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Constructive understanding of bipolar disorder and schizophrenia by transomics and modeling

Planned Research

Project AreaConstructive understanding of multi-scale dynamism of neuropsychiatric disorders
Project/Area Number 18H05435
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionJuntendo University (2020-2022)
Institute of Physical and Chemical Research (2018-2019)

Principal Investigator

加藤 忠史  順天堂大学, 医学部, 教授 (30214381)

Co-Investigator(Kenkyū-buntansha) 石川 充  慶應義塾大学, 医学部(信濃町), 特任講師 (10613995)
吉川 武男  国立研究開発法人理化学研究所, 脳神経科学研究センター, チームリーダー (30249958)
Project Period (FY) 2018-06-29 – 2023-03-31
Project Status Granted (Fiscal Year 2022)
Budget Amount *help
¥171,470,000 (Direct Cost: ¥131,900,000、Indirect Cost: ¥39,570,000)
Fiscal Year 2022: ¥34,580,000 (Direct Cost: ¥26,600,000、Indirect Cost: ¥7,980,000)
Fiscal Year 2021: ¥33,670,000 (Direct Cost: ¥25,900,000、Indirect Cost: ¥7,770,000)
Fiscal Year 2020: ¥33,670,000 (Direct Cost: ¥25,900,000、Indirect Cost: ¥7,770,000)
Fiscal Year 2019: ¥36,530,000 (Direct Cost: ¥28,100,000、Indirect Cost: ¥8,430,000)
Fiscal Year 2018: ¥33,020,000 (Direct Cost: ¥25,400,000、Indirect Cost: ¥7,620,000)
Keywords統合失調症 / 双極性障害 / iPS細胞 / 視床室傍核 / ミトコンドリアDNA / カルシウム / トランスクリプトーム解析
Outline of Annual Research Achievements

令和2年度は、双極性障害と腎疾患を合併する家系で見出されたNtrk1 E492K変異を再現した脳特異的コンディショナルノックインマウスを作製し、行動解析を行うと共に、患者iPS細胞由来神経細胞の解析を行った。その結果、Ntrk1変異を持つマウスは、アセチルコリンエステラーゼ阻害薬によりうつ様行動を示し、海馬神経細胞の樹状突起の分枝が減少していた。変異を持つ患者由来の神経細胞でも、神経突起伸展が減少していた。また、変異Polgトランスジェニックマウスの視床室傍核および対照脳領域において、次世代シーケンサーを用いたミトコンドリアDNA解析法を確立し、解析を行い、ミトコンドリアDNA(mtDNA)欠失のサイズが二峰性の分布を示すことを明らかにし、これが短いmtDNAの速い複製速度と大欠失mtDNAを持つミトコンドリアの選択的排除という2つのメカニズムで説明できることを数理モデリングにより明らかにした。また、双極型統合失調感情障害に関して不一致な一卵性双生児ペアよりiPS細胞を樹立して、脳オルガノイドを作成して、シングルセルRNAシーケンスを行ったところ、GABAニューロンへの分化が促進していること、大脳皮質様構造が小さいことなどを見出し、その原因としてWntシグナリングの関与を見出した。統合失調症患者の死後脳の脳梁(白質)と前頭葉(灰白質)の脂質分析を行い、統合失調症患者の脳梁においてスフィンゴ脂質の一種であるsphingosine-1-phosphate (S1P)の含量が低下していることを明らかにした。S1Pの低下は、大うつ病や双極性障害の患者死後脳では見られなかった。また、対照群と比較して統合失調症患者脳梁でS1Pの分解酵素および受容体の遺伝子発現が上昇していることも明らかにした。

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

予定した計画を着実に遂行した。

Strategy for Future Research Activity

これまで、統合失調症のiPS細胞研究を担当してきた分担研究者の吉川武男氏が、定年退職となったため、iPS細胞研究のエキスパートである石川充氏に新たに分担研究者として加わっていただき、iPS細胞を用いた病態解明を進めて行く予定である。

Report

(3 results)
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • 2018 Annual Research Report

Research Products

(12 results)

All 2021 2020 2019 Other

All Int'l Joint Research (2 results) Journal Article (9 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 9 results,  Open Access: 9 results) Remarks (1 results)

  • [Int'l Joint Research] University of California San Diego/Lieber Institute for Brain Development,/University of Southern California(米国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] University of Melbourne/Swinburne University(オーストラリア)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Identification and functional characterization of the extremely long allele of the serotonin transporter-linked polymorphic region.2021

    • Author(s)
      1.Ikegame T, Hidaka Y, Nakachi Y, Murata Y, Watanabe R, Sugawara H, Asai T, Kiyota E, Saito T, Ikeda M, Sasaki T, Hashimoto M, Ishikawa T, Takebayashi M, Iwata N, Kakiuchi C, Kato T, Kasai K, Bundo M, Iwamoto K
    • Journal Title

      Transl Psychiatry.

      Volume: 11;11(1) Issue: 1 Pages: 119-119

    • DOI

      10.1038/s41398-021-01242-9

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Unbiased PCR-free spatio-temporal mapping of the mtDNA mutation spectrum reveals brain region-specific responses to replication instability2020

    • Author(s)
      Bagge Emilie Kristine、Fujimori-Tonou Noriko、Kubota-Sakashita Mie、Kasahara Takaoki、Kato Tadafumi
    • Journal Title

      BMC Biology

      Volume: 18 Issue: 1 Pages: 150-150

    • DOI

      10.1186/s12915-020-00890-5

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ntrk1 mutation co-segregating with bipolar disorder and inherited kidney disease in a multiplex family causes defects in neuronal growth and depression-like behavior in mice2020

    • Author(s)
      Nakajima Kazuo、Miranda Alannah、Craig David W.、Shekhtman Tatyana、Kmoch Stanislav、Bleyer Anthony、Szelinger Szabolcs、Kato Tadafumi、Kelsoe John R.
    • Journal Title

      Translational Psychiatry

      Volume: 10 Issue: 1 Pages: 407-407

    • DOI

      10.1038/s41398-020-01087-8

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Promoter Activity-Based Case-Control Association Study on SLC6A4 Highlighting Hypermethylation and Altered Amygdala Volume in Male Patients With Schizophrenia2020

    • Author(s)
      Ikegame T, Bundo M, Okada N, Murata Y, Koike S, Sugawara H, Saito T, Ikeda M, Owada K, Fukunaga M, Yamashita F, Koshiyama D, Natsubori T, Iwashiro N, Asai T, Yoshikawa A, Nishimura F, Kawamura Y, Ishigooka J, Kakiuchi C, Sasaki T, Abe O, Hashimoto R, Iwata N, Yamasue H, Kato T, Kasai K, Iwamoto K
    • Journal Title

      Schizophrenia Bulletin

      Volume: 46 Issue: 6 Pages: 1577-1586

    • DOI

      10.1093/schbul/sbaa075

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Developmental excitation-inhibition imbalance underlying psychoses revealed by single-cell analyses of discordant twins-derived cerebral organoids2020

    • Author(s)
      Sawada Tomoyo、Chater Thomas E.、Sasagawa Yohei、Yoshimura Mika、Fujimori-Tonou Noriko、Tanaka Kaori、Benjamin Kynon J. M.、Paquola Apu C. M.、Erwin Jennifer A.、Goda Yukiko、Nikaido Itoshi、Kato Tadafumi
    • Journal Title

      Molecular Psychiatry

      Volume: 25 Issue: 11 Pages: 2695-2711

    • DOI

      10.1038/s41380-020-0844-z

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Establishment of Quantitative PCR Assays for Active Long Interspersed Nuclear Element-1 Subfamilies in Mice and Applications to the Analysis of Aging-Associated Retrotransposition2020

    • Author(s)
      Kuroki Ryota、Murata Yui、Fuke Satoshi、Nakachi Yutaka、Nakashima Jun、Kujoth Gregory C.、Prolla Tomas A.、Bundo Miki、Kato Tadafumi、Iwamoto Kazuya
    • Journal Title

      Frontiers in Genetics

      Volume: 11 Pages: 519206-519206

    • DOI

      10.3389/fgene.2020.519206

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Evidence for Altered Metabolism of Sphingosine-1-phosphate in the Corpus Callosum of Patients with Schizophrenia2020

    • Author(s)
      Esaki, K., Balan, S., Iwayama, Y., Shimamoto-Mitsuyama, C., Hirabayashi, Y., Dean, B. & Yoshikawa, T.
    • Journal Title

      Schizophrenia Bulletin

      Volume: - Issue: 5 Pages: 1172-1181

    • DOI

      10.1093/schbul/sbaa052

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Presynaptic dysregulation of the paraventricular thalamic nucleus causes depression-like behavior.2019

    • Author(s)
      Kato TM, Fujimori-Tonou N, Mizukami H, Ozawa K., Fujisawa S, Kato T.
    • Journal Title

      Sci Rep

      Volume: 9 Issue: 1 Pages: 16506-16506

    • DOI

      10.1038/s41598-019-52984-y

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies2019

    • Author(s)
      Kato T
    • Journal Title

      Psychiatry and Clinical Neurosciences

      Volume: 73 Issue: 9 Pages: 526-540

    • DOI

      10.1111/pcn.12852

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Remarks] 精神疾患動態研究チーム

    • URL

      http://mdmd.riken.jp/

    • Related Report
      2018 Annual Research Report

URL: 

Published: 2018-07-20   Modified: 2022-07-01  

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