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Elucidating Brain and Heart Pathophysiology of Mental Disorders through Multilayered Analysis: The Embodiment of the Diseasome

Research Project

Project/Area Number 20K20602
Research Category

Grant-in-Aid for Challenging Research (Pioneering)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 52:General internal medicine and related fields
Research InstitutionNagoya University

Principal Investigator

Ozaki Norio  名古屋大学, 医学系研究科, 特任教授 (40281480)

Project Period (FY) 2020-07-30 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥26,000,000 (Direct Cost: ¥20,000,000、Indirect Cost: ¥6,000,000)
Fiscal Year 2022: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2021: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
Fiscal Year 2020: ¥11,180,000 (Direct Cost: ¥8,600,000、Indirect Cost: ¥2,580,000)
Keywords22q11.2欠失 / 3q29欠失 / iPS細胞 / 精神疾患 / 心疾患
Outline of Research at the Start

精神疾患の発症に強く関連するゲノム変異22q11.2欠失、3q29欠失を有する患者では心疾患も合併することが多い。しかし従来、精神疾患の病態解明研究において、脳病態の解明に専ら焦点づけられ、心臓病態と脳病態との関係性に関してはアプローチされることが乏しかった。本研究は脳と心臓の病態に関連性について、22q11.2欠失、3q29欠失患者の臨床所見・iPS細胞・モデルマウスから包括的に明らかにして、将来は、効果に優れ、副作用の少ない精神疾患治療薬の開発に繋がることを目指している。

Outline of Final Research Achievements

In this study, we aimed to elucidate cardiac pathology using patient-derived iPS cells and model mice with genomic variants such as 22q11.2 deletion and 3q29 deletion, which are risk factors for both psychiatric and cardiac disorders.
Bulk RNA-seq analysis of cardiomyocytes derived from iPS cells from healthy controls and patients with 22q11.2 deletion (22qdel-PT) suggested Golgi and endoplasmic reticulum abnormalities in cardiomyocytes derived from 22qdel-PT. It has been reported that Golgi and endoplasmic reticulum abnormalities in the heart contribute to the development and progression of cardiac diseases such as heart failure and arrhythmia, and may be one of the causes of vulnerability in heart of 22qdel-PT. We have also shown that the endoplasmic reticulum stress response is abnormal in dopaminergic neurons derived from 22qdel-PT. These results suggest that endoplasmic reticulum abnormalities may be common in the pathological background of both heart and brain.

Academic Significance and Societal Importance of the Research Achievements

従来、精神疾患の病態解明研究においては、統合失調症等精神疾患患者は短命で、その死因として心臓死が多いことが示されているにも関わらず、脳病態の解明に専ら焦点づけられ、心臓病態と脳病態との関係性に関してはアプローチされることすら乏しかった。本研究により、精神疾患と心疾患双方のリスクである22q11.2欠失患者心筋細胞におけるゴルジ体および小胞体異常の存在が明らかとなったことは、精神疾患患者の心身両面における健康寿命延伸、22q11.2欠失患者の家族からの、「心臓に病気があっても安全に使える治療法の開発を」という思いの実現に繋がり得る成果である。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (23 results)

All 2024 2023 2022 2021 2020

All Journal Article (18 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 18 results,  Open Access: 17 results) Presentation (5 results)

  • [Journal Article] Association between copy number variations in parkin (PRKN) and schizophrenia and autism spectrum disorder: A case-control study2024

    • Author(s)
      Lo T, Yamamoto M(34人中10番目)
    • Journal Title

      Neuropsychopharmacology Reports

      Volume: 44(1) Issue: 1 Pages: 42-50

    • DOI

      10.1002/npr2.12370

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Phenotypes for general behavior, activity, and body temperature in 3q29 deletion model mice2024

    • Author(s)
      Mori D、Ikeda R、Sawahata M、Yamaguchi S、Kodama A、Hirao T、Arioka Y、Okumura H、Inami C、Suzuki T、Hayashi Y、Kato H、Nawa Y、Miyata S、Kimura H、Kushima I、Aleksic B、Mizoguchi H、Nagai T、Nakazawa T、Hashimoto R、Kaibuchi K、Kume K、Yamada K、Ozaki N
    • Journal Title

      Translational Psychiatry

      Volume: 14 Issue: 1 Pages: 138-138

    • DOI

      10.1038/s41398-023-02679-w

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Shedding light on latent pathogenesis and pathophysiology of mental disorders: the potential of iPS cell technology2023

    • Author(s)
      Arioka, Y. Okumura, H. Sakaguchi, H. Ozaki, N.
    • Journal Title

      Psychiatry Clin Neurosci

      Volume: - Issue: 6 Pages: 308-314

    • DOI

      10.1111/pcn.13545

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical characterization of patients with schizophrenia and 16p13.11 duplication: A case series2023

    • Author(s)
      Kimura Hiroki、Kushima Itaru、Banno Masahiro、Inada Toshiya、Yoshimi Akira、Aleksic Branko、Ozaki Norio
    • Journal Title

      Neuropsychopharmacology Reports

      Volume: - Issue: 2 Pages: 267-271

    • DOI

      10.1002/npr2.12334

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural aging of human neurons is opposite of the changes in schizophrenia2023

    • Author(s)
      Mizutani Ryuta、Saiga Rino、Yamamoto Yoshiro、Uesugi Masayuki、Takeuchi Akihisa、Uesugi Kentaro、Terada Yasuko、Suzuki Yoshio、De Andrade Vincent、De Carlo Francesco、Takekoshi Susumu、Inomoto Chie、Nakamura Naoya、Torii Youta、Kushima Itaru、Iritani Shuji、Ozaki Norio、Oshima Kenichi、Itokawa Masanari、Arai Makoto
    • Journal Title

      PLOS ONE

      Volume: 18 Issue: 6 Pages: e0287646-e0287646

    • DOI

      10.1371/journal.pone.0287646

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Histological Analysis of a Mouse Model of the 22q11.2 Microdeletion Syndrome2023

    • Author(s)
      Tabata Hidenori、Mori Daisuke、Matsuki Tohru、Yoshizaki Kaichi、Asai Masato、Nakayama Atsuo、Ozaki Norio、Nagata Koh-ichi
    • Journal Title

      Biomolecules

      Volume: 13 Issue: 5 Pages: 763-763

    • DOI

      10.3390/biom13050763

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Interaction of genetic liability for attention deficit hyperactivity disorder (ADHD) and perinatal inflammation contributes to ADHD symptoms in children2023

    • Author(s)
      Takahashi Nagahide、Nishimura Tomoko、Harada Taeko、Okumura Akemi、Iwabuchi Toshiki、Rahman Md Shafiur、Kuwabara Hitoshi、Takagai Shu、Usui Noriyoshi、Makinodan Manabu、Matsuzaki Hideo、Ozaki Norio、Itoh Hiroaki、Nomura Yoko、Newcorn Jeffrey H.、Tsuchiya Kenji J.
    • Journal Title

      Brain, Behavior, & Immunity - Health

      Volume: 30 Pages: 100630-100630

    • DOI

      10.1016/j.bbih.2023.100630

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The genetic architecture of schizophrenia: review of large-scale genetic studies2023

    • Author(s)
      Kato, H. Kimura, H. Kushima, I. Takahashi, N. Aleksic, B. Ozaki, N.
    • Journal Title

      J Hum Genet

      Volume: 68 Issue: 3 Pages: 175-182

    • DOI

      10.1038/s10038-022-01059-4

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Variable psychiatric manifestations in patients with 16p11.2 duplication: a case series of 4 patients2022

    • Author(s)
      Hayashi Yu、Kushima Itaru、Aleksic Branko、Senaha Tetsu、Ozaki Norio
    • Journal Title

      Psychiatry and Clinical Neurosciences

      Volume: 76 Issue: 3 Pages: 86-88

    • DOI

      10.1111/pcn.13324

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Exome sequencing analysis of Japanese autism spectrum disorder case-control sample supports an increased burden of synaptic function-related genes2022

    • Author(s)
      Kimura H, Okada T, Sebat J, et al.
    • Journal Title

      Translational Psychiatry

      Volume: 12 Issue: 1 Pages: 265-265

    • DOI

      10.1038/s41398-022-02033-6

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cross-disorder analysis of genetic and regulatory copy number variations in bipolar disorder, schizophrenia, and autism spectrum disorder2022

    • Author(s)
      Kushima Itaru、Nakatochi Masahiro、Aleksic Branko、Okada Takashi、(中略)、Ozaki Norio
    • Journal Title

      Biological Psychiatry

      Volume: - Issue: 5 Pages: 362-374

    • DOI

      10.1016/j.biopsych.2022.04.003

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Treatment‐resistant schizophrenia in patients with 3q29 deletion: A case series of four patients2022

    • Author(s)
      Nawa Yoshihiro、Kushima Itaru、Aleksic Branko、Yamamoto Maeri、Kimura Hiroyuki、Banno Masahiro、Hashimoto Ryota、Ozaki Norio
    • Journal Title

      Psychiatry and Clinical Neurosciences

      Volume: - Issue: 7 Pages: 338-339

    • DOI

      10.1111/pcn.13361

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Establishment of induced pluripotent stem cells from a patient with 16p13.11 duplication and VPS13B deletion2022

    • Author(s)
      Okumura, H. Arioka, Y. Kushima, I. Mori, D. Ozaki, N.
    • Journal Title

      Stem Cell Res

      Volume: 64 Pages: 102884-102884

    • DOI

      10.1016/j.scr.2022.102884

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Exome sequencing of Japanese schizophrenia multiplex families supports the involvement of calcium ion channels2022

    • Author(s)
      Toyama Miho、Takasaki Yuto、Branko Aleksic、Kimura Hiroki、Kato Hidekazu、Nawa Yoshihiro、Kushima Itaru、Ishizuka Kanako、Shimamura Teppei、Ogi Tomoo、Ozaki Norio
    • Journal Title

      PLOS ONE

      Volume: 17(5) Issue: 5 Pages: e0268321-e0268321

    • DOI

      10.1371/journal.pone.0268321

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Autism spectrum disorder comorbid with obsessive compulsive disorder and eating disorder in a woman with NBEA deletion2021

    • Author(s)
      Kato Hidekazu、Kushima Itaru、Yoshimi Akira、Ishizuka Kanako、Kimura Hiroki、Aleksic Branko、Takahashi Nagahide、Okada Takashi、Ozaki Norio
    • Journal Title

      Psychiatry and Clinical Neurosciences

      Volume: 76 Issue: 1 Pages: 36-38

    • DOI

      10.1111/pcn.13309

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Chromosome 22q11.2 deletion causes PERK-dependent vulnerability in dopaminergic neurons2021

    • Author(s)
      Arioka Yuko、Shishido Emiko、Kushima Itaru、Suzuki Toshiaki、Saito Ryo、Aiba Atsu、Mori Daisuke、Ozaki Norio
    • Journal Title

      EBioMedicine

      Volume: 63 Pages: 103138-103138

    • DOI

      10.1016/j.ebiom.2020.103138

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Morphological alteration of myelin-oligodendrocytes in a schizophrenic patient with 22q11.2 deletion syndrome: An autopsy study2020

    • Author(s)
      Torii Youta、Iritani Shuji、Marui Tomoyasu、Sekiguchi Hirotaka、Habuchi Chikako、Fujishiro Hiroshige、Kushima Itaru、Oshima Kenichi、Niizato Kazuhiro、Hayashida Shotaro、Masaki Katsuhisa、Kira Jun-ichi、Yoshida Mari、Ozaki Norio
    • Journal Title

      Schizophrenia Research

      Volume: 223 Pages: 353-355

    • DOI

      10.1016/j.schres.2020.07.003

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Comprehensive analysis of a novel mouse model of the 22q11.2 deletion syndrome: a model with the most common 3.0-Mb deletion at the human 22q11.2 locus2020

    • Author(s)
      Saito Ryo、Koebis Michinori、Nagai Taku、Shimizu Kimiko、Liao Jingzhu、Wulaer Bolati、Sugaya Yuki、Nagahama Kenichiro、Uesaka Naofumi、Kushima Itaru、Mori Daisuke、Maruyama Kazuaki、Nakao Kazuki、Kurihara Hiroki、Yamada Kiyofumi、Kano Masanobu、Fukada Yoshitaka、Ozaki Norio、Aiba Atsu
    • Journal Title

      Translational Psychiatry

      Volume: 10 Issue: 1 Pages: 35-35

    • DOI

      10.1038/s41398-020-0723-z

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] COVID-19拡大とうつ病・双極性障害:生物心理社会的観点から2022

    • Author(s)
      尾崎紀夫
    • Organizer
      2022日本うつ病リワーク協会年次大会特別講演
    • Related Report
      2022 Research-status Report
  • [Presentation] アルコール使用性障害を高頻度に合併する統合失調症の発症に関わるゲノム変異から病態解明へ:22q11.2欠失を例として2022

    • Author(s)
      尾崎紀夫
    • Organizer
      2022アルコール・薬物依存合同総会 「アルコール・薬物濫用と関連疾患の医学的解決」
    • Related Report
      2022 Research-status Report
  • [Presentation] 精神疾患の連続性を踏まえた個別化医療-Diseasomeの観点から2022

    • Author(s)
      尾崎紀夫
    • Organizer
      第41回日本精神科診断学会ランチョンセミナー
    • Related Report
      2022 Research-status Report
  • [Presentation] 精神疾患及び向精神薬の運転技能への影響を考える2022

    • Author(s)
      尾崎紀夫
    • Organizer
      BPCNPNPPP4学会合同年会教育講演
    • Related Report
      2022 Research-status Report
  • [Presentation] 精神疾患リスクゲノム変異を起点とした多様な試料を用いた病態解明2022

    • Author(s)
      尾崎紀夫
    • Organizer
      BPCNPNPPP4学会合同年会シンポジウム 精神疾患研究におけるヒトiPSC研究最前線
    • Related Report
      2022 Research-status Report

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Published: 2020-08-03   Modified: 2025-01-30  

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