Understanding of pathophysiological mechanisms and development of the treatment of schizophrenia based on novel gene polymorphisms of glyoxalase 1.

• Project/Area Number: 18K07551
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Kanazawa University
• Principal Investigator: Harashima Ai 金沢大学, 医学系, 助教 (50705522)
• Co-Investigator(Kenkyū-buntansha): 棟居 聖一 金沢大学, 医学系, 助教 (10399040)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 転写調節

Outline of Final Research Achievements

Glyoxalase 1 (GLO1) has been known to be associated with schizophrenia. However, the mechanism remains unknown. In this study, we revealed that novel gene polymorphisms in the human GLO1 promoter were involved in the pathogenesis of schizophrenia using human samples as well as iPS cells derived from the patients. In addition, we identified a novel gene mutation in human GLO1 promoter region in the patients with schizophrenia. The gene mutation was found to be specific to schizophrenia. These findings suggest that GLO1 gene could be a target for the treatment and prophylaxis of schizophrenia.

Academic Significance and Societal Importance of the Research Achievements

100人に1人が発症する患者数の多い精神疾患である統合失調症の病態形成メカニズムを明らかにすることは、新たな治療法、治療薬の開発にとって極めて重要である。本研究では、これまで不明であったGlyoxalase 1（GLO1）と統合失調症との関連性を明らかにするとともに、統合失調症特異的なGLO1遺伝子変異の発見にも成功した。本研究の成果の学術的意義は大きい。また、本研究の成果によりこれまでにない新たな統合失調症の治療法、治療薬が開発される可能性があり、社会的意義も大きいと考えられる。

Research Products

• [Journal Article] Transport of oxytocin to the brain after peripheral administration by membrane-bound or soluble forms of receptors for advanced glycation end-products. (2021)
  • Author(s): Munesue S, Liang MingKun, Harashima A, Zhong J, Furuhara K, Boitsova E, Cherepanov SM, Gerasimenko M, Yuhi T, Yamamoto Y, Higashida H.
  • Journal Title: J Neuroendocrinol Volume: 33 Issue: 3
  • DOI: 10.1111/jne.12963
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Receptor for advanced glycation end-products (RAGE) plays a critical role in retrieval behavior of mother mice at early postpartum. (2021)
  • Author(s): Gerasimenko M, Lopatina O, Munesue S, Harashima A, Yokoyama S, Yamamoto Y, Higashida H.
  • Journal Title: Physiol Behav Volume: 235 Pages: 113395-113395
  • DOI: 10.1016/j.physbeh.2021.113395
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pyridoxamine improves diabetes-evoked delayed bone repair in mice. (2021)
  • Author(s): Ugaji S, Kimura K, Yamamoto Y, Munesue S, Harashima A, Aikawa T, Yoshida Y, Hamada T, Hikichi T, Matsubara H, Tsuchiya H.
  • Journal Title: J Transl Sci Volume: in press
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] RAGE signaling antagonist suppresses mouse macrophage foam cell formation. (2021)
  • Author(s): Leerach N, Munesue S, Harashima A, Kimura K, Oshima Y, Kawano S, Tanaka M, Niimura A, Sakulsak N, Yamamoto H, Hori O, Yamamoto Y.
  • Journal Title: Biochem Biophys Res Commun Volume: 555 Pages: 74-80
  • DOI: 10.1016/j.bbrc.2021.03.139
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Glycation reaction and the role of the receptor for advanced glycation end-products in immunity and social behavior (2020)
  • Author(s): Leerach Nontaphat、Harashima Ai、Munesue Seiichi、Kimura Kumi、Oshima Yu、Goto Hisanori、Yamamoto Hiroshi、Higashida Haruhiro、Yamamoto Yasuhiko
  • Journal Title: Glycoconjugate Journal Volume: in press Issue: 3 Pages: 303-310
  • DOI: 10.1007/s10719-020-09956-6
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Aquaporin 1 elicits cell motility and coordinates vascular bed formation by downregulating thrombospondin type-1 domain-containing 7A in glioblastoma (2020)
  • Author(s): Oishi M, Munesue S, Harashima A, Nakada M, Yamamoto Y, Hayashi Y
  • Journal Title: Cancer Med Volume: 9 Issue: 11 Pages: 3904-3917
  • DOI: 10.1002/cam4.3032
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clonal hematopoiesis by SLIT1-mutated hematopoietic stem cells due to a breakdown of the autocrine loop involving Slit1 in acquired aplastic anemia (2019)
  • Author(s): Hosokawa K, Mizumaki H, Elbadry M, Saito C, Espinoza JL, An DTT, Katagiri T, Harashima A, Kikuchi A, Kanai A, Matsui H, Inaba T, Taniwaki M, Yamamoto Y, Nakao S
  • Journal Title: Leukemia Volume: 33 Issue: 11 Pages: 2732-2766
  • DOI: 10.1038/s41375-019-0510-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Neuroprotective effects of endogenous secretory receptor for advanced glycation end-products in brain ischemia. (2019)
  • Author(s): Shimizu Y, Harashima A, Munesue S, Oishi M, Hattori T, Hori O, Kitao Y, Yamamoto H, Leerach N, Nakada M, Yamamoto Y, Hayashi Y.
  • Journal Title: Aging Dis Volume: in press
  • Peer Reviewed
• [Journal Article] Monitoring of Heat Shock Response and Phenotypic Changes in Hepatocellular Carcinoma After Heat Treatment (2019)
  • Author(s): Zaimoku R, Miyashita T, Tajima H, Takamura H, Harashima A, Munesue S, Yamamoto Y, Ninomiya I, Fushida S, Harada K
  • Journal Title: Anticancer Research Volume: 39 Issue: 10 Pages: 5393-5401
  • DOI: 10.21873/anticanres.13733
  • Peer Reviewed
• [Journal Article] Protective role of endogenous secretory RAGE against contact hypersensitivity in mouse ear skin. (2019)
  • Author(s): Sagara A, Harashima A, Munesue S, Kimura K, Leerach N, Oshima Y, Kinoshita Y, Sakai N, Kaneko S, Wada T, Tsuneyama K, Yamamoto H, Yamamoto Y.
  • Journal Title: Glycative Stress Res Volume: 6 Pages: 270-277
  • NAID: 40022229100
  • Peer Reviewed
• [Journal Article] CD38, CD157, and RAGE as Molecular Determinants for Social Behavior. (2019)
  • Author(s): .Higashida H, Hashii M, Tanaka Y, Matsukawa S, Higuchi Y, Gabata R, Tsubomoto M, Seishima N, Teramachi M, Kamijima T, Hattori T, Hori O, Tsuji C, Cherepanov SM, Shabalova AA, Gerasimenko M, Minami K, Yokoyama S, Munesue SI, Harashima A, Yamamoto Y, Salmina AB, Lopatina O.
  • Journal Title: Cells. Volume: 9(1) Issue: 1 Pages: 62-62
  • DOI: 10.3390/cells9010062
  • NAID: 120006859506
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Citrullinated histone H3: early biomarker of neutrophil extracellular traps in septic liver damage (2019)
  • Author(s): Nomura K, Miyashita T, Yamamoto Y, Munesue S, Harashima A, Takayama H, Fushida S, Ohta T
  • Journal Title: J Surg Res Volume: 234 Pages: 132-138
  • DOI: 10.1016/j.jss.2018.08.014
  • Peer Reviewed
• [Journal Article] Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice. (2019)
  • Author(s): Yamamoto Y, Liang M, Munesue S, Deguchi K, Harashima A, Furuhara K, Yuhi T, Zhong J, Akther S, Goto H, Eguchi Y, Kitao Y, Hori O, Shiraishi Y, Ozaki N, Shimizu Y, Kamide T, Yoshikawa A, Hayashi Y, Nakada M, Lopatina O, Gerasimenko M, Komleva Y, Malinovskaya N, Salmina AB, Asano M, Nishimori K, Higashida H et al.,
  • Journal Title: Commun Biol Volume: ２ Issue: 1 Pages: 76-76
  • DOI: 10.1038/s42003-019-0325-6
  • NAID: 120006605138
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] In vitro anticancer effects of a RAGE inhibitor discovered using a structure-based drug design system (2018)
  • Author(s): El-Far Ali、Munesue Seiichi、Harashima Ai、Sato Akira、Shindo Mika、Nakajima Shingo、Inada Mana、Tanaka Mariko、Takeuchi Akihiko、Tsuchiya Hiroyuki、Yamamoto Hiroshi、Shaheen Hazem、El-Sayed Yasser、Kawano Shuhei、Tanuma Sei-Ichi、Yamamoto Yasuhiko
  • Journal Title: Oncology Letters Volume: 15 Pages: 4627-4634
  • DOI: 10.3892/ol.2018.7902
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Anti-tumor effects of a nonsteroidal anti-inflammatory drug zaltoprofen on chondrosarcoma via activating peroxisome proliferator-activated receptor gamma and suppressing matrix metalloproteinase-2 expression. (2018)
  • Author(s): Higuchi T, Takeuchi A, Munesue S, Yamamoto N, Hayashi K, Kimura H, Miwa S, Inatani H, Shimozaki S, Kato T, Aoki Y, Abe K, Taniguchi Y, Aiba H, Murakami H, Harashima A, Yamamoto Y, Tsuchiya H.
  • Journal Title: Cancer Med. Volume: 印刷中 Issue: 5 Pages: 1944-1954
  • DOI: 10.1002/cam4.1438
  • NAID: 120006605139
  • Peer Reviewed / Open Access
• [Presentation] 可溶型RAGEは脳血管内皮細胞上の膜型RAGEによる血中オキシトシンの脳内輸送を阻害しない (2020)
  • Author(s): 棟居聖一、原島愛、木村久美、Nontaphat Leerach、大島由、新村朱子、東田陽博、山本靖彦
  • Organizer: 第30回日本メイラード学会（オンライン）
• [Presentation] 細胞内メチルグリオキサールの可視化解析 (2019)
  • Author(s): 引地 俊文, 木村 久美, 棟居 聖一, 原島 愛, Nontaphat Leerach, 大島 由, 木下 結衣, 松原 秀憲, 土屋 弘行, 山本 靖彦
  • Organizer: 第29回日本メイラード学会年会
• [Presentation] 原子間力顕微鏡を用いたグリケーションの可視化への挑戦 (2019)
  • Author(s): 木下結衣、棟居聖一、木村久美、原島愛、Nontaphat Leerach、大島由、古寺哲幸、山本靖彦
  • Organizer: 第29回日本メイラード学会年会
• [Presentation] Drug library screening to identify new compounds for inducing ectodomain shedding of RAGE and formation of soluble RAGE (2018)
  • Author(s): Shuhei Kawano, Hanae Miyazawa, Seiichi Munesue, Ai Harashima, Mariko Tanaka, Duong Thi Minh Thoa, Nontaphat Leerach, Yu Ooshima, Yui Kinoshita, Hiroshi Yamamoto, Yasuhiko Yamamoto
  • Organizer: 13th International Symposium on the Maillard Reaction
  • Int'l Joint Research
• [Presentation] In vitro anticancer effects of a novel RAGE inhibitor on suppression of tumor malignant phenotypes in human fibrosarcoma cells (2018)
  • Author(s): Seiichi Munesue, Ai Harashima, Akihiko Takeuchi, Mariko Tanaka, Shuhei Kawano, Nantaphat Leerach, Yu Ooshima, Yui Kinoshita, Akira Sato, Mika Shindo, Shingo Nakajima, Mana Inada, Sei-ichi Tanuma, Yasuhiko Yamamoto
  • Organizer: 13th International Symposium on the Maillard Reaction
  • Int'l Joint Research
• [Presentation] RAGE細胞内シグナル伝達阻害剤によるマクロファージ浸潤・泡沫化抑制効果 (2018)
  • Author(s): Nontaphat LEERACH、棟居聖一、原島 愛、木村久美、大島 由、河野修平、田中麻莉子、木下結衣、山本靖彦
  • Organizer: 第28回日本メイラード学会
• [Presentation] 新規RAGE阻害薬による線維肉腫細胞の悪性化抑制効果の検討 (2018)
  • Author(s): 山本靖彦、棟居聖一、原島 愛、武内章彦、田中麻莉子、河野修平、佐藤 聡、新藤実香、中島槙吾、稲田 愛、田沼靖一
  • Organizer: 第18回日本抗加齢医学会総会