Analysis of D-serine dynamics in the brain and development of novel drugs against excitotoxicity

• Project/Area Number: 25293059
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: University of Toyama
• Principal Investigator: Mori Hisashi 富山大学, 大学院医学薬学研究部(医学), 教授 (00239617)
• Co-Investigator(Kenkyū-buntansha): TOYOOKA Naoki 富山大学, 大学院理工学研究部(工学), 教授 (10217565)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥14,820,000 (Direct Cost: ¥11,400,000、Indirect Cost: ¥3,420,000); Fiscal Year 2015: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2014: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2013: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
• Keywords: D-セリン / セリンラセマーゼ / マウスモデル / 興奮性神経毒性 / 創薬 / 神経変性疾患 / NMDA受容体

Outline of Final Research Achievements

In this study, we have tried to reveal the roles of D-serine in the neural functions and dysfunctions and examined the roles of D-serine producing enzyme serine racemase (SR) in vivo. We have found the novel roles of SR and D-serine in D-aspartate production, pain regulation in the spinal chord, and barrier function in the skin. Furthermore, to analyze the molecular basis of D-serine dynamics regulation in the brain, we have tried to generate two new mouse models, 1) neuronal D-serine transporter (Asc-1) conditional knockout mouse and 2) astrocyte-selective expression of D-serine degradation enzyme (Dsd-1) in mouse.
We also developed a novel SR inhibitor which is effective to suppress over-excitation in the brain. This compound will be a lead drug expected to suppress neuronal excitotoxicity.

Research Products

• [Int'l Joint Research] Technion-Israel Institute of Technology(イスラエル)
• [Int'l Joint Research] Ezrath Nashim-Herzog Memorial Hospital(イスラエル)
• [Int'l Joint Research] Columbia University(米国)
• [Journal Article] Nuclear compartmentalization of serine racemase regulates D-serine production: Implications for N-methyl-D-aspartate (NMDA) receptor activation. (2015)
  • Author(s): Kolodney, G., Dumin, E., Safory, H., Rosenberg, D., Mori, H., Radzishevsky, I., Wolosker, H.
  • Journal Title: J. Biol. Chem. Volume: 290 Issue: 6 Pages: 31037-50
  • DOI: 10.1074/jbc.a115.699496
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Neuromodulatory effect of Gαs- or Gαq-coupled GPCR on NMDAR selectively activates the NMDAR/Ca2+/calcineurin/CREB-regulated transcriptional coactivator 1 (CRTC1) pathway to effectively induce Bdnf expression in neurons. (2015)
  • Author(s): Fukuchi M, Tabuchi A, Kuwana Y, Watanabe S, Inoue M, Takasaki I, Izumi H, Tanaka A, Inoue R, Mori H, Komatsu H, Takamori H, Okuno H, Bito H, Tsuda M.
  • Journal Title: J Neurosci. Volume: 35 Issue: 14 Pages: 5606-5624
  • DOI: 10.1523/jneurosci.3650-14.2015
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and electrophysiological effects of D-serine in a schizophrenic patient positive for anti N-methyl-D-aspartate receptor antibodies. (2015)
  • Author(s): Heresco-Levy, U., Durrant, A. R., Ermilov, M., Javitt, D. C., Miya, K., Mori, H.
  • Journal Title: Biological Psychiatry Volume: 77 Issue: 6 Pages: e27-e29
  • DOI: 10.1016/j.biopsych.2014.08.023
  • Peer Reviewed
• [Journal Article] Is D-aspartate produced by glutamic-oxaloacetic transaminase -1 like 1(Got1l1), a putative aspartate racemase? (2015)
  • Author(s): Tanaka-Hayashi A, Hayashi S, Inoue R, Ito T, Konno K, Yoshida T, Watanabe M, Yoshimura T, Mori H
  • Journal Title: Amino Acids Volume: 47 Issue: 1 Pages: 79-86
  • DOI: 10.1007/s00726-014-1847-3
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] In silico and pharmacological screenings identify novel serine racemase inhibitors. (2014)
  • Author(s): Hisashi Mori, Ryogo Wada, Jie Li, Tetsuya Ishimoto, Mineyuki Mizuguchi, Takayuki Obita, Hiroaki Gouda, Shuichi Hirono, Naoki Toyooka.
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 24 Issue: 16 Pages: 3732-3735
  • DOI: 10.1016/j.bmcl.2014.07.003
  • Peer Reviewed
• [Journal Article] ncreased sensitivity to inflammatory pain induced by subcutaneous formalin injection in serine racemase knock-out mice. (2014)
  • Author(s): Tabata-Imai, A., Inoue, R., Mori, H.
  • Journal Title: PLOS ONE Volume: 9 Issue: 8 Pages: e105282-e105282
  • DOI: 10.1371/journal.pone.0105282
  • Peer Reviewed / Open Access
• [Journal Article] Localization of serine racemase and its role in the skin. (2014)
  • Author(s): Inoue R, Yoshihisa Y, Tojo Y, Okamura C, Yashida Y, Kishimoto J, Luan X, Watanabe M, Mizuguchi M, Nabeshima Y, Hamase K, Matsunaga K, Shimizu T, Mori H
  • Journal Title: J Invest Dermatol Volume: 134 Issue: 6 Pages: 610-618
  • DOI: 10.1038/jid.2014.22
  • Peer Reviewed / Open Access
• [Journal Article] 海馬におけるD-セリンの役割 (2013)
  • Author(s): 井上蘭, 森寿
  • Journal Title: Clinical Neuroscience Volume: 31 Pages: 1409-10
• [Presentation] D-セリンとセリンラセマーゼの生体機能 (2015)
  • Author(s): 森寿, 井上蘭
  • Organizer: 第38回日本分子生物学会年会 ワークショップ
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-03
  • Invited
• [Presentation] セリンラセマーゼのD-アスパラギン酸生合成への関与 (2015)
  • Author(s): 伊藤智和, 林田美郁, 小林爽季, 武藤菜摘, 林亜由美, 吉村徹, 森寿.
  • Organizer: 第11回D-アミノ酸学会学術講演会
  • Place of Presentation: 長岡
  • Year and Date: 2015-08-05
• [Presentation] Intrinsic role of serine racemase in apoptosis and metabolism. (2015)
  • Author(s): Gourango T., Inoue, R., Yoshida, T., Ishimoto, T., Nakagawa, T., Mori, H.
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-07-30
• [Presentation] Increased sensitivity to inflammatory pain induced by subcutaneous formalin injection in serine racemase KO mice (2014)
  • Author(s): H Mori, A Tabata-Imai, R Inoue
  • Organizer: IDAR2014
  • Place of Presentation: 宇都宮
  • Year and Date: 2014-09-04
  • Invited
• [Presentation] セリンラセマーゼノックアウトマウスでの炎症性疼痛感受性の上昇
  • Author(s): 田端彩子, 森寿, 井上蘭
  • Organizer: Neuro2013（日本神経科学会大会）
  • Place of Presentation: 京都
• [Presentation] セリンラセマーゼ遺伝子欠損マウス脳におけるD-アスパラギン酸濃度の低下
  • Author(s): 堀尾茉央, 石間環, 藤田有子, 井上蘭, 森寿, 橋本謙二
  • Organizer: 第9回D-アミノ酸研究会学術講演会
  • Place of Presentation: 大阪
• [Presentation] 皮膚におけるセリンラセマーゼの発現および機能解析
  • Author(s): 井上蘭, 吉久陽子, 東條洋介, 岡村智恵子, 吉田雄三, 岸本治朗, Luan Xinghua, 渡辺雅彦, 水口峰之, 鍋島裕子, 浜瀬健司, 松永憲治, 清水忠道, 森寿
  • Organizer: 第9回D-アミノ酸研究会学術講演会
  • Place of Presentation: 大阪
• [Presentation] セリンラセマーゼとD-セリンの生体機能
  • Author(s): 森寿
  • Organizer: 第87回日本薬理学会年会シンポジウム
  • Place of Presentation: 仙台
  • Invited
• [Presentation] セリンラセマーゼ新規阻害剤の開発
  • Author(s): 和田亮吾, Li Jie, 合田浩昭, 広野修一, 水口峰之, 豊岡尚樹, 森寿
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台
• [Book] 情動学シリーズ２「情動学習の分子機構、情動の仕組みとその異常」山脇成人、西条寿夫編集 (2015)
  • Author(s): 井上蘭、森寿
  • Total Pages: 16
  • Publisher: 朝倉書店