Functional analysis of D-serine-metabolizing enzymes using RNA interference : Application to treatment of schizophrenia

• Project/Area Number: 19590258
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Tokai University
• Principal Investigator: HASHIMOTO Atsushi Tokai University, 医学部, 准教授 (80271592)
• Co-Investigator(Kenkyū-buntansha): YOSHIKAWA Masanobu 東海大学, 医学部, 講師 (90276791) ; KOBAYASHI Hiroyuki 東海大学, 医学部, 教授 (60195807)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: D-セリン / セリンラセマーゼ / 統合失調症 / D-アミノ酸オキシダーゼ / RNA干渉 / ノックアウトマウス

Research Abstract

本研究では、セリンラセマーゼ(SR)に対するsiRNAを用いてSRノックダウンラットの作出及びSRノックアウト(KO)マウスを用いてSRの機能解析を行う。ラット脳内にSRに対するsiRNAを投与したが、mRNA及びD-セリン含量に有意な差はみられなかった。一方、SR-KOマウスの大脳皮質D-セリン含量は正常マウスの約5%に減少していることが明らかになった。今後は、このKOマウスを用いて分子生物学的・行動学的、及び薬理学的な研究を行い、SRの脳内における機能及び統合失調症との関連を解析していく予定である。

Research Products

• [Journal Article] Mice lacking D-amino acid oxidase activity exhibit marked reduction of methamphetamine -induced stereotypy. (2008)
  • Author(s): Hashimoto A., Konno R., Yano H., Yoshikawa M., Tamaki R., Matsumoto H., Kobayashi H.
  • Journal Title: Eur. J. Pharmacol. 586 Pages: 221-225
  • Peer Reviewed
• [Journal Article] Long-term treatment with morphine increases the D-serine content in the rat brain by regulating the mRNA and protein expressions of serine racemase and D-amino acid oxidase (2008)
  • Author(s): N., Tsukamoto, H., Kawaguchi M., Kobayashi M., Oka, T., Hashimoto, A.
  • Journal Title: J. Pharmacol. Sci. 107 Pages: 270-276
  • NAID: 10024321297
  • Peer Reviewed
• [Journal Article] Midazolam attenuates the antinociception induced by D-serine or morphine at the supraspinal level in rats. (2008)
  • Author(s): Ito K., Yoshikawa M., Maeda M., Jin X.L., Takahashi S., Matsuda M., Tamaki R., Kobayashi H., Suzuki T., Hashimoto A.
  • Journal Title: morphine at the supraspinal level in rats. 586 Pages: 139-144
  • Peer Reviewed
• [Journal Article] Mice lacking D-amino acid oxidase activity exhibit marked reduction of methamphetamine-induced stereotypy. (2008)
  • Author(s): Hashimoto A., et al.
  • Journal Title: European Journal of Pharmacology 586 Pages: 221-225
  • Peer Reviewed
• [Journal Article] Long-term treatment with morphine increases the D-serine content in the rat brain by regulating the mRNA and protein expressions of serine racemase and D-amino acid oxidase. (2008)
  • Author(s): Yoshikawa M., et al.
  • Journal Title: J. Pharmcol. Sci. 107 Pages: 270-276
  • NAID: 10024321297
  • Peer Reviewed
• [Journal Article] Midazolam attenuates the antinociception induced by D-serine or morphine at the supraspinal level in rats. (2008)
  • Author(s): Ito K., et al.
  • Journal Title: European Journal of Pharmacology 586 Pages: 139-144
  • Peer Reviewed
• [Journal Article] Mice lacking D-amino acid oxidase activity exhibit marked reduction of methamphetamine-induced stereotypy. (2008)
  • Author(s): Atsushi Hashimoto, et. al.
  • Journal Title: European Journal of Pharmacology (in press)
  • Peer Reviewed
• [Journal Article] Activation of supraspinal NMDA receptors by both D-serine alone or in combination with morphine leads to the potentiation of antinociception in tail-flick (2007)
  • Author(s): Yoshikawa M., Ito K., Maeda M., Akahori K., Takahashi S., Jin X.L., Matsuda M., Suzuki T., Oka T., Kobayashi H., Hashimoto A.
  • Journal Title: Eur. J. Pharmacol. 565 Pages: 89-97
  • Peer Reviewed
• [Journal Article] The serine racemase mRNA is predominantly expressed in rat brain neurons (2007)
  • Author(s): Yoshikawa M., Takayasu N., Hashimoto A., Sato Y., Tamaki R., Tsukamoto H., Kobayashi H., Noda S.
  • Journal Title: Arch. Histol. Cytol. 70 Pages: 127-134
  • NAID: 10019551068
  • Peer Reviewed
• [Journal Article] Effects of MK-801 on the expression of serine racemase and D-amino acid oxidase mRNAs and on the D-serine levels in rat brain. (2007)
  • Author(s): Hashimoto A., Yoshikawa M., Andoh H., Yano H., Matsumoto H., Kawaguchi M., Oka T., Kobayashi H.
  • Journal Title: Eur. J. Pharmacol 555 Pages: 17-22
  • Peer Reviewed
• [Journal Article] Effects of MK-801 0n the expression of serine racemase and D-aminoacid oxidase mRNAs and on the D-serine levels in rat brain (2007)
  • Author(s): Atsushi Hashimoto, et. al.
  • Journal Title: European Journal of Pharmacology 555 Pages: 17-22
  • Peer Reviewed
• [Journal Article] Activation of suprasphinal NMDA receptors by both D-serine alone or in combination with morphine leads to the potentiation of antinociception in tail-flick test of rats. (2007)
  • Author(s): Masanobu Yoshikawa, et. al.
  • Journal Title: European Journal of Pharmacology 565 Pages: 89-97
  • Peer Reviewed
• [Presentation] ケタミン長期投与によるD-セリン代謝関連酵素遺伝子発現変化 (2009)
  • Author(s): 渡辺ら
  • Organizer: 第82回日本薬理学会年会
  • Place of Presentation: パシフイコ横浜
  • Year and Date: 2009-03-16
• [Presentation] ケタミン長期投与によるD-セリン代謝酵素遺伝子発現の変化 (2009)
  • Author(s): 渡邊真理子、吉川正信、竹山和秀、村田智彦、金幸禄、小林智美、橋本篤司、小林広幸、鈴木利保
  • Organizer: 第82回日本薬理学会年会
  • Place of Presentation: 横浜
• [Presentation] D-セリン関連タンパク質のmRNAは唾液腺において発現する (2008)
  • Author(s): 吉川正信、四宮敬史、小林智美、赤堀一仁、橋本篤司、小林広幸、川口充
  • Organizer: 第81回日本薬理学会年会
  • Place of Presentation: 横浜
• [Presentation] セリンラセマーゼmRNAは主に神経細胞に発現する (2007)
  • Author(s): 吉川 正信, ら
  • Organizer: 第50回日本神経化学会大会
  • Place of Presentation: パシヒコ横浜
  • Year and Date: 2007-09-11
• [Presentation] セリンラセマーゼMrnaは主に神経細胞に発現する (2007)
  • Author(s): 吉川正信、高安直子、野田節子、佐藤雄一、小林広幸、橋本篤司
  • Organizer: 第50回日本神経化学会大会
  • Place of Presentation: 横浜