Investigation on pathophysiology of schizophrenia by using linearity of endophenotype

• Project/Area Number: 19H03589
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: ITOKAWA Masanari 公益財団法人東京都医学総合研究所, 精神行動医学研究分野, 副所長 (40332324)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2021: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2020: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2019: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
• Keywords: 中間表現型 / 統合失調症 / レア・バリアント / 分子マーカー / 線形性 / カルボニルストレス

Outline of Research at the Start

本研究の目的は、動態に線形性を有する血中分子を中間表現型として活用し、統合失調症の病態を解明することである。高血圧では、アンギオテンシン転換酵素などの昇圧分子と遺伝子型との間にgenotype-phenotype correlation（遺伝子型・表現型相関）が認められ、昇圧分子と血圧の間にも相関関係が成立する。多くの内科疾患では遺伝子‐中間分子‐表現型の間に線形性が認められるため、病態研究や治療薬開発に数学や薬理学が有効に活用できる。

Outline of Final Research Achievements

The aim of this research is elucidation of pathophysiology of schizophrenia by using linearity of endophenotype as serum molecules. We found social behavioral disorders as phenotype using model mice constructed with endophenotype of vitamin B6 and AGEs. We identified neural structural changes and vascular abnormalities in schizophrenia by using Spring8.

Academic Significance and Societal Importance of the Research Achievements

高血圧や糖尿病と比較して統合失調症の病態解明が遅れる要因を、症状の線形性の有無に帰着させる発想に独自性があると考える。missing heritability問題をあえてゲノムで解決せずに、バイオケミカルに決着を図る点に学術的意義がある。大型放射光施設を用いて統合失調症の神経構造の変化をとらえた点、および特発性の代謝病態を示唆するサンプルで変化が大きかった点は、統合失調症を提案したクレペリンが代謝性の脳病理変化を想定していたことを支持しており、この点に学術的意義があると考える。

Research Products

• [Journal Article] Schizophrenia-Mimicking Layers Outperform Conventional Neural Network Layers (2022)
  • Author(s): Mizutani Ryuta、Noguchi Senta、Saiga Rino、Yamashita Yuichi、Miyashita Mitsuhiro、Arai Makoto、Itokawa Masanari
  • Journal Title: Frontiers in Neurorobotics Volume: 16 Pages: 851471-851471
  • DOI: 10.3389/fnbot.2022.851471
  • Peer Reviewed / Open Access
• [Journal Article] Vitamin B6 deficiency hyperactivates the noradrenergic system, leading to social deficits and cognitive impairment (2021)
  • Author(s): Toriumi Kazuya、Miyashita Mitsuhiro、Suzuki Kazuhiro、Yamasaki Nao、Yasumura Misako、Horiuchi Yasue、Yoshikawa Akane、Asakura Mai、Usui Noriyoshi、Itokawa Masanari、Arai Makoto
  • Journal Title: Translational Psychiatry Volume: 11 Issue: 1 Pages: 262-262
  • DOI: 10.1038/s41398-021-01381-z
  • Peer Reviewed / Open Access
• [Journal Article] Brain capillary structures of schizophrenia cases and controls show a correlation with their neuron structures. (2021)
  • Author(s): Saiga R, Uesugi M, Takeuchi A, Uesugi K, Suzuki Y, Takekoshi S, Inomoto C, Nakamura N, Torii Y, Kushima I, Iritani S, Ozaki N, Oshima K, Itokawa M, Arai M, Mizutani R.
  • Journal Title: Sci Rep. Volume: 11 Issue: 1 Pages: 11768-11768
  • DOI: 10.1038/s41598-021-91233-z
  • Peer Reviewed / Open Access
• [Journal Article] Advanced glycation end products and cognitive impairment in schizophrenia (2021)
  • Author(s): Kobori Akiko、Miyashita Mitsuhiro、Miyano Yasuhiro、Suzuki Kazuhiro、Toriumi Kazuya、Niizato Kazuhiro、Oshima Kenichi、Imai Atsushi、Nagase Yukihiro、Yoshikawa Akane、Horiuchi Yasue、Yamasaki Syudo、Nishida Atsushi、Usami Satoshi、Takizawa Shunya、Itokawa Masanari、Arai Heii、Arai Makoto
  • Journal Title: PLOS ONE Volume: 16 Issue: 5 Pages: e0251283-e0251283
  • DOI: 10.1371/journal.pone.0251283
  • Peer Reviewed / Open Access
• [Journal Article] Combined glyoxalase 1 dysfunction and vitamin B6 deficiency in a schizophrenia model system causes mitochondrial dysfunction in the prefrontal cortex (2021)
  • Author(s): Toriumi Kazuya、Berto Stefano、Koike Shin、Usui Noriyoshi、Dan Takashi、Suzuki Kazuhiro、Miyashita Mitsuhiro、Horiuchi Yasue、Yoshikawa Akane、Asakura Mai、Nagahama Kenichiro、Lin Hsiao-Chun、Sugaya Yuki、Watanabe Takaki、Kano Masanobu、Ogasawara Yuki、Miyata Toshio、Itokawa Masanari、Konopka Genevieve、Arai Makoto
  • Journal Title: Redox Biology Volume: 45 Pages: 102057-102057
  • DOI: 10.1016/j.redox.2021.102057
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-sucrose diets contribute to brain angiopathy with impaired glucose uptake and psychosis-related higher brain dysfunctions in mice (2021)
  • Author(s): Hirai Shinobu, Toriumi Kazuya (4番目/24人中), et al.
  • Journal Title: Science Advances Volume: 7 Issue: 46 Pages: 1-5
  • DOI: 10.1126/sciadv.abl6077
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] AKR1A1 Variant Associated With Schizophrenia Causes Exon Skipping, Leading to Loss of Enzymatic Activity (2021)
  • Author(s): Iino Kyoka, Toriumi Kazuya (2番目/23人中), et al.
  • Journal Title: Frontiers in Genetics Volume: 12 Pages: 762999-762999
  • DOI: 10.3389/fgene.2021.762999
  • Peer Reviewed / Open Access
• [Journal Article] Cooperation of LIM domain-binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia. (2021)
  • Author(s): Ohnishi T, Kiyama Y, Arima-Yoshida F, Kadota M, Ichikawa T, Yamada K, Watanabe A, Ohba H, Tanaka K, Nakaya A, Horiuchi Y, Iwayama Y, Toyoshima M, Ogawa I, Shimamoto-Mitsuyama C, Maekawa M, Balan S, Arai M, Miyashita M, Toriumi K, et al.
  • Journal Title: EMBO Mol Med Volume: 13 Issue: 4
  • DOI: 10.15252/emmm.202012574
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structural diverseness of neurons between brain areas and between cases. (2021)
  • Author(s): Mizutani R, Saiga R, Yamamoto Y, Uesugi M, Takeuchi A, Uesugi K, Terada Y, Suzuki Y, De Andrade V, De Carlo F, Takekoshi S, Inomoto C, Nakamura N, Torii Y, Kushima I, Iritani S, Ozaki N, Oshima K, Itokawa M, Arai M.
  • Journal Title: Transl Psychiatry. Volume: 11 Issue: 1 Pages: 49-49
  • DOI: 10.1038/s41398-020-01173-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Peroxisome proliferator-activated receptor α as a novel therapeutic target for schizophrenia (2020)
  • Author(s): Wada, Maekawa, Ohnishi et al.
  • Journal Title: EBioMedicine Volume: 62 Pages: 103130-103130
  • DOI: 10.1016/j.ebiom.2020.103130
  • Peer Reviewed / Open Access
• [Journal Article] LDB2 locus disruption on 4p16.1 as a risk factor for schizophrenia and bipolar disorder (2020)
  • Author(s): Horiuchi, Ichikawa, Ohnishi et al.
  • Journal Title: Human Genome Variation Volume: 7 Issue: 1 Pages: 31-31
  • DOI: 10.1038/s41439-020-00117-7
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced Carbonyl Stress and Disrupted White Matter Integrity in Schizophrenia. (2020)
  • Author(s): Son S, Arai M, Toriumi K, Mizuta H, Miyata J, Hayashi T, Aso T, Itokawa M, Murai T.
  • Journal Title: Schizophr Res Volume: 223 Pages: 242-248
  • DOI: 10.1016/j.schres.2020.08.007
  • Peer Reviewed / Open Access
• [Journal Article] バイオマーカーへの期待．代替マーカー (2020)
  • Author(s): 宮下光弘、石田裕昭、鈴木一浩、宮野康寛、鳥海和也、吉川茜、堀内泰江、今井淳、長瀬幸弘、糸川昌成、新井誠
  • Journal Title: 精神科 Volume: 37(6) Pages: 621-626
  • Peer Reviewed
• [Journal Article] 慢性期統合失調症の１症例へのヨーガ療法介入 (2020)
  • Author(s): 井上智子, 宮下光弘, 鈴木一浩, 吉川茜, 堀内泰江, 鳥海和也, 木村慧心, 糸川昌成, 新井誠
  • Journal Title: 精神科治療学 Volume: 35(6) Pages: 649-655
  • Peer Reviewed
• [Journal Article] Potential prognostic impact of EBV RNA-seq reads in gastric cancer: a reanalysis of The Cancer Genome Atlas cohort (2020)
  • Author(s): Sadato D, Ogawa M, Hirama C, Hishima T, Horiguchi S, Harada Y, Shimoyama T, Itokawa M, Ohashi K, Oboki K
  • Journal Title: FEBS Open Bio Volume: 10 Issue: 3 Pages: 455-467
  • DOI: 10.1002/2211-5463.12803
  • Peer Reviewed / Open Access
• [Journal Article] Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology. (2019)
  • Author(s): Ide M, et al. .... Kimura H, Yoshikawa T.
  • Journal Title: EMBO Mol Med. Volume: 11(12) Issue: 12
  • DOI: 10.15252/emmm.201910695
  • NAID: 120007132855
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 精神症状と病因の非対応 (2019)
  • Author(s): 糸川昌成
  • Journal Title: PSYCHIATRY Volume: VOL.36 No.1 Pages: 77-85
• [Journal Article] Cutting‐edge morphological studies of post‐mortem brains of patients with schizophrenia and potential applications of X‐ray nanotomography (nano‐CT) (2019)
  • Author(s): Itokawa Masanari、Oshima Kenichi、Arai Makoto、Torii Yota、Kushima Itaru、Iritani Shuji、Ozaki Norio、Saiga Rino、Mizutani Ryuta
  • Journal Title: Psychiatry and Clinical Neurosciences Volume: 74 Issue: 3 Pages: 176-182
  • DOI: 10.1111/pcn.12957
  • Peer Reviewed
• [Journal Article] 放射光ナノトモグラフィ法を用いた統合失調症における神経細胞の構造変化の解析－脳組織の幾何学－ (2019)
  • Author(s): 糸川昌成, 大島健一, 新井誠, 鳥居洋太, 久島周, 入谷修司, 尾崎紀夫, 雑賀里乃, 水谷隆太
  • Journal Title: 精神神経学雑誌 Volume: 121(12) Pages: 926-940
  • NAID: 40022115112
• [Journal Article] 神経細胞の形の個人差と統合失調症脳での構造変化 (2019)
  • Author(s): 雑賀里乃, 水谷隆太, 竹腰進, 井野元智恵, 中村直哉, 鳥居洋太, 久島周, 入谷修司, 尾崎紀夫, 糸川昌成, 大島健一, 新井誠
  • Journal Title: 分子精神医学 Volume: Vol.19 No.4 Pages: 54-57
• [Journal Article] 無意識の縁起論 (2019)
  • Author(s): 糸川昌成
  • Journal Title: 日本生物学的精神医学会誌 Volume: 30(3) Pages: 93-93
  • NAID: 130007777472
• [Journal Article] 統合失調症早期支援の現状と今後の展望－学校をめぐる取り組みを中心に－ (2019)
  • Author(s): 吉川茜, 菅原誠, 糸川昌成, 熊谷直樹
  • Journal Title: PSYCHIATRY Volume: VOL.35 No.1 Pages: 115-123
  • NAID: 40021927518
  • Peer Reviewed
• [Presentation] 統合失調症にバイオマーカーはあるのか (2021)
  • Author(s): 糸川昌成
  • Organizer: 日本精神神経科診療所協会第27回学術研究会
• [Presentation] 病いは物語である (2021)
  • Author(s): 糸川昌成
  • Organizer: 第11回都医学研シンポジウム
• [Presentation] 生物学的精神医学はどこまでKraepelinの夢に迫れたのだろう (2021)
  • Author(s): 糸川昌成
  • Organizer: 第15回日本統合失調症学会
• [Presentation] microRNA遺伝子部分欠失を伴う思春期発症カルボニルストレス性統合失調症患者の一例 (2021)
  • Author(s): 吉川茜, 久島周, 鈴木一浩, 宮下光弘, 鳥海和也, 堀内泰江, 尾崎紀夫, 糸川昌成, 新井誠
  • Organizer: 第15回日本統合失調症学会
• [Presentation] Glo１遺伝子欠損とビタミンB6欠乏による新たなカルボニルストレス性統合失調症マウスモデルの解析 (2021)
  • Author(s): 鳥海和也, 鈴木一浩, 小池伸, 宮下光弘, 堀内泰江, 吉川茜, 小笠原裕樹, 糸川昌成, 新井誠
  • Organizer: 第15回日本統合失調症学会
• [Presentation] 非侵襲的測定法を用いた統合失調症と週末糖化産物(advanced glycation end-products, AGEs)の関連研究 (2021)
  • Author(s): 宮下光弘, 鈴木一浩, 鳥海和也, 堀内泰江, 吉川茜, 江越正俊, 宮野康寛, 糸川昌成, 新井誠
  • Organizer: 第15回日本統合失調症学会
• [Presentation] 統合失調症の予防・治療におけるAGEsの意義 (2020)
  • Author(s): 宮下光弘、鈴木一浩、吉川茜、堀内泰江、鳥海和也、石田裕昭、宮野康寛、今井淳司、長瀬幸弘、糸川昌成、新井誠
  • Organizer: 第93回日本生化学会大会
• [Presentation] モノアミン変動を介したヤマブシタケ(Hericium erinaceus)の統合失調症治療可能性の検討 (2020)
  • Author(s): 王恬冉, 鈴木一浩、鳥海和也、宮下光弘、東江璃子、朝倉舞、糸川昌成、新井誠
  • Organizer: 第93回日本生化学会大会
• [Presentation] Schizophrenia paradox-A material or an event- (2019)
  • Author(s): Itokawa M
  • Organizer: 6th Congress of ASCNP
  • Int'l Joint Research
• [Presentation] Methylglyoxal in plasma associate with anxiety in healthy individual (2019)
  • Author(s): Suzuki K, Toriumi K, Miyashita M, Yoshikawa A, Horiuchi Y, Koike S, Ogasawara Y, Itokawa M, Washizuka S, Arai M
  • Organizer: 6th Congress of ASCNP
  • Int'l Joint Research
• [Presentation] Vitamin B6-deficient animal model for schizophrenia with carbonyl stress (2019)
  • Author(s): Toriumi K, Suzuki K, Asakura M, Miyashita M, Horiuchi Y, Kobori A, Itokawa M, Arai M
  • Organizer: 6th Congress of ASCNP
  • Int'l Joint Research
• [Presentation] Efficacy and side effect of Pyridoxamine for patients with schizophrenia (2019)
  • Author(s): Miyashita M, Toriumi K, Suzuki K, Horiuchi Y, Yoshikawa A, Kobori A, Itokawa M, Arai M
  • Organizer: 6th Congress of ASCNP
• [Presentation] The utility of patients derived Neuron/glial cells for the schizophrenia disease model (2019)
  • Author(s): Horiuchi Y, Egoshi M, Toriumi K, Miyashita M, Itokawa M, Arai M
  • Organizer: 6th Congress of ASCNP
• [Presentation] 分子生物学者が見た病のイニシエーション (2019)
  • Author(s): 糸川昌成
  • Organizer: 日本デイケア学会第24回年次大会
• [Presentation] ヨーガ療法による自律神経活動変化 (2019)
  • Author(s): 井上智子, 榛葉俊一, 宮下光弘, 鈴木一浩, 堀内泰江, 鳥海和也, 糸川昌成, 木村慧心，新井誠
  • Organizer: 第115回日本精神神経学会学術総会
• [Presentation] 心のエビデンスとは何か－ベッドサイドのオートファジー－ (2019)
  • Author(s): 糸川昌成
  • Organizer: 第17回IGC第13回COCORO合同会議
• [Presentation] 標準化を超えて (2019)
  • Author(s): 糸川昌成
  • Organizer: 第14回日本統合失調症学会
• [Remarks] 統合失調症プロジェクト
  • URL: https://www.igakuken.or.jp/schizo-dep/