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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

Kato Tadafumi  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 Completed (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双極性障害 / 統合失調症 / ミトコンドリア / 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 Final Research Achievements

We identified the paraventricular nucleus of the thalamus (PVT) as a candidate brain region from analysis of mutant Polg mice, and conducted single-cell omics analysis and circuit manipulation to understand the circuit dynamics of the PVT, showing that hyperexcitability of the neural circuit involving the PVT may be related to the molecular pathophysiology of bipolar disorder. Furthermore, we reconstructed the pathophysiology by creating a mouse model in which the PVT is overexcited and showed that hyperexcitability of the PVT causes a bipolar disorder-like behavioral phenotype. In addition, we created new genetically engineered mouse models of bipolar disorder, using genes identified from genomic analyses of bipolar disorder, and analyzed their behavior and examined their brain pathology. In addition, using patients-derived iPS cells, we investigated the phenotype at the cellular level.

Academic Significance and Societal Importance of the Research Achievements

近年、双極性障害・統合失調症研究の中心は、大規模なゲノム研究となっていたが、その次のステップは、大規模ゲノム研究で見出された遺伝子に関する動物モデルや脳オーガノイドを用いて、細胞・回路レベルでの病態理解を進めることであった。本研究では、双極性障害および統合失調症のゲノム解析研究の進展を背景に、世界的に未踏の領域である、精神疾患の多階層を繋げた病態モデリングに挑み、成功を収めるなど、世界の流れを先取りして、精神疾患の病態を分子から神経回路に至る階層を超えて理解するフレームワークを提供することができた。こうした研究により、精神疾患の神経回路レベルでの理解と診断・治療への流れが加速すると期待される。

Report

(6 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (20 results)

All 2023 2021 2020 2019 Other

All Int'l Joint Research (2 results) Journal Article (16 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 16 results,  Open Access: 16 results) Remarks (2 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] Deep exome sequencing identifies enrichment of deleterious mosaic variants in neurodevelopmental disorder genes and mitochondrial tRNA regions in bipolar disorder2023

    • Author(s)
      Nishioka M, Takayama J, Sakai N, Kazuno A, Ishiwata M, Ueda J, Hayama T, Fujii K, Someya T, Kuriyama S, Tamiya G, Takata A, Kato T
    • Journal Title

      Molecular Psychiatry

      Volume: -

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of epigenetically active L1 promoters in the human brain and their relationship with psychiatric disorders2023

    • Author(s)
      Watanabe Risa、Nakachi Yutaka、Matsubara Hikari、Ueda Junko、Ishii Takao、Ukai Wataru、Hashimoto Eri、Kasai Kiyoto、Simizu Siro、Kato Tadafumi、Bundo Miki、Iwamoto Kazuya
    • Journal Title

      Neuroscience Research

      Volume: - Pages: 37-51

    • DOI

      10.1016/j.neures.2023.05.001

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cell-type-specific DNA methylation analysis of the frontal cortices of mutant Polg1 transgenic mice with neuronal accumulation of deleted mitochondrial DNA2021

    • Author(s)
      Sugawara H, Bundo M, Kasahara T, Nakachi Y, Ueda J, Kubota-Sakashita M, Iwamoto K, Kato T
    • Journal Title

      Molecular Brain

      Volume: 15 Issue: 1 Pages: 9-9

    • DOI

      10.1186/s13041-021-00894-4

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Systematic analysis of exonic germline and postzygotic de novo mutations in bipolar disorder2021

    • Author(s)
      Nishioka Masaki、Kazuno An-a、Nakamura Takumi、Sakai Naomi…Oka Takashi、Matoba Nana、Kataoka Muneko、Alkanaq Ahmed N.、Hamanaka Kohei、Tsuboi Takashi、Sengoku Toru、Ogata Kazuhiro、Iwata Nakao、Ikeda Masashi、Matsumoto Naomichi、Kato Tadafumi、Takata Atsushi
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 3750-3750

    • DOI

      10.1038/s41467-021-23453-w

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Brain-specific heterozygous loss-of-function of ATP2A2, endoplasmic reticulum Ca<sup>2+</sup>pump responsible for Darier's disease, causes behavioral abnormalities and a hyper-dopaminergic state2021

    • Author(s)
      Nakajima Kazuo、Ishiwata Mizuho、Weitemier Adam Z、Shoji Hirotaka、Monai Hiromu、Miyamoto Hiroyuki、Yamakawa Kazuhiro、Miyakawa Tsuyoshi、McHugh Thomas J、Kato Tadafumi
    • Journal Title

      Human Molecular Genetics

      Volume: 30 Issue: 18 Pages: 1762

    • DOI

      10.1093/hmg/ddab137

    • URL

      https://localhost/en/publications/130cd18d-9c2e-4d91-9796-145b0a3ede56

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder2021

    • Author(s)
      Bundo M, Ueda J, Nakachi Y, Kasai K, Kato T, Iwamoto K.
    • Journal Title

      Molecular Psychiatry

      Volume: 26 Issue: 7 Pages: 3407-3418

    • DOI

      10.1038/s41380-021-01079-0

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Functional and behavioral effects of de novo mutations in calcium-related genes in patients with bipolar disorder2021

    • Author(s)
      Nakamura T, Nakajima K, Kobayashi Y, Itohara S, Kasahara T, Tsuboi T, Kato T.
    • Journal Title

      Human Molecular Genetics

      Volume: 30 Issue: 19 Pages: 1851

    • DOI

      10.1093/hmg/ddab152

    • URL

      https://pure.teikyo.jp/en/publications/e3d9f066-a169-4965-83b5-efd1f80e861d

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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] 順天堂大学医学部/大学院医学研究科 気分障害分子病態学講座 精神医学講座・ゲノミクス研究プロジェクト

    • URL

      https://www.juntendo-molecular-psychiatry.com/results/

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
  • [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: 2024-01-30  

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