病態解析研究部門 研究内容

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病態解析研究部門 研究内容

 当研究室では、精神疾患の病態解明、新しい診断法、治療法の開発に関する研究を進めています。これらの研究は、国内外の多くの大学、研究機関、企業等と共同で進めています。
当研究室の研究に興味があり、大学院(社会人大学院生も含む)への進学などを希望される方は橋本(hashimoto[at]faculty.chiba-u.jp)まで連絡ください。
千葉大学大学院医学薬学府の応募要項はこちらをご参照ください
(http://www.m.chiba-u.ac.jp/admissions/graduate.html)。

1.統合失調症の病態解明と新しい治療薬の開発

 統合失調症のグルタミン酸仮説および発達障害仮説に基づいた病態解明に関する研究、生物学的マーカーの開発や精神神経薬理学的手法、分子生物学的手法等を用いた新しい治療薬の開発研究(臨床研究試験も含めて)を進めている。

  • Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N, Nakazato M, Kumakiri C, Okada S, Hasegawa H, Imai K, Iyo M. Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen Psychiatry. 60(6): 572-576, 2003.
  • Yamada K*, Ohnishi T*, Hashimoto K*, Ohba H, Iwayama-Shigeno Y, Takao H, Toyota T, Minabe Y, Nakamura K, Shimizu E, Itokawa M, Mori N, Iyo M, Yoshikawa T. Identification of multiple serine racemase (SRR) mRNA isoforms and genetic analyses of SRR and DAO in schizophrenia and D-serine levels. Biol Psychiatry. 57(12): 1493-1503, 2005. (*equal contribution).
  • Hashimoto K, Fujita Y, Iyo M. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of fluvoxamine: role of sigma-1 receptors. Neuropsychopharmacology. 2007 Mar; 32(3):514-521.
  • Zhang L, Shirayama Y, Iyo M, Hashimoto K. Minocycline attenuates hyperlocomotion and prepulse inhibition deficits in mice after administration of the NMDA receptor antagonist dizocilpine. Neuropsychopharmacology. 2007 Sept; 32 (9): 2001-2010.
  • Hashimoto K, Ishima T, Fujita Y, Matsuo M, Kobashi T, Takahagi M, Tsukada H, Iyo M. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the novel selective α7 nicotinic receptor agonist SSR180711. Biol. Psychiatry 2008 Jan 1; 63(1): 92-97.
  • Matsuzawa D, Obata T, Shirayama Y, Nonaka H, Kanazawa Y, Yoshitome E, Takanashi J, Matsuda T, Shimizu E, Ikehira H, Iyo M, Hashimoto K. Negative correlation between brain glutathione levels and negative symptoms in schizophrenia: a 3T 1H-MRS study. PLoS ONE 2008 April; 4 (3): e1944.
  • Hashimoto K, Fujita Y, Horio M, Kunitachi S, Iyo M, Ferraris D, Tsukamoto T. Co-administration of D-amino acid oxidase inhibitor potentiates the efficacy of D-serine on prepulse inhibition deficits after administration of dizocilpine. Biol. Psychiatry 2009 June 15; 65 (12): 1103-1106.
  • Hashimoto K: Glycine transportor-1: a potential therapeutic target for schizophrenia. Curr. Pharm. Des. 2011 March; 17 (2): 112-120.
  • Ishikawa M, Hashimoto K: Alpha-7 nicotinic receptor: a potential therapeutic target for schizophrenia. Curr. Pharm. Des. 2011 March; 17 (2): 121-129.
  • Matsuzawa D, Hashimoto K: MRS study of antioxidant defense system in schizophrenia. Antioxi. Redox Sig. 2011 Oct 1; 15 (7): 2057-2065.

2.気分障害、摂食障害、自閉症等の病態解明と新しい治療薬の開発

 うつ病、摂食障害、自閉症(高機能自閉症、アスペルガー障害)等の病態研究と新しい診断方法および治療法の開発に関する研究を進めている。

  • Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nakazato M, Watanabe H, Shinoda N, Okada S, Iyo M. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry. 54(1): 70-75, 2003.
  • Nakazato M, Hashimoto K, Shimizu E, Kumakiri C, Koizumi H, Okamura N, Mitsumori M, Komatsu N, Iyo M. Decreased levels of serum brain-derived neurotrophic factor in female patients with eating disorders. Biol Psychiatry. 54(4): 485-490, 2003.
  • Hashimoto K, Shimizu E, Iyo M. Critical role of brain-derived neurotrophic factor in mood disorders. Brain Res Brain Res Rev. 45(2): 104-114, 2004.
  • Hashimoto K. BDNF variant linked to anxiety-related behaviors. BioEssays. 29(2): 116-119, 2007.
  • Suzuki K, Hashimoto K, Iwata Y, Nakamura K, Tsujii M, Tsuchiya KJ, Sekine Y, Suda S, Sugihara G, Matsuzaki H, Minabe Y, Sugiyama T, Kawai M, Takei N, Mori N. Decreased serum levels of epidermal growth factor in adult patients with high-functioning autism. Biol Psychiatry. 2007 Aug 1; 62(3): 267-269.
  • Tsuchiya K, Hashimoto K, Iwata Y, Tsujii M, Sekine Y, Sugihara G, Matsuzaki H, Suda S, Kawai M, Nakamura K, Minabe Y, Yagi A, Iyo M, Takei N., Mori N. Decreased serum levels of PECAM-1 in subjects with high-functioning autism: a negative correlation with head circumference at birth. Biol Psychiatry. 2007 Nov. 1; 62 (9): 1056-1058.
  • Hashimoto K, Sawa A, Iyo M. Increased levels of glutamate in brains from patients with mood disorders. Biol Psychiatry. 2007 Dec 1; 25 (11): 1310-1316.
  • Hashimoto K. Emerging role of glutamate in the pathophysiology of major depressive disorder. Brain Res. Rev. 2009 Oct; 61 (2): 105-123.
  • Hashimoto K. Brain-derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions. Psychiatry Clin. Neurosci. 2010 Aug; 64 (4): 341-357.
  • Hashimoto K: The role of glutamate on the action of antidepressants. Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 August 15; 35 (7): 1558-1568.
  • Tokita K, Yamaji T, Hashimoto K: Roles of glutamate signaling in preclinical and/or mechanistic models of depression. Pharmacol. Biochem. Behav. 2012 February; 100 (4): 688-704.

3.麻薬・覚せい剤による脳障害の治療法の開発

 近年我が国において、覚せい剤や麻薬の乱用が増加しており、大きな社会問題となっている。しかしながら、現在のところ、これらの薬物乱用による脳障害の治療法は無い。当研究室では、乱用薬物の作用メカニズムの解明、薬物依存に関連する脆弱性遺伝子と新しい治療法の開発等に関する研究を進めている。

  • Hashimoto K, Tsukada H, Nishiyama S, Fukumoto D, Kakiuchi T, Shimizu E, Iyo M. Protective effects of N-acetyl-L-cysteine on the reduction of dopamine transporters in the striatum of monkeys treated with methamphetamine. Neuropsychopharmacology. 29(11): 2018-2023, 2004.
  • Hashimoto K, Tsukada H, Nishiyama S, Fukumoto D, Kakiuchi T, Iyo M. Protective effects of minocycline on the reduction of dopamine transporters in the striatum after administration of methamphetamine: A PET study in conscious monkeys. Biol Psychiatry. 61 (5): 577-581, 2007.
  • Matsuzawa D, Hashimoto K, Miyatake R, Shirayama Y, Shimizu E, Maeda K, Suzuki Y, Mashimo Y, Sekine Y, Inada T, Ozaki N, Iwata N, Harano M, Komiyama T, Yamada M, Sora I, Ujike H, Hata A, Sawa A, Iyo M. Identification of functional polymorphisms in the promoter region of the human PICK1 gene and their association with methamphetamine psychosis. Am J Psychiatry. 2007 Jul; 164(7): 1105-1114.
  • Hashimoto K, Ishima T. A novel target of action of minocycline in NGF-induced neurite outgrowth in PC12 cells: translation initiation factor eIF4AI. PLoS One 2010 Nov.; 5 (11): e15430.
  • Sofuoglu M, Mooney M, Kosten TR, Walters A, Hashimoto K: Minocycline attenuates subjective-rewarding effects of dextroamphetamine in humans. Psychopharmacol. 2011 Jan 31; 213 (1): 61-68.

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