Understanding brain and cardiac pathology in schizophrenia using 22q11.2 deletion patient-derived iPS cells.

• Project/Area Number: 18K19511
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 52:General internal medicine and related fields
• Research Institution: Nagoya University
• Principal Investigator: Ozaki Norio 名古屋大学, 医学系研究科, 教授 (40281480)
• Project Period (FY): 2018-06-29 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
• Keywords: 22q11.2欠失 / iPS細胞 / 統合失調症 / 脳病態 / 心臓病態

Outline of Final Research Achievements

We have to solve the two main issues in schizophrenia: (1) the existence of many refractory cases due to unclear brain pathophysiology, (2) the high mortality rate due to complications of cardiac disease and cardiovascular side effects of antipsychotic drugs. To tackle the above-mentioned issues, we aimed to generate cardiomyocytes and neurons from 22q11.2 deletion syndrome patient-derived iPS cells and clarify the pathophysiology of heart and brain. As a result, we revealed the involvement of vulnerability to endoplasmic reticulum stress in dopaminergic neurons as one of the causes in brain pathophysiology. In addition, we established the method of differentiation into cardiomyocytes and electrophysiological analysis of cardiomyocytes. However, due to the discontinuation of the cardiomyocytes differentiation kit, we were forced to suspend our research and were not able to conduct a detailed analysis during this study.

Academic Significance and Societal Importance of the Research Achievements

統合失調症の臨床課題の解決には心臓及び脳双方の病態とその関連性についての理解が不可欠である。本研究では22q11.2欠失症候群患者からiPS細胞を樹立し、心筋細胞及び神経細胞を作製した。これらは統合失調症患者の心臓と脳双方の病態を反映するモデルとして有用と考えられ、今後の詳細な解析により病態解明への一歩となることが期待される。さらに、神経細胞を用いた解析では統合失調症患者の脳病態の一つとして小胞体ストレスに対する脆弱性の関与を明らかにしており、病態に基づく治療薬や将来的な発症予防法の開発に繋がることが期待される。

Research Products

• [Journal Article] Chromosome 22q11.2 deletion causes PERK-dependent vulnerability in dopaminergic neurons (2021)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Morphological alteration of myelin-oligodendrocytes in a schizophrenic patient with 22q11.2 deletion syndrome: An autopsy study (2020)
  • 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
  • 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 locus (2020)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Generation and analysis of novel Reln-deleted mouse model corresponding to exonic Reln deletion in schizophrenia (2020)
  • Author(s): Masahito Sawahata, Daisuke Mori, Yuko Arioka, Hisako Kubo, Itaru Kushima, Kanako Kitagawa, Akira Sobue, Emiko Shishido, Mariko Sekiguchi, Akiko Kodama, Ryosuke Ikeda, Branko Aleksic, Hiroki Kimura, Kanako Ishizuka, Taku Nagai, Kozo Kaibuchi, Toshitaka Nabeshima, Kiyofumi Yamada, Norio Ozaki
  • Journal Title: Psychiatry and clinical neurosciences Volume: 1 Issue: 5 Pages: 1-10
  • DOI: 10.1111/pcn.12993
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Psychiatric-disorder-related behavioral phenotypes and cortical hyperactivity in a mouse model of 3q29 deletion syndrome. (2019)
  • Author(s): Baba M, Yokoyama K, Seiriki K, Naka Y, Matsumura K, Kondo M, Yamamoto K, Hayashida M, Kasai A, Ago Y, Nagayasu K, Hayata-Takano A, Takahashi A, Yamaguchi S, Mori D, Ozaki N, Yamamoto T, Takuma K, Hashimoto R, Hashimoto H, Nakazawa T.
  • Journal Title: Neuropsychopharmacology Volume: 44(12) Issue: 12 Pages: 2125-2135
  • DOI: 10.1038/s41386-019-0441-5
  • NAID: 130007811380
  • Peer Reviewed / Open Access
• [Journal Article] Proteomic analysis of lymphoblastoid cell lines from schizophrenic patients (2019)
  • Author(s): Yoshimi A, Yamada S, Kunimoto S, Aleksic B, Hirakawa A, Ohashi MS, Matsumoto A, Hada K, Itoh N, Arioka Y, Kimura H, Kushima I, Nakamura Y, Shiino T, Mori D, Tanaka S, Hamada S, Noda Y, Nagai T, Yamada K, Ozaki N
  • Journal Title: Translational Psychiatry Volume: 9 Issue: 1 Pages: 126-126
  • DOI: 10.1038/s41398-019-0461-2
  • Peer Reviewed / Open Access
• [Journal Article] Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights (2018)
  • Author(s): Kushima I, Aleksic B, Nakatochi M, Shimamura T, Okada T, Uno Y, Morikawa M, Ishizuka K, Shiino T, Kimura H, Arioka Y, Yoshimi A, Takasaki Y, Yu Y, Nakamura Y, Ozaki N
  • Journal Title: Cell reports Volume: 24(11) Pages: 2838-2856
  • Peer Reviewed
• [Presentation] 精神疾患患者由来ゲノム・iPS細胞・死後脳の情報整備による大規模解析から根本的治療薬創成へ (2019)
  • Author(s): 尾崎紀夫
  • Organizer: 精神神経学会研究推進委員会シンポジウム
• [Presentation] 22q11.2 deletion syndrome: clinical phenotypes to pathogenesis of mental disorders associated with this variant. (2019)
  • Author(s): Ozaki N
  • Organizer: The 59th Annual Meeting of the Japanese Teratology Society The 13th World Congress of International Cleft Lip and Palate Foundation CLEFT2019
  • Int'l Joint Research / Invited
• [Presentation] Drug development for schizophrenia based on the pathogenesis from rare disease-susceptibility variants. (2019)
  • Author(s): Ozaki N
  • Organizer: ASCNP2019DrugDevelopment
  • Int'l Joint Research