an idiopathic autism mouse model.2022

    • Author(s)
      Lin C-W, Septyaningtrias DE, Chao H-W, Konda M, Atarashi K, Takeshita K, Tamada K, Nomura J, Sassagawa Y, Tanaka K, Nikaido I, Honda K, McHugh TL, Takumi T
    • Journal Title

      Mol Psychiatr

      Volume: in press Issue: 8 Pages: 3343-3354

    • DOI

      10.1038/s41380-022-01566-y

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] シングルセル,オルガノイド研究による細胞腫特異的自閉症リスク因子の同定2022

    • Author(s)
      Nomura J, Takumi T.
    • Journal Title

      日本生物学的精神医学会誌

      Volume: 33 Pages: 48-52

    • Related Report
      2022 Research-status Report
    • Open Access
  • [Journal Article] Autism in a dish: ES cell models of autism with copy number variations reveal cell-type-specific vulnerability2022

    • Author(s)
      Nomura Jun、Zuko Amila、Kishimoto Keiko、Mutsumine Hiroaki、Fukatsu Kazumi、Nomura Yoshiko、Liu Xiaoxi、Nakai Nobuhiro、Takahashi Eiki、Kouno Tsukasa、Shin Jay W.、Takumi Toru、ES library team
    • Journal Title

      BioRxiv

      Volume: -

    • DOI

      10.1101/2022.02.02.478766

    • Related Report
      2021 Research-status Report
    • Open Access / Int'l Joint Research
  • [Journal Article] Reciprocal differentiation via GABAergic components and ASD-related phenotypes in hES with 1q21.1 CNV2021

    • Author(s)
      Nomura Yoshiko、Nomura Jun、Nishikawa Toru、Takumi Toru
    • Journal Title

      BioRxiv

      Volume: -

    • DOI

      10.1101/2021.09.13.460033

    • Related Report
      2021 Research-status Report
    • Open Access
  • [Journal Article] Molecular signatures from multi-omics of autism spectrum disorders and schizophrenia.2021

    • Author(s)
      Nomura J, Mardo M, Takumi T
    • Journal Title

      J Neurochem

      Volume: 159 Issue: 4 Pages: 647-659

    • DOI

      10.1111/jnc.15514

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Transcriptome analysis of human neural cells derived from isogenic embryonic stem cells with 16p11.2 deletion2021

    • Author(s)
      Nomura Yoshiko、Nomura Jun、Kamiguchi Hiroyuki、Nishikawa Toru、Takumi Toru
    • Journal Title

      Neuroscience Research

      Volume: N/A Pages: 114-123

    • DOI

      10.1016/j.neures.2021.03.005

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Presentation] Autism in a Dish.2023

    • Author(s)
      NOMURA, J., TAKUMI, T.
    • Organizer
      The 64th Annual Meeting of the Japanese Society of Neuropathology, The 66th Annual Meeting of the Japanese Society for Neurochemistry
    • Related Report
      2023 Annual Research Report
  • [Presentation] Brain Science of Neurodevelopmental Disorders.,2023

    • Author(s)
      NOMURA, J., TAKUMI, T.
    • Organizer
      The 11thCongress of The Asian Society for Child and Adolescent Psychiatry & Allied Professions (ASCAPAP).
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 神経発達症と相関する染色体領域改変マウスの表現型解析2023

    • Author(s)
      野村淳, 内匠透
    • Organizer
      科学技術振興機構 ムーンショット型研究開発事業目標9: 第2回マウスの会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 細胞モデルを用いた結節性硬化症の病態シグナル解析2023

    • Author(s)
      野村淳, 内匠透,
    • Organizer
      第11回日本結節性硬化症学会総会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] ES cell models of autism with copy number variations reveal cell-type-specific vulnerability,2023

    • Author(s)
      野村淳
    • Organizer
      The 7th NSN Kobe (Neuroscience Network in Kobe) Research Seminar
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Autism in a dish: ES cell models of autism with copy number variations reveal cell-type-specific vulnerability2023

    • Author(s)
      Nomura J. Takumi T
    • Organizer
      The 2nd International Symposium Multiscale Brain / MCCS-Asia
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] ES cell models of autism with copy number variations reveal cell-type-specific vulnerability2023

    • Author(s)
      Nomura J.
    • Organizer
      The 1st NSN (Neuroscience Network in Kobe) Research Seminar 2023
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] Autism in a dish., Comprehensive analysis identified CNV- and cell type specific vulnerability of autism spectrum disorder.2023

    • Author(s)
      Nomura J, Takumi T.
    • Organizer
      第4回理化学研究所BDR・神戸大学合同シンポジウム
    • Related Report
      2022 Research-status Report
  • [Presentation] Nomura J. Takumi T.2023

    • Author(s)
      シングルセル解析による細胞種特異的自閉症リスク因子の同定
    • Organizer
      令和4年度シグナル伝達医学研究展開センター研究発表会
    • Related Report
      2022 Research-status Report
  • [Presentation] Nomura J. Takumi T.2022

    • Author(s)
      シングルセル解析による自閉症リスク因子・パスウェイの同定
    • Organizer
      BPCNPNPPP4学会(日本神経精神薬理学会/日本生物学的精神医学会/日本臨床精神神経薬理学会/日本精神薬学会)合同年会
    • Related Report
      2022 Research-status Report

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Published: 2021-04-28   Modified: 2025-01-30  

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