Establishment of animal model harboring a homologous mutation ofhuman epilepsy and analysis of genomics"

• Project/Area Number: 18300137
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Laboratory animal science
• Research Institution: Hirosaki University
• Principal Investigator: UENO Shinya Hirosaki University, 大学院・医学研究科, 教授 (00312158)
• Co-Investigator(Kenkyū-buntansha): ARAKI Kimi 熊本大学, 学内共同利用施設等, 准教授 (90211705) ; OKAMOTO Motohiro 三重大学, 大学院・医学研究科, 教授 (10281916) ; TOMIYAMA Masahiko 弘前大学, 大学院・医学研究科, 准教授 (40311542) ; FUKUZAWA Masashi 弘前大学, 農学生命科学部, 准教授 (10231557) ; MIGITA Keisuke 弘前大学, 大学院・医学研究科, 助教 (10352262) ; YAMADA Junko 弘前大学, 大学院・医学研究科, 助教 (30334965) ; MORIYAMA Tomoko 弘前大学, 大学院・医学研究科, 助教 (90400134)
• Research Collaborator: KANEKO Sunao 弘前大学, 大学院・医学研究科, 教授 (40106852)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,380,000 (Direct Cost: ¥15,200,000、Indirect Cost: ¥3,180,000); Fiscal Year 2008: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000); Fiscal Year 2007: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2006: ¥4,600,000 (Direct Cost: ¥4,600,000)
• Keywords: 脳・神経 / てんかん / 疾患モデル / 遺伝子改変動物 / イオンチャネル / AChチャネル

Research Abstract

ヒト常染色体優性夜間前頭葉てんかん責任遺伝子(nACh receptor 遺伝子変異 : S284L)を導入したラット(S284L-Tg)を作出し、脳波解析、行動解析、電気生理的機能解析の結果、Facevalidity(疾患とモデルの表現型の妥当性)、Construct validity(疾患とモデルのメカニズムの妥当性)、Predictive validity(疾患治療薬がモデルにも有効)の3点をクリアする世界初のてんかんモデルラットであることを示し報告した(J.Neurosci 28 (2008) 12465-12476))。

Research Products

• [Journal Article] Establishment of germline-competentembryonic stem cell lines from the MSM/Msstrain (2009)
  • Author(s): Araki, K., Takeda, N., Yoshiki, A.,Obata, Y., Nakagata, N., Shiroishi, T. Moriwaki, K. and Yamamura, K.
  • Journal Title: Mamm Genome 20 Pages: 14-20
  • Peer Reviewed
• [Journal Article] Orexin A decreases ketamine-induced anesthesia time in the rat : the relevance to brain noradrenergic neuronal activity (2009)
  • Author(s): Tose R, Kushikata T, Yoshida H, Kudo M, Furukawa K, Ueno S & Hirota K.
  • Journal Title: Anesthesia and analgesia 108 Pages: 491-495
  • Peer Reviewed
• [Journal Article] Interaction between orexinergic neurons and NMDA receptors in the control of locus coeruleus-cerebrocortical noradrenergic activity of the rat (2009)
  • Author(s): Tose R, Kushikata T, Yoshida H, Kudo M, Furukawa K, Ueno S & Hirota K.
  • Journal Title: Brain Res 1250 Pages: 81-87
  • Peer Reviewed
• [Journal Article] Defective development of the gall bladder and cystic duct in Lgr4-hypomorphic mice (2009)
  • Author(s): Yamashita, R., Takegawa, Y., Sakumoto, M., Nakahara, M., Kawazu, H., Hoshii, T., Araki, K., Yokouchi, Y. and Yamamura, K.
  • Journal Title: Dev. Dyn 238 Pages: 993-1000
  • Peer Reviewed
• [Journal Article] Rad18 is required for long-term maintenance of spermatogenesis in mouse testes (2009)
  • Author(s): Sun, J., Yomogida, K., Sakao, S., Yamamoto, H., Yoshida, K., Watanabe, K., Morita, T., Araki, K., Yamamura, K. and Tateishi, S.
  • Journal Title: Mech Dev 126 Pages: 173-183
  • Peer Reviewed
• [Journal Article] Age-related pulmonary emphysema in mice lacking α/β hydrolase domain containing 2 gene (2009)
  • Author(s): Jin, S., Zhao, G., Li, Z., Nishimoto, Y., Isohama, Y., Shen, J., Ito, T., Takeya, M., Araki K., He, P. and Yamamura, K.
  • Journal Title: Biochem. Biophys. Res. Commun 380 Pages: 419-424
  • Peer Reviewed
• [Journal Article] Establishment of germline-competent embryonic stem cell lines from the MSM/Ms strain (2009)
  • Author(s): Araki, K., Takeda, N., Yoshiki, A., Obata, Y., Nakagata, N., Shiroishi, T., Moriwaki, K. and Yamamura, K.
  • Journal Title: Mamm Genome 20 Pages: 14-20
  • Peer Reviewed
• [Journal Article] Rats Harboring S284L Chrna4 MutationShow Attenuation of Synaptic and Extrasynaptic GABAergic Transmission and Exhibit the Nocturnal Frontal LobeEpilepsy Phenotyp J (2008)
  • Author(s): Zhu G, Okada M, Yoshida S, Ueno S, MoriF, Takahara T, Saito R, Miura Y, Kishi A,Tomiyama M, Sato A, Kojima T, Fukuma G,Wakabayashi K, Hase K, Ohno H, Kijima H, Takano Y, Mitsudome A, Kaneko S & Hirose S.
  • Journal Title: Neurosci 28 Pages: 12465-12476
  • Peer Reviewed
• [Journal Article] A new family of transcription factors (2008)
  • Author(s): Yamada Y, Wang HY, Fukuzawa M, Barton GJ, Williams JG
  • Journal Title: Development 135 Pages: 3093-3101
  • Peer Reviewed
• [Journal Article] GABAergicdepolarization of the axon initial segmentin cortical principal neurons is caused bythe Na-K-2Cl cotransporter NKCC1. J. (2008)
  • Author(s): Khirug S, Yamada J, Afzalov R, Voipio J, Khiroug L, Kaila K
  • Journal Title: Neurosci 28 Pages: 4635-4639
  • Peer Reviewed
• [Journal Article] Rats Harboring S284L Chrna4 Mutation Show Attenuation of Synaptic and Extrasynaptic GABAergic Transmission and Exhibit the Nocturnal Frontal Lobe Epilepsy Phenotype (2008)
  • Author(s): Zhu G, Okada M, Yoshida S, Ueno S, Mori F, Takahara T, Saito R, Miura Y, Kishi A, Tomiyama M, Sato A, Kojima T, Fukuma G, Wakabayashi K, Hase K, Ohno H, Kijima H, Ta kano Y, Mitsudome A, Kaneko S & Hirose S.
  • Journal Title: Journal of Neuroscience 28 Pages: 12465-12476
  • Peer Reviewed
• [Journal Article] GABAergic depolarization of the axon initial segment in cortical princinal neurons is caused by the Na-K-2C1 cotransporter NKCC1 (2008)
  • Author(s): Stanislav Khirug, Junko Yamada et.al.
  • Journal Title: The Journal of Neuroscience 20(18) Pages: 4635-39
  • Peer Reviewed
• [Journal Article] Caffeine-inducible ATP release is mediated by Ca2+-signal transducing system from the endoplasmic reticulum to mitochondria (2008)
  • Author(s): Katsuragi T, Sato C, Usune S, Ueno S, Segawa M & Migita K.
  • Journal Title: Naunyn-Schmiedeberg's archives of pharmacology 378 Pages: 93-101
  • Peer Reviewed
• [Journal Article] A new family of transcription factors (2008)
  • Author(s): Yamada Y, Wang HY, Fukuzawa M. Barton G. T. Williams JG.
  • Journal Title: Development 135 Pages: 3093-3101
  • Peer Reviewed
• [Journal Article] GABAergic depolarization of the axon initial segment in cortical princinal neurons is caused by the Na-K-2C1 cotransnorter NKCC1 (2008)
  • Author(s): Stanislav Khirug, Junko Yamad a et.al.
  • Journal Title: The Journal of Neuroscience 28(18) Pages: 4635-39
  • Peer Reviewed
• [Journal Article] Involvement of autophagy in trypsinogen activation (2008)
  • Author(s): Hashimoto, D., Ohmuraya, M., Hirota, M., Yamamoto, A., Suyama, K., Baba, H., Araki, K., Mizushima, N. and Yamamura., K.
  • Journal Title: J. Cell Biol 181 Pages: 1065-1072
  • Peer Reviewed
• [Journal Article] Early pre-implantation lethality in mice carrying truncated mutation in the RNA polymerase 1-2 gene (2008)
  • Author(s): Chen, H., Li, Z., Haruna, K., Li, Z., Li. Z., Semba, K., Araki, M., Yamamura, K. and Araki, K.
  • Journal Title: Biochem. Biophys. Res. Commun 365 Pages: 636-642
  • Peer Reviewed
• [Journal Article] Gene trap mutagenesis in mice : New perspectives and tools in cancer research (2008)
  • Author(s): Yamamura, K. and Araki, K.
  • Journal Title: Cancer Sci 99 Pages: 1-6
  • NAID: 10024000620
  • Peer Reviewed
• [Journal Article] C/EBP homologous protein is crucial for the acceleration of experimental pancreatitis (2008)
  • Author(s): Suyama, K., Ohmuraya, M., Hirota, M., Ozaki, N., Ida, S., Endo, M., Araki, K., Gotoh, T., Baba, H. and Yamamura, K.
  • Journal Title: Biochem. Biophys. Res. Commun 367 Pages: 176-182
  • Peer Reviewed
• [Journal Article] Recognition of forked and single-stranded DNA structures by human RAD18 complexed with RAD6B protein triggers its recruitment to stalled replication forks (2008)
  • Author(s): Tsuji, Y., Watanabe, K., Araki, K., Shinohara, M., Yamagata, Y., Tsurimoto, T., Hanaoka, F., Yamamura, K., Yamaizumi, M., and Tateishi, S.
  • Journal Title: Genes to Cells 13 Pages: 343-354
  • Peer Reviewed
• [Journal Article] Guided Differentiation of ES Cells into Pdx1-Expressing Regional Specific Definitive Endoderm (2008)
  • Author(s): Shiraki,N., Yoshida, T., Araki, K., Umezawa, A., Higuchi, Y., Goto, H., Kume, K., and Kume, S.
  • Journal Title: Stem Cells 26 Pages: 874-885
  • Peer Reviewed
• [Journal Article] Inconsistency between hepatic expression and serum concentration of transthyretin in mice humanized at the transthyretin locus (2008)
  • Author(s): Zhao, G., Li, Z., Araki, K., Haruna, K., Yamaguchi, K., Araki, M., Takeya, M., Ando, Y. and Yamamura, K.
  • Journal Title: Genes to Cells 13 Pages: 1257-1268
  • Peer Reviewed
• [Journal Article] Characterization of Ayu17-449 gene expression and resultant kidney pathology in a knockout mouse model (2008)
  • Author(s): Tang, H., Araki. K., Li., Z. and Yamamura. K.
  • Journal Title: Transgenic Res 17 Pages: 599-608
  • Peer Reviewed
• [Journal Article] Expression pattern of serine protease inhibitor kazal type 3 (Spink3) during mouse embryonic development (2008)
  • Author(s): Wang, J., Ohmuraya, M., Hirota, M., Baba, H., Araki, K. and Yamamura, K.
  • Journal Title: Histochem. Cell Biol 130 Pages: 387-397
  • Peer Reviewed
• [Journal Article] Molecular Basis forthe GABAA Receptor-Mediated TonicInhibition in Rat Somatosensory Cortex (2007)
  • Author(s): Yamada J, Furukawa T, Ueno S, Yamamoto S & Fukuda A.
  • Journal Title: Cereb Cortex 17 Pages: 1782-1787
  • Peer Reviewed
• [Journal Article] Insertion of α7 Nicotinic Receptors atNeocortical Layer V GABAergic Synapses IsInduced by a Benzodiazepine, Midazolam (2007)
  • Author(s): Yamamoto S, Yamada J, Ueno S, Kubota H, Furukawa T, Yamamoto S & Fukuda A.
  • Journal Title: Cereb Cortex 17 Pages: 653-660
  • Peer Reviewed
• [Journal Article] Contribution ofCa2+-dependent protein kinase C in thespinal cord to the development ofmechanical allodynia in diabetic mice (2007)
  • Author(s): Honda K., Koguchi M., Koga K., NakajimaK., Kobayashi F., Migita K., Ogata S.,Hirabara Y. Takano Y.
  • Journal Title: Biol. Pharm. Bull 30 Pages: 930-933
  • Peer Reviewed
• [Journal Article] Carbamazepine prevents breakdown ofneurotransmitter release induced byhyperactivation of ryanodine receptor (2007)
  • Author(s): Yoshida S, Okada M, Zhu G, Kaneko S.
  • Journal Title: Neuropharmacology 52 Pages: 1538-1546
  • Peer Reviewed
• [Journal Article] Molecular Basis for the GABAA Receptor-Mediated Tonic Inhibition in Rat Somatosensory Cortex. (2007)
  • Author(s): Ymada J, Furukawa T, Ueno S, Yamamoto S, Fukuda A.
  • Journal Title: Cereb Cortex 17 Pages: 1782-1787
  • Peer Reviewed
• [Journal Article] Contribution of Ca^<2+>-dependent protein kinase C in the spinal cord to the development of mechanical allodynia in diabetic mice. (2007)
  • Author(s): Honda K., Koguchi M., Koga K., Nakajima K., Kobayashi F., Migita K., Ogata S., Hirabara Y., Takano Y.
  • Journal Title: Biol. Pharm. Bull. 30 Pages: 990-993
  • NAID: 110006273304
  • Peer Reviewed
• [Journal Article] Carbamazepine prevents breakdown of neurotransmitter release induced by hyperactivation of ryanodine receptor. (2007)
  • Author(s): Yoshida S, Okada M, Zhu G, Kaneko S.
  • Journal Title: Neuropharmacology 52 Pages: 1538-1546
  • Peer Reviewed
• [Journal Article] Staphylococcal enterotoxin induces emesis through increasing serotonin release in intestine and it is downregulated by cannabinoid receptor 1. (2007)
  • Author(s): Hu DL, Zhu G, Mori F, Omoe K, Okada M, Wakabayashi K, Kaneko S, Shinagawa K, Nakane A.
  • Journal Title: Cell Microbiol. 9 Pages: 2267-2277
  • Peer Reviewed
• [Journal Article] Effects ofinterleukin-1beta on hippocampalglutamate and GABA releases associatedwith Ca2+-induced Ca2+ releasing systems (2006)
  • Author(s): Gang Zhu, G., Okada, M., Yoshida, S. Mori, F. Ueno, S. , et.al.
  • Journal Title: Epilepsy Res 71 Pages: 107-116
  • Peer Reviewed
• [Journal Article] Brain-type creatine kinase activates neuron-specific K+-C1-co-transporter KCC2 (2006)
  • Author(s): Inoue, K., Yamada, J., Ueno, S., Fukuda, A
  • Journal Title: J Neurochem 96・2 Pages: 598-608
• [Journal Article] Molecular Basis for the GABAA Receptor-Mediated Tonic Inhibiti on in Rat Somatosensory Cortex (2006)
  • Author(s): Yamada, J., Furukawa, T., Ueno, S., Yamamoto, S., Fukuda, A.
  • Journal Title: Cereb Cortex E-pub Sep22
• [Journal Article] Insertion of at Nicotinic Receptors at Neocortical Layer V GAB Aergic Synapses is induced by a Benzodiazepine, Midazolam (2006)
  • Author(s): Yamamoto, S., Yamada, J., Ueno, S., Kubota, H., et al.
  • Journal Title: Cereb Cortex E-pub Apr20
• [Journal Article] Effects of interleukin-lbeta on hippocampal glutamate and GABA releases associated with Ca2+-induced Ca2+ releasing systems. (2006)
  • Author(s): Gang Zhu, G., Okada, M., Yoshida, S., Mori, F., Ueno, S., et al.
  • Journal Title: Epilepsy Res 71・2-3 Pages: 107-116
• [Journal Article] Impaired expression of Importin/karyopherin betal leads to post-implantation lethality. (2006)
  • Author(s): Miura, K., Yoshinobu, K., Imaizumi, T., Haruna, K., et al.
  • Journal Title: Biochem. Biophys. Res. Commun. 341 Pages: 132-138
• [Journal Article] Negative selection with the Diphtheria toxin a fragment Gene Improves frequency of Cre-Mediated Cassette Exchange in ES Cells (2006)
  • Author(s): Araki, K., Araki, M., Yamamura, K.
  • Journal Title: J. Biochem. 140 Pages: 793-798
  • NAID: 10018840450
• [Presentation] Involvement of P2X_2 and P2X_3 receptors in dorsal root ganglion neurons of streptozotocin-induced diabetic neuropathy (2009)
  • Author(s): 右田啓介, 他
  • Organizer: 弘前国際医学フォーラム第11回学術集会
  • Place of Presentation: 弘前大学医学部コミュニケーションセンター
  • Year and Date: 2009-03-28
• [Presentation] GABAergic depolarization of the axon initial segment in cortical arincipal neurons is mediated by NKCC1 (2009)
  • Author(s): Junko Yamada, et.al.
  • Organizer: Hirosaki International Forum
  • Place of Presentation: 弘前大学
  • Year and Date: 2009-03-27
• [Presentation] ADNFLEモデルラットにおけるGABA伝達機構の障害 (2009)
  • Author(s): 上野伸哉
  • Organizer: 第82回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2009-03-18
• [Presentation] 神経因性疼痛モデルマウスの大脳皮質II/III層錐体細胞におけるシナプス応答 (2009)
  • Author(s): 右田啓介
  • Organizer: 第82回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2009-03-17
• [Presentation] ミノサイクリンによる神経因性疼痛抑制効果 (2009)
  • Author(s): 松本恵理子, 他
  • Organizer: 第82回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2009-03-17
• [Presentation] PRIP-1 is involved in GABAAreceptor-mediated tonic inhibition inbasolateral (2008)
  • Author(s): Yamada J
  • Organizer: SFN2008
  • Place of Presentation: ワシントンDC(米国)
  • Year and Date: 2008-11-16
• [Presentation] PRIP-1 is involved in GABA_A receptor-mediated tonic inhibition in basolateral (2008)
  • Author(s): Junko Yamada, et.al.
  • Organizer: Neuroscience 2008
  • Place of Presentation: ワシントンDC(米国)
  • Year and Date: 2008-11-16
• [Presentation] GABAergic depolarization ofthe axon initial segment is caused by NKCC1 in cortical principal neurons (2008)
  • Author(s): Yamada J
  • Organizer: Neuroscience2008
  • Place of Presentation: 東京国際フォーラム
  • Year and Date: 2008-07-10
• [Presentation] GABAergic depolarization of the axon initial segment is caused by NKCC1 in cortical principal neurons (2008)
  • Author(s): Junko Yamada, et.al.
  • Organizer: Neuroscience 2008
  • Place of Presentation: 東京国際フォーラム
  • Year and Date: 2008-07-10
• [Presentation] 糖尿病モデルと坐骨神経部分結紮モデルでのアロディニア発症時における脊髄内形態変化の比較 (2008)
  • Author(s): 右田啓介, 他
  • Organizer: 第31回日本神経科学大会
  • Place of Presentation: 東京国際フォーラム
  • Year and Date: 2008-07-09
• [Presentation] Establishment ofembryonic stem cell lines derived from MSM/Ms strain originated from Mus musculusmolossinus (2008)
  • Author(s): Araki, K, et.al.
  • Organizer: 41st Annual Meeting for the Japanese Society of Developmental Biologists (Jointly sponsored by the International Society of DevelopmentalBiologists)
  • Place of Presentation: 徳島
  • Year and Date: 2008-05-28
• [Presentation] : MSM/Ms系統からの生殖系列キメラが高率に得られるES細胞株の樹立 (2008)
  • Author(s): 荒木喜美, 竹田直樹, 吉木淳, 山田源, 中潟直己, 城石俊彦, 森脇和郎, 山村研一
  • Organizer: 日本実験動物科学技術2008(第55回日本実験動物学会総会、第42回日本実験動物技術者協力会総会)
  • Place of Presentation: 仙台
• [Presentation] Establishment of embryonic stem cell lines derived from MSM/Ms strain originated from Mus musculus molossinus (2008)
  • Author(s): Araki, K., Takeda, N., Yoshiki, A., Yamada, G., Nakagata, N., Shiroishi, T., Moriwaki, K., Yamamura, K.
  • Organizer: 41^<st> Annual Meeting for the Japanese Society of Developmental Biologists (Jointly spons ored by the International Society of Develo pmental Biologists)
  • Place of Presentation: 徳島
• [Presentation] 可変型遺伝子トラップクローンを用いたCre-driverマウスの効率的作製 (2008)
  • Author(s): 荒木喜美, 陳輝, 湊理恵, 鶴田優子, 牟田真由美, 吉信公美子, 吉木淳, 荒木正健, 山村研一
  • Organizer: BMB2008(第31回日本分子生物学会年会・第81回日本生化学会大会合同大会)
  • Place of Presentation: 神戸
• [Presentation] GABAA受容体輸送とIP3結合能を有するタンパク(RPIP-1)欠損マウスのフェノタイプ解析とその発症機構の検討 (2007)
  • Author(s): 上野 伸哉, 朱 剛, 森 文秋, 若林 孝一, 吉田 淑子, 上村 雄一朗, 岡田 元宏, 兼子 直
  • Organizer: Neuro2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-09-12
• [Presentation] Enhanced GABArelease in the medial globus pallidus of a ratmodel of L-DOPA-induced dyskinesia (2007)
  • Author(s): Tomiyama M, Arai A, Kimura T, Watanabe M, Kawarabayashi T, Shoji M.
  • Organizer: XVII WFN World Congress on Parkinson's Diseaseand Related Disorders
  • Place of Presentation: Amsterdam
• [Presentation] Enhanced GABA release in the medial globus pallidus of a rat model of L-DOPA-induced dyskinedia. (2007)
  • Author(s): Tomiyama M, Arai A, Kimura T, Watanabe M, Kawarabayashi T, Shoji M.
  • Organizer: XVII WFN World Congress on Parkinson's Disease and RelatedDisorders.
  • Place of Presentation: Amsterdam