1996 Fiscal Year Annual Research Report

ヒト型薬理学実験モデルマウスの開発

Research Project

Project/Area Number	07557012
Section	試験
Research Institution	The University of Tokyo
Principal Investigator	勝木元也東京大学, 医科学研究所, 教授 (20051732)
Co-Investigator(Kenkyū-buntansha)	横山峯介三菱化学生命科学研究所, 室長中尾和貴東京大学, 医科学研究所, 寄付研究部門教員中村健司東京大学, 医科学研究所, 助手 (90253533) 饗場篤東京大学, 医科学研究所, 助教授 (20271116)
Keywords	ジーンターゲッティング / 標的遺伝子組換え / 標的遺伝子置換 / セロトニン受容体 / 薬理作用 / 発生工学 / 遺伝子工学 / ES細胞
Research Abstract	動物実験による薬理作用の研究は、ヒト疾患に有効な薬の開発にとって最も重要なものの一つである。ところが、生体に作用する化学物質の薬理作用が、ヒトと動物とで異なる場合がある。すなわち、薬の効き方が動物種によって異なる場合である。神経伝達物質受容体に対する薬理作用がヒトとマウスとで異なる場合も多く認められる。もしマウスの受容体をヒト型に変換させることができれば、従来不可能であった様々な薬理学的動物実験が可能となるであろう。これまで、このような遺伝子変換は困難であったが、最近の遺伝子工学と発生工学とによって計画的に遺伝子を変換したマウス個体を作ることができるようになった。我々は、この方法をさに一歩進めて、標的とする目的の遺伝子に点突然変異や欠失、またヒトをはじめとする異種遺伝子に置き換える方法の開発に成功した(標的遺伝子置換法)。この方法を、セロトニン受容体1Bに適用し、薬理作用がヒトと異なるマウスを、ヒト型に変換することを試みた。その結果、昨年度はセロトニン受容体1B遺伝子の標的組換え体ES細胞の単離し、今年度その細胞からキメラマウスが誕生した。今後このキメラマウスから子孫を探る計画である。

Research Products
(13 results)

All Other

All Publications (13 results)

[Publications] Kadatani,H.,et al.: "Motor discoordination results from combined gene disruption of the NMDA receptor NR2A and NR2C subunits,but not from single disruption of the NR2A or NR2C subunits." J Neurosci. 16. 7859-7867 (1996)
[Publications] Yokoi,M.,et al.: "Impariment of hippocampal mossy fiber LTD in mice lacking mGluR2." Science. 273. 645-647 (1996)
[Publications] Kato,T.,et al.: "Inactivation of hepatitis C virus cDNA transgene by hypermethylation intransgenic mice." Arch Virol. 141. 951-958 (1996)
[Publications] Inoue,R.,et al.: "Rare activation of the human c-Ha-ras transgene of mice in hemangioendothelial sarcomas and liver tumors induced by Glu-P-1." Jpn J Cancer Res. 87. 583-588 (1996)
[Publications] Ohbo,K.,et al.: "Modulation of hematopoiesis in mice with a truncated mutant of the interleukin-2 receptor gamma chain." Blood. 87. 956-967 (1996)
[Publications] Li,Y.,et al.: "Establishiment of transgenic mice carrying human fetus-specific CYP3A7." Arch Biochem Biophys. 329. 235-240 (1996)
[Publications] Gondo,Y.,et al.: "A novel positive detection system of in vivo mutations in rpsL(strA) transgenic mice." Mutation Res. 360. 1-14 (1996)
[Publications] Norimura,T.,et al.: "p53-dependent apoptosis suppresses redeation-induced teratogenesis." Nature Medicine. 2. 577-580 (1996)
[Publications] Yamaguchi,T.,et al.: "Dopamine D2 receptor plays a critical role in cell proliferation and proopiomelanocortin expression in the pituitary." Genes to Cells. 1. 253-268 (1996)
[Publications] Tokita,Y.,et al.: "Characterization of excitatory amino acid neurotoxicity in N-methyl-D-aspartate receptor-deficient mouse cortical neuronal cells." Eur J Neurosci. 8. 69-78 (1996)
[Publications] Shibata,H.,et al.: "Dysfunction of the Orleans reeler gene arising from exon skipping due to transposition of a full-length copy of an active L1 sequence into the skipped exon." Hum Mol Genet. 5. 989-993 (1996)
[Publications] Kitamoto,T.,et al.: "Humanized prion protein knock-in by Cre-induced site-specific recombination in the mouse." Biochem Biophys Res Commun. 222. 742-747 (1996)
[Publications] Tsuzuki,T.,et al.: "Targeted disruption of the Rad51 gene leads to lethality in embryonic mice." Proc Natl Acad Sci USA. 93. 6236-6240 (1996)

1996 Fiscal Year Annual Research Report

ヒト型薬理学実験モデルマウスの開発

Principal Investigator

勝木 元也 東京大学, 医科学研究所, 教授 (20051732)

Research Products

[Publications] Kadatani,H.,et al.: "Motor discoordination results from combined gene disruption of the NMDA receptor NR2A and NR2C subunits,but not from single disruption of the NR2A or NR2C subunits." J Neurosci. 16. 7859-7867 (1996)

[Publications] Yokoi,M.,et al.: "Impariment of hippocampal mossy fiber LTD in mice lacking mGluR2." Science. 273. 645-647 (1996)

[Publications] Kato,T.,et al.: "Inactivation of hepatitis C virus cDNA transgene by hypermethylation intransgenic mice." Arch Virol. 141. 951-958 (1996)

[Publications] Inoue,R.,et al.: "Rare activation of the human c-Ha-ras transgene of mice in hemangioendothelial sarcomas and liver tumors induced by Glu-P-1." Jpn J Cancer Res. 87. 583-588 (1996)

[Publications] Ohbo,K.,et al.: "Modulation of hematopoiesis in mice with a truncated mutant of the interleukin-2 receptor gamma chain." Blood. 87. 956-967 (1996)

[Publications] Li,Y.,et al.: "Establishiment of transgenic mice carrying human fetus-specific CYP3A7." Arch Biochem Biophys. 329. 235-240 (1996)

[Publications] Gondo,Y.,et al.: "A novel positive detection system of in vivo mutations in rpsL(strA) transgenic mice." Mutation Res. 360. 1-14 (1996)

[Publications] Norimura,T.,et al.: "p53-dependent apoptosis suppresses redeation-induced teratogenesis." Nature Medicine. 2. 577-580 (1996)

[Publications] Yamaguchi,T.,et al.: "Dopamine D2 receptor plays a critical role in cell proliferation and proopiomelanocortin expression in the pituitary." Genes to Cells. 1. 253-268 (1996)

[Publications] Tokita,Y.,et al.: "Characterization of excitatory amino acid neurotoxicity in N-methyl-D-aspartate receptor-deficient mouse cortical neuronal cells." Eur J Neurosci. 8. 69-78 (1996)

[Publications] Shibata,H.,et al.: "Dysfunction of the Orleans reeler gene arising from exon skipping due to transposition of a full-length copy of an active L1 sequence into the skipped exon." Hum Mol Genet. 5. 989-993 (1996)

[Publications] Kitamoto,T.,et al.: "Humanized prion protein knock-in by Cre-induced site-specific recombination in the mouse." Biochem Biophys Res Commun. 222. 742-747 (1996)

[Publications] Tsuzuki,T.,et al.: "Targeted disruption of the Rad51 gene leads to lethality in embryonic mice." Proc Natl Acad Sci USA. 93. 6236-6240 (1996)

勝木元也東京大学, 医科学研究所, 教授 (20051732)