1991 年度実績報告書

外来遺伝子DNA導入による新しいモデル動物の開発

研究課題

研究課題/領域番号	03206101
研究機関	九州大学
研究代表者	勝木元也九州大学, 生体防御医学研究所, 教授 (20051732)
研究分担者	山村研一熊本大学, 医学部, 教授 (90115197) 森正敬熊本大学, 医学部, 教授 (40009650) 近藤寿人名古屋大学, 理学部, 教授 (70127083) 木村穣東海大学, 医学部, 助教授 (10146706) 岩倉洋一郎東京大学, 医科学研究所, 助教授 (10089120)
キーワード	モデル動物 / トランスジェニックマウス / ジ-ンタ-ゲッティング / 標的遺伝子置換法 / キメラマウス / 高血圧 / 高脂血症
研究概要	本研究の目的である外来遺伝子導入による新しいモデル動物の開発は順調に進み、次のような実績があがった。高血圧症のモデルは、すでにラットのレニンおよびアンジオテンシノ-ゲン遺伝子導入マウスが系統化され有用性が証明されているが、本年度はヒトの同遺伝子導入マウスが確立し、ラットの場合よりはるかに高い血圧を示した。高脂血症のモデルとしてアポEタンパク遺伝子導入マウスが得られ、VLDLが顕著に減少する事が確認された。ATLウイルス遺伝子導入マウスは関節リュ-マチに似た症状を呈した。ヒトのATL感染者にも現れる症状として注目される。このように優性に働く遺伝子を導入して作ったトランスジェニックマウスは、オンコジ-ン導入マウスを含めヒト疾患のモデルとして病態の解析、治療法の検討に有用であることが示された。また、本年度特に力を入れた遺伝子標的導入法(ジ-ンタ-ゲッティング)の確立は、予想通り順調に進み、Nーmyc,p53などの遺伝子が組換えられた細胞が出来、キメラマウスを通して子孫へと伝達された。また、この方法を用いて、神経系で働く未知遺伝子の検索のためのレポ-タ-遺伝子の構築が終わり、少なくとも7個の新しい遺伝子を見いだすことが出来た。遺伝子機能を壊すことによって本来生体が有していた機能と、特定の遺伝子との関係を直接個体レベルで測定できる遺伝子標的導入法からさらに進んで、標的遺伝子を任意の構造に置き換える標的遺伝子置換法の開発も進められた。細胞レベルではほぼ成功し、キメラマウス作成の段階に達した。以上の結果を基礎に、遺伝子導入による新しいモデル動物作成の方法と、それを用いた研究の成果を来年度までにまとめる予定である。

研究成果
(22件)

すべてその他

すべて文献書誌 (22件)

[文献書誌] K.Ando;M.Katsuki,et al.: "Chemically Induced forestomach papillomas in transgenic mice carry mutant human c-Ha-ras transgenes" Cancer Res.52. 978-982 (1991)
[文献書誌] N.Kaneda;M.Katsuki,et al.: "Tissue-specific and high-level expression of the human tyrosine bydroxylase gene in transgenic mice" Neuron. 6. 583-594 (1991)
[文献書誌] S.Takahashi;M.Katsuki,et al.: "Expression of the human angiotensinogen gene in transgenic mice and transfected cells" Biochem.Biophys.Res.Commun.180. 1103-1109 (1991)
[文献書誌] Y.Iwakura,et al.: "Induction of inflammatory arthropathy resembling rheumatoid arthritis in mice transgenic for HTLV-1" Science. 253. 1026-1028 (1991)
[文献書誌] T.Tani;Y.Ohshima,et al.: "mRNA-type introns in V6 small nuclear RNA genes:implications for the catalysis in pre-mRNA splicing" Genes & Development. 5. 1022-1031 (1991)
[文献書誌] T.Mori;T.Kamataki,et al.: "The in vitro effects of lipid peroxidation on the content of individual forms of cytochrome P-450 in liver microsomes of guinea pigs" Pharmacol.Res.24. 143-148 (1991)
[文献書誌] M.Sawada;T.Kamataki,et al.: "Stable expression of monkey cytochrome P-450 I Al cDNA in Chinese hamster CHL cells and its application for detection of mutagenicity of aflatoxin B_1" Mutation Res.265. 23-29 (1991)
[文献書誌] K.Ubukata;T.Kamataki,et al.: "A new form of cytochrome P-450 responsible for the mutagenic activation of 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) in human livers" Cancer Res.
[文献書誌] K.Takagi;M.Kimura,M.Katsuki: "A rapid and efficient protocol of the inverted PCR using two primer pairs" Biotechniques.
[文献書誌] H.Kondoh;M.Mori,et al.: "Expression of the chicken"δ 2-crystallin"gene in mouse cells:Evidence for encoding of argininosuccinate lyase" Gene. 99. 267-271 (1991)
[文献書誌] S.Sawai;H.Kondoh,et al.: "Embryonic lethality resulting from disruption of both N-myc alleles in mouse zygtes" New Biologist. 3. 861-869 (1991)
[文献書誌] N.Takamatsu;T.Shiba,et al.: "Deletion analysis of the 5'untranslated leader sequence of tobacco mosaic virus RNA" J.Virology. 65. 1619-1622 (1991)
[文献書誌] K.Yoshioka;T.Shiba,et al.: "Identification of an unusual structure in the Drosophila melanogaster transposable element copia:Evidence of copia transposition through an RNA intermediate" GENE. 103. 179-184 (1991)
[文献書誌] R.Kageyama,et al.: "Molecular characterization of transcription factors that bind to the cAMP responsive region of the substance P precursor gene:cDNA cloning of a novel C/EBP-related factor" J.Biological Chemistry. 226. 15525-15531 (1991)
[文献書誌] M.Hirata;R.Kageyama,et al.: "Cloning and expression of cDNA for a human thromboxane A_2 receptor" Nature. 349. 617-620 (1991)
[文献書誌] M.Takiguchi;M.Mori: "In vitro analysis of the rat liver-type arginase promotor" Journal of Biological Chemistry. 266. 9186-9193 (1991)
[文献書誌] T.Era;K.Yamamura,et al.: "Differentiation of growth signal requirement of B lymphocyte precursor is directed by expression of immunoglobulin" EMBO Journal. 10. 337-342 (1991)
[文献書誌] G.Yamada;K.Yamamura,et al.: "Specific depletion of the B-cell population induced by aberrant expression of human interferon regulatory factor 1 gene in transgenic mice" Proceedings of the National Academy of Sciences (USA). 88. 532-536 (1991)
[文献書誌] S.Yi,;K.Yamamura,et al.: "Systemic amyloidosis in transgenic mice carrying the human mutant transthyretin (Met30) gene:Pathologic similarity to human familial amyloidotic polyneuropathy,type 1" American Journal of Pathology. 138. 403-412 (1991)
[文献書誌] A.Tominaga;K.Yamamura,et al.: "Transgenic mice expressing a B cell growth and differentiation factor gene (Interleukin 5) develop eosinophilia and autoantibody production" Journal of Experimental Medicine. 173. 429-437 (1991)
[文献書誌] T.Mineta;K.Yamamura,et al.: "(BALB/c x C57BL/6)F_1 mice are tolerant to undetectable mixed haplotype Aβ^dAα^b and mixed isotype Aβ^dEα^d self class II molecules" International Immunology. 3. 453-460 (1991)
[文献書誌] H.Niwa;K.Yamamura,et al.: "Efficient selection for high-expression transfectants with a novel eukaryotic vector" Gene. 108. 193-200 (1991)

1991 年度 実績報告書

外来遺伝子DNA導入による新しいモデル動物の開発

研究代表者

勝木 元也 九州大学, 生体防御医学研究所, 教授 (20051732)

研究成果

[文献書誌] K.Ando;M.Katsuki,et al.: "Chemically Induced forestomach papillomas in transgenic mice carry mutant human c-Ha-ras transgenes" Cancer Res.52. 978-982 (1991)

[文献書誌] N.Kaneda;M.Katsuki,et al.: "Tissue-specific and high-level expression of the human tyrosine bydroxylase gene in transgenic mice" Neuron. 6. 583-594 (1991)

[文献書誌] S.Takahashi;M.Katsuki,et al.: "Expression of the human angiotensinogen gene in transgenic mice and transfected cells" Biochem.Biophys.Res.Commun.180. 1103-1109 (1991)

[文献書誌] Y.Iwakura,et al.: "Induction of inflammatory arthropathy resembling rheumatoid arthritis in mice transgenic for HTLV-1" Science. 253. 1026-1028 (1991)

[文献書誌] T.Tani;Y.Ohshima,et al.: "mRNA-type introns in V6 small nuclear RNA genes:implications for the catalysis in pre-mRNA splicing" Genes & Development. 5. 1022-1031 (1991)

[文献書誌] T.Mori;T.Kamataki,et al.: "The in vitro effects of lipid peroxidation on the content of individual forms of cytochrome P-450 in liver microsomes of guinea pigs" Pharmacol.Res.24. 143-148 (1991)

[文献書誌] M.Sawada;T.Kamataki,et al.: "Stable expression of monkey cytochrome P-450 I Al cDNA in Chinese hamster CHL cells and its application for detection of mutagenicity of aflatoxin B_1" Mutation Res.265. 23-29 (1991)

[文献書誌] K.Ubukata;T.Kamataki,et al.: "A new form of cytochrome P-450 responsible for the mutagenic activation of 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) in human livers" Cancer Res.

[文献書誌] K.Takagi;M.Kimura,M.Katsuki: "A rapid and efficient protocol of the inverted PCR using two primer pairs" Biotechniques.

[文献書誌] H.Kondoh;M.Mori,et al.: "Expression of the chicken"δ 2-crystallin"gene in mouse cells:Evidence for encoding of argininosuccinate lyase" Gene. 99. 267-271 (1991)

[文献書誌] S.Sawai;H.Kondoh,et al.: "Embryonic lethality resulting from disruption of both N-myc alleles in mouse zygtes" New Biologist. 3. 861-869 (1991)

[文献書誌] N.Takamatsu;T.Shiba,et al.: "Deletion analysis of the 5'untranslated leader sequence of tobacco mosaic virus RNA" J.Virology. 65. 1619-1622 (1991)

[文献書誌] K.Yoshioka;T.Shiba,et al.: "Identification of an unusual structure in the Drosophila melanogaster transposable element copia:Evidence of copia transposition through an RNA intermediate" GENE. 103. 179-184 (1991)

[文献書誌] R.Kageyama,et al.: "Molecular characterization of transcription factors that bind to the cAMP responsive region of the substance P precursor gene:cDNA cloning of a novel C/EBP-related factor" J.Biological Chemistry. 226. 15525-15531 (1991)

[文献書誌] M.Hirata;R.Kageyama,et al.: "Cloning and expression of cDNA for a human thromboxane A_2 receptor" Nature. 349. 617-620 (1991)

[文献書誌] M.Takiguchi;M.Mori: "In vitro analysis of the rat liver-type arginase promotor" Journal of Biological Chemistry. 266. 9186-9193 (1991)

[文献書誌] T.Era;K.Yamamura,et al.: "Differentiation of growth signal requirement of B lymphocyte precursor is directed by expression of immunoglobulin" EMBO Journal. 10. 337-342 (1991)

[文献書誌] G.Yamada;K.Yamamura,et al.: "Specific depletion of the B-cell population induced by aberrant expression of human interferon regulatory factor 1 gene in transgenic mice" Proceedings of the National Academy of Sciences (USA). 88. 532-536 (1991)

[文献書誌] S.Yi,;K.Yamamura,et al.: "Systemic amyloidosis in transgenic mice carrying the human mutant transthyretin (Met30) gene:Pathologic similarity to human familial amyloidotic polyneuropathy,type 1" American Journal of Pathology. 138. 403-412 (1991)

[文献書誌] A.Tominaga;K.Yamamura,et al.: "Transgenic mice expressing a B cell growth and differentiation factor gene (Interleukin 5) develop eosinophilia and autoantibody production" Journal of Experimental Medicine. 173. 429-437 (1991)

[文献書誌] T.Mineta;K.Yamamura,et al.: "(BALB/c x C57BL/6)F_1 mice are tolerant to undetectable mixed haplotype Aβ^dAα^b and mixed isotype Aβ^dEα^d self class II molecules" International Immunology. 3. 453-460 (1991)

[文献書誌] H.Niwa;K.Yamamura,et al.: "Efficient selection for high-expression transfectants with a novel eukaryotic vector" Gene. 108. 193-200 (1991)

1991 年度実績報告書

勝木元也九州大学, 生体防御医学研究所, 教授 (20051732)