Application of chiral-specificity of amino acids on the novel development of antipsychotic drugs for schizophrenia

• Project/Area Number: 26461713
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Tokyo Metropolitan Tama Medical Center (Department of Clinical Research) (2016-2017); Tokyo Medical and Dental University (2014-2015)
• Principal Investigator: YAMAMOTO Naoki 東京都立多摩総合医療センター(臨床研究・教育研修センター(臨床研究部)), 精神神経科, 部長 (70312296)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: D－セリン / NMDA受容体 / 統合失調症 / D－アミノ酸 / グリシン / グルタミン酸 / NMDA / PCP / D-アミノ酸

Outline of Final Research Achievements

In this study I have focused on chiral-specificity of amino acids to understand molecular basis in developing novel antipsychotic drugs for schizophrenia. D-Serine, an NMDA receptor coagonist, plays a crucial role in neurocognitive functions. From a pathophysiological aspect, dysfunction of D-serine/NMDA receptor signaling system may be involved in schizophrenia-related symptoms. To obtain further insights into the molecular basis of schizophrenia and other related mental disorders, I have investigated the genetic association of candidate genes and schizophrenia as case-control study. I obtained profiles of the relationship of these genes, including the splicing system of them, and schizophrenia.

Research Products

• [Journal Article] Association studies of WD repeat domain 3 and chitobiosyldiphosphodolichol beta- mannosyltransferase genes with schizophrenia in a Japanese population. (2018)
  • Author(s): Momoko Kobayashi, Daisuke Jitoku, Yoshimi Iwayama, Naoki Yamamoto, Tomoko Toyota, Katsuaki Suzuki, Mitsuru Kikuchi, Tasuku Hashimoto, Nobuhisa Kanahara, Akeo Kurumaji, Takeo Yoshikawa, Toru Nishikawa
  • Journal Title: PLoS ONE Volume: 13 Issue: 1 Pages: e0190991-e0190991
  • DOI: 10.1371/journal.pone.0190991
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association of schizophrenia onset age and white matter integrity with treatment effect of D-cycloserine: a randomized placebo- controlled double-blind crossover study (2017)
  • Author(s): Kazuo Takiguchi, Akihito Uezato, Michio Itasaka, Hidenori Atsuta, Kenji Narushima, Naoki Yamamoto, Akeo Kurumaji, Makoto Tomita, Kazunari Oshima, Kosaku Shoda, Mai Tamaru, Masahito Nakataki, Mitsutoshi Okazaki, Sayuri Ishiwata, Yasuyoshi Ishiwata, Masato Yasuhara, Kunimasa Arima,Tetsuro Ohmori, Toru Nishikawa
  • Journal Title: BMC Psychiatry, Volume: 17 Issue: 1 Pages: 249-263
  • DOI: 10.1186/s12888-017-1410-3
  • NAID: 120006772556
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic and molecular risk factors within the newly identified primate-specific exon of the SAP97/DLG1 gene in the 3q29 schizophrenia-associated locus. (2017)
  • Author(s): Akihito Uezato, Naoki Yamamoto, Daisuke Jitoku, Emiko Haramo, Eri Hiraaki, Yoshimi Iwayama, Tomoko Toyota, Masakazu Umino, Asami Umino, Yasuhide Iwata, Katsuaki Suzuki, Mitsuru Kikuchi, Tasuku Hashimoto, Nobuhisa Kanahara, Akeo Kurumaji, Takeo Yoshikawa, Toru Nishikawa.
  • Journal Title: American Journal of Medical Genetics(Part B): Neuropsychiatric_Genetics, Volume: 174 Issue: 8 Pages: 798-804
  • DOI: 10.1002/ajmg.b.32595
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Reduced cortical expression of a newly identified splicing variant of the DLG1 gene in patients with early-onset schizophrenia. (2015)
  • Author(s): Uezato A, Yamamoto N, Iwayama Y, Hiraoka S, Hiraaki E, Umino A, Haramo E, Umino M, Yoshikawa T, Nishikawa T.
  • Journal Title: Transl Psychiatry Volume: 5 Issue: 1 Pages: 130-130
  • DOI: 10.1186/s12888-016-0835-4
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 統合失調症のグルタミン酸仮説と診断の可能性. (2015)
  • Author(s): 上里彰仁, 山本直樹, 西川徹.
  • Journal Title: 精神科治療学 Volume: 30 Pages: 11-17
• [Journal Article] Association study of H2AFZ with schizophrenia in a Japanese case-control sample. (2015)
  • Author(s): Jitoku D, Yamamoto N, Iwayama Y, Toyota T, Miyagi M, Enokida T, Tasaka Y, Umino M, Umino A, Uezato A, Iwata Y, Suzuki K, Kikuchi M, Hashimoto T, Kanahara N, Kurumaji A, Yoshikawa T, Nishikawa T.
  • Journal Title: J Neural Transm Volume: 122 Pages: 915-923
  • Peer Reviewed / Open Access
• [Journal Article] RBM10 regulates alternative splicing. (2014)
  • Author(s): Inoue A, Yamamoto N, Kimura M, Nishio K, Yamane H, Nakajima K.
  • Journal Title: FEBS Lett. Volume: 588 Pages: 942-947
  • Peer Reviewed / Open Access
• [Presentation] A case of Hyperekplexia treated as epilepsy (2017)
  • Author(s): 日野慶子、後藤知英)、玉井眞一郎、寺澤佑哉、櫻井薫、福島康浩、山口順嗣、鷺坂彰吾、竹谷健、森野道晴、山本直樹
  • Organizer: 第51回日本てんかん学会学術集会
• [Presentation] Phencyclidineに発達依存的応答を示す遺伝子PRT7と統合失調症との関連解析 (2015)
  • Author(s): 山本直樹、本間斐、治徳大介、海野麻未、岩山佳美、吉川武男、西川徹
  • Organizer: 第37回日本生物学的精神医学会年会
  • Place of Presentation: タワーホール船堀（東京都江戸川区））
  • Year and Date: 2015-09-24
• [Presentation] 統合失調症と性染色体：二動原体X染色体（p11）型ターナー症候群の解析（第２報） (2015)
  • Author(s): 山本直樹、西川徹
  • Organizer: 第111回日本精神神経学会学術総会
  • Place of Presentation: 大阪国際会議場（大阪市）
  • Year and Date: 2015-06-04
• [Presentation] フェンサイクリジンによって発達段階依存的に発現誘導を受けるnon-coding RNA prt6 および標的候補遺伝子の薬理学的特性および統合失調症における遺伝子関連解析 (2014)
  • Author(s): 山本直樹、竹林裕直、治徳大介、海野真一、海野麻未、岩山佳美、吉川武男、西川徹
  • Organizer: 第24回日本臨床精神神経薬理学会第44回日本神経精神薬理学会合同年会
  • Place of Presentation: 名古屋市、名古屋国際会議場
  • Year and Date: 2014-11-20 – 2014-11-22
• [Presentation] 統合失調症関連遺伝子とクロマチン制御 (2014)
  • Author(s): 山本 直樹、西川 徹
  • Organizer: 第36回日本生物学的精神医学会第57回日本神経化学会大会合同年会
  • Place of Presentation: 奈良市、奈良県文化会館奈良県新公会堂
  • Year and Date: 2014-09-29 – 2014-10-01
• [Presentation] HSPA1B遺伝子と統合失調症の関連解析 (2014)
  • Author(s): 白石知也、山本直樹、治徳大介、岩山佳美、吉川武男、西川徹
  • Organizer: 第36回日本生物学的精神医学会第57回日本神経化学会大会合同年会
  • Place of Presentation: 奈良市、奈良県文化会館奈良県新公会堂
  • Year and Date: 2014-09-29 – 2014-10-01
• [Presentation] Splicing制御因子SRSF1遺伝子と統合失調症の関連解析 (2014)
  • Author(s): 野中美佐、山本直樹、治徳大介、岩山佳美、吉川武男、西川徹
  • Organizer: 第36回日本生物学的精神医学会第57回日本神経化学会大会合同年会
  • Place of Presentation: 奈良市、奈良県文化会館奈良県新公会堂
  • Year and Date: 2014-09-29 – 2014-10-01
• [Presentation] Identification of developmentally regulated NMDA receptor antagonist phencyclidine-responsive transcripts in the rat brain. (2014)
  • Author(s): Yamamoto N, Takebayashi H, Umino A, Nishikawa T.
  • Organizer: 29th CINP World Congress of Neuropsychopharmacology2014
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2014-06-22 – 2014-06-26
• [Book] 南山堂医学大辞典 (2015)
  • Author(s): 山本直樹
  • Total Pages: 3101
  • Publisher: 南山堂