2020 Fiscal Year Annual Research Report
Development of biomarkers for predicting disease progression and treatment response for schizophrenia using large-scale patient resources and iPS technology.
Project/Area Number |
18KT0022
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Research Institution | National Center of Neurology and Psychiatry |
Principal Investigator |
橋本 亮太 国立研究開発法人国立精神・神経医療研究センター, 精神保健研究所 精神疾患病態研究部, 部長 (10370983)
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Co-Investigator(Kenkyū-buntansha) |
中澤 敬信 東京農業大学, 生命科学部, 教授 (00447335)
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Project Period (FY) |
2018-07-18 – 2021-03-31
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Keywords | 精神疾患 / バイオリソース / iPS細胞 / バイオマーカー |
Outline of Annual Research Achievements |
本研究では、統合失調症の分子病態を明らかにすることのみならず、同定した分子メカニズムをもとに、患者の血中DNAといったバイオリソースを駆使して、治療応答性のバイオマーカーの開発をめざしている。統合失調症患者のうち、クロザピンが効果的であった患者、及びクロザピン抵抗性化まで進行した患者を選択し、独自に樹立した患者iPS細胞を神経幹細胞、未成熟神経細胞、および成熟神経細胞に分化させ、それぞれの細胞における神経機能の異常を解析するとともに、発症前の幼少期、発症オンセット、発症後、その後の治療抵抗性化、さらにはクロザピン抵抗性化という各ステップの分子病態を明らかにするための研究を推進してきた。今年度は、クロザピン応答性が異なる患者群に注目し、患者由来のiPS細胞を分化させた成熟神経細胞を用いて、シナプス機能の電気生理学的解析を実施した。その結果、クロザピンが効果的であった患者由来の神経細胞に比べて、治療抵抗性患者由来の神経細胞では、自発性微少興奮性シナプス後電流の振幅が大きいこと、およびその頻度が高いことを示唆する結果を得た。興奮性シナプス伝達を担っているAMPA型グルタミン酸受容体(AMPA受容体)の発現量は、健常者のものに比べて、患者神経細胞で高いことが明らかになった。また、AMPA受容体のシナプス部位への輸送を担っているAMPA受容体会合分子群のうち、TARP-8の発現量も高いことが明らかになった。また、当該患者群の臨床データの解析や血液サンプル由来のRNA発現解析を実施した。本年度の成果より、AMPA受容体に関する新たな統合失調症の分子病態が明らかになったほか、AMPA受容体の動態に着目した治療応答性のバイオマーカーの開発につながる基礎データを提供することができた。
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[Journal Article] Intranasal oxytocin administration ameliorates social behavioral deficits in POGZWT/Q1038R mouse model of autism spectrum disorder.2021
Author(s)
Kitagawa K, Matsumura K, Baba M, Kondo M, Takemoto T, Nagayasu K, Ago Y, Seiriki K, Hayata-Takano A, Kasai A, Takuma K, Hashimoto R, Hashimoto H, Nakazawa T.
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Journal Title
Mol Brain
Volume: 14
Pages: 56
DOI
Peer Reviewed / Open Access
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[Journal Article] Impaired inhibition of return during free-viewing behaviour in patients with schizophrenia.2021
Author(s)
Okada K, Miura K, Fujimoto M, Morita K, Yoshida M, Yamamori H, Yasuda Y, Iwase M, Shinozaki T, Fujita I, Hashimoto R.
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Journal Title
Sci Rep
Volume: 11
Pages: 3237
DOI
Peer Reviewed / Open Access
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[Journal Article] Platelet-Derived Growth Factor BB: A Potential Diagnostic Blood Biomarker for Differentiating Bipolar Disorder from Major Depressive Disorder.2021
Author(s)
Idemoto K, Ishima T, Niitsu T, Hata T, Yoshida S, Hattori K, Horai T, Otsuka I, Yamamori H, Toda S, Kameno Y, Ota K, Oda Y, Kimura A, Hashimoto T, Mori N, Kikuchi M, Minabe Y, Hashimoto R, Hishimoto A, Nakagome K, Iyo M, Hashimoto K.
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Journal Title
Psychiatr Res
Volume: 134
Pages: 48-56
DOI
Peer Reviewed / Open Access
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[Journal Article] Relationship between white matter microstructure and work hours.2021
Author(s)
Matsumoto J, Fukunaga M, Miura K, Nemoto K, Koshiyama D, Okada N, Morita K, Yamamori H, Yasuda Y, Fujimoto M, Hasegawa N, Watanabe Y, Kasai K, Hashimoto R.
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Journal Title
Neurosci Lett
Volume: 740
Pages: 135428
DOI
Peer Reviewed / Open Access
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[Journal Article] Delayed prefrontal hemodynamic response associated with suicide risk in autism spectrum disorder.2021
Author(s)
Ota T, Iida J, Okazaki K, Ishida R, Takahashi M, Okamura K, Yamamuro K, Kishimoto N, Kimoto S, Yasuda Y, Hashimoto R, Makinodan M, Kishimoto T.
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Journal Title
Psychiatry Res
Volume: 289
Pages: 112971
DOI
Peer Reviewed / Open Access
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[Journal Article] Ethnicity-Dependent Effects of Schizophrenia Risk Variants of the OLIG2 Gene on OLIG2 Transcription and White Matter Integrity.2020
Author(s)
Komatsu H, Takeuchi H, Kikuchi Y, Ono C, Yu Z, Iizuka K, Takano Y, Kakuto Y, Funakoshi S, Ono T, Ito J, Kunii Y, Hino M, Nagaoka A, Iwasaki Y, Yamamori H, Yasuda Y, Fujimoto M, Azechi H, Kudo N, Hashimoto R, Yabe H, Yoshida M, Saito Y, Kakita A, Fuse N, Kawashima R, Taki Y, Tomita H.
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Journal Title
Schizophr Bull
Volume: 46(6)
Pages: 1619-1628
DOI
Peer Reviewed / Open Access
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[Journal Article] Promoter Activity-Based Case-Control Association Study on SLC6A4 Highlighting Hypermethylation and Altered Amygdala Volume in Male Patients With Schizophrenia.2020
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.
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Journal Title
Schizophr Bull
Volume: 46(6)
Pages: 1577-1586
DOI
Peer Reviewed / Open Access
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[Journal Article] Lipocalin-type prostaglandin D synthase regulates light-induced phase advance of the central circadian rhythm in mice.2020
Author(s)
Kawaguchi C, Shintani N, Hayata-Takano A, Hatanaka M, Kuromi A, Nakamura R, Yamano Y, Shintani Y, Nagai K, Tsuchiya S, Sugimoto Y, Ichikawa A, Okuno Y, Urade Y, Hirai H, Nagata KY, Nakamura M, Narumiya S, Nakazawa T, Kasai A, Ago Y, Takuma K, Baba A, Hashimoto H.
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Journal Title
Commun Biol
Volume: 3(1)
Pages: 557
DOI
Peer Reviewed / Open Access
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[Journal Article] Association between the superior longitudinal fasciculus and perceptual organization and working memory: A diffusion tensor imaging study.2020
Author(s)
Koshiyama D, Fukunaga M, Okada N, Morita K, Nemoto K, Yamashita F, Yamamori H, Yasuda Y, Matsumoto J, Fujimoto M, Kudo N, Azechi H, Watanabe Y, Kasai K, Hashimoto R.
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Journal Title
Neurosci Lett
Volume: 738
Pages: 135349
DOI
Peer Reviewed / Open Access
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[Journal Article] Increased Dendritic Orientation Dispersion in the Left Occipital Gyrus is Associated with Atypical Visual Processing in Adults with Autism Spectrum Disorder.2020
Author(s)
Matsuoka K, Makinodan M, Kitamura S, Takahashi M, Yoshikawa H, Yasuno F,Ishida R, Kishimoto N, Yasuda Y, Hashimoto R, Taoka T, Miyasaka T, Kichikawa K, Kishimoto T.
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Journal Title
Cereb Cortex
Volume: 30(11)
Pages: 5617-5625
DOI
Peer Reviewed / Open Access
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[Journal Article] Activation of the VPAC2 Receptor Impairs Axon Outgrowth and Decreases Dendritic Arborization in Mouse Cortical Neurons by a PKA-Dependent Mechanism.2020
Author(s)
Takeuchi S, Kawanai T, Yamauchi R, Chen L, Miyaoka T, Yamada M, Asano S, Hayata-Takano A, Nakazawa T, Yano K, Horiguchi N, Nakagawa S, Takuma K, Waschek JA, Hashimoto H, Ago Y.
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Journal Title
Front Neurosci
Volume: 14
Pages: 521
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Associations of childhood experiences with event-related potentials in adults with autism spectrum disorder.2020
Author(s)
Okazaki K, Ota T, Makinodan M, Kishimoto N, Yamamuro, Ishida R, Takahashi M, Yasuda Y, Hashimoto R, Iida J, Kishimoto T.
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Journal Title
Sci Rep
Volume: 10(1)
Pages: 13447
DOI
Peer Reviewed / Open Access
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[Journal Article] Investigating DNA methylation of SHATI/NAT8L promoter sites in blood of unmedicated patients with major depressive disorder.2020
Author(s)
Miyanishi H, Uno K, Iwata M, Kikuchi Y, Yamamori H, Yasuda Y, Ohi K, Hashimoto R, Hattori K, Yoshida S, Goto Y, Sumiyoshi T, Nitta A.
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Journal Title
Biol Pharm Bull
Volume: 43(7)
Pages: 1067-1072
DOI
Peer Reviewed / Open Access
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[Journal Article] The Self-Construal Scale: a potential tool for predicting subjective well-being of individuals with autism spectrum disorder.2020
Author(s)
Kaneko S, Kato T, Makinodan M, Komori T, Ishida R, Kishimoto N, Takahashi M, Yasuda Y, Hashimoto R, Iwasaka H, Tanaka A, Uchida Y, Kanba S, Kishimoto T.
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Journal Title
Autism Res
Volume: 13(6)
Pages: 947-958
DOI
Peer Reviewed / Open Access
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[Journal Article] Plasma levels of matrix metalloproteinase-9 (MMP-9) are associated with cognitive performance in patients with schizophrenia.2020
Author(s)
Kudo N, Yamamori H, Ishima T, Nemoto K, Yasuda Y, Fujimoto M, Azechi H, Niitsu T, Numata S, Ikeda M, Iyo M, Ohmori T, Fukunaga M, Watanabe Y, Hashimoto K, Hashimoto R.
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Journal Title
Neuropsychopharmacol Rep
Volume: 40(2)
Pages: 150-156
DOI
Peer Reviewed / Open Access
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[Journal Article] Polygenetic Risk Scores for Major Psychiatric Disorders Among Schizophrenia Patients, Their First-Degree Relatives, and Healthy Participants.2020
Author(s)
Ohi K, Nishizawa D, Shimada T, Kataoka Y, Hasegawa J, Shioiri T, Kawasaki Y, Hashimoto R, Ikeda K.
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Journal Title
Int J Neuropsychopharmacol
Volume: 23(3)
Pages: 157-164
DOI
Peer Reviewed / Open Access
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[Journal Article] Polygenic Architecture of Human Neuroanatomical Diversity.2020
Author(s)
Biton A, Traut N, Poline JB, Aribisala BS, Bastin ME, Bulow R, Cox SR, Deary IJ, Fukunaga M, Grabe HJ, Hagenaars S, Hashimoto R, Kikuchi M, Munoz Maniega S, Nauck M, Royle NA, Teumer A, Valdes Hernandez M, Volker U, Wardlaw JM, Wittfeld K, Yamamori H; Alzheimer’s Disease Neuroimaging Initiative, Bourgeron T, Toro R.
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Journal Title
Cereb Cortex
Volume: 30(4)
Pages: 2307-2320
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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