1999 Fiscal Year Annual Research Report

転写因子遺伝子標的破壊マウスにおける肝機能障害に関する研究

Research Project

Project/Area Number	09470047
Research Institution	Chiba University
Principal Investigator	滝口正樹千葉大学, 医学部, 教授 (40179578)
Co-Investigator(Kenkyū-buntansha)	日和佐隆樹千葉大学, 医学部, 助教授 (30260251)
Keywords	転写調節因子 / 標的遺伝子破壊マウス / 代謝異常 / CCAAT / enhancer-binding protein / C / EBP / オルニチンサイクル / 高アンモニア血症 / 低血糖
Research Abstract	近年,多くの標的遺伝子破壊マウスが作出されているが,その中にはヒトの疾患モデルとして有用なものが少なくない。最近,CCAAT/enhancer-binding protein(C/EBP)ファミリーと呼ばれる転写調節因子群に属する因子の標的遺伝子破壊マウスが広範な肝機能障害を示すことが明らかになってきた。同遺伝子ファミリー各メンバーの標的破壊マウスにおける病態の解析およびその治療法の検討を目的として,報告者らが従来より研究を行ってきたアンモニア解毒系のオルニチンサイクル酵素遺伝子の発現異常の解析を行った。(1)C/EBPα遺伝子標的破壊マウスの病態の解析-従来C/EBPα標的破壊マウスは,肝臓における糖新生系酵素の発現不全に由来する低血糖により,出生後数時間で死亡することが報告されていたが,これに加え,同マウスは肝臓のオルニチンサイクル酵素の発現不全から高アンモニア血症を呈することを明らかにした。現在,グルココルチコイドおよびcAMP投与によりC/EBPβ等を誘導することによりC/EBPα欠損を補償しうるか否かを検討中である。また,オルニチンサイクルの最後の酵素であるアルギナーゼの唾液腺における発現が障害されているか否かを調べ,肝臓における障害の臓器特異性を検討中である。(2)C/EBPβ標的破壊マウスにおけるオルニチンサイクル酵素遺伝子のホルモン応答性の障害の解析-C/EBPβ標的破壊マウスの初代培養肝細胞において,オルニチンサイクルの2つの酵素遺伝子のグルココルチコイドおよびグルカゴンにによる誘導がほぼ完全に消失していることを明らかにした。現在,個体レベルでグルココルチコイドおよびグルカゴンの効果が増強される絶食時において,オルニチンサイクル酵素の誘導に障害が見られるか否かを検討中である。

Research Products
(16 results)

All Other

All Publications (16 results)

[Publications] Tomomura, M., et al.: "Suppressed expression of the urea cycle enzyme genes in the liver of carnitine-deficient juvenile visceral steatosis (JVS) mice in infancy and during starvation in adulthood"J. Biochem.. 121. 172-177 (1997)
[Publications] Yoshida, E., et al.: "Functional association between CBP and HNF4 in trans-activation"Biochem. Biophys. Res. Commun.. 241. 664-699 (1997)
[Publications] Sonoki, T., et al.: "Coinduction of nitric-oxide synthase and arginase I in cultured rat peritoneal macrophages and rat tissues in vivo by lipopolysaccharide"J. Biol. Chem.. 272. 3689-3693 (1997)
[Publications] Osada,S., et al.: "Identification of an extended half-site motif required for the function of peroxisome proliferator-activated receptor α"Genes to Cells. 2. 315-327 (1997)
[Publications] Gotoh, T., et al.: "The glucocorticoid-responsive gene cascade: activation of the rat arginase gene through induction of C/EBPβ"J. Biol. Chem.. 272. 3694-3698 (1997)
[Publications] Yamaguchi, Y., et al.: "Mechanisms of transcription in eosinophils: GATA-1, but not GATA-2, transactivates the promoter of the eosinophil granule major basic protein gene"Blood. 91. 3447-3458 (1998)
[Publications] Takiguchi, M., et al.: "The C/EBP family of transcription factors in the liver and other organs (Review)"Int. J. Exp. Pathol.. 79. 369-391 (1998)
[Publications] Kimura, T., et al.: "Hypoglycemia-associated hyperammonemia caused by impaired expression of ornithine cycle enzyme genes in C/EBPα knockout mice"J. Biol. Chem.. 273. 27505-27510 (1998)
[Publications] Miyanaka, K., et al.: "Immunohistochemical localization of arginase II and other enzymes of arginine metabolism in rat kidney and liver"Histochem. J.. 30. 741-751 (1998)
[Publications] Mori, M., et al.: "Regulation of the urea cycle enzyme genes in nitric oxide synthesis (Review)"J. inherit. Metab. Dis.. 21. 59-71 (1998)
[Publications] Iwase, K., et al.: "Precise distribution of neuronal nitric oxide synthase mRNA in the rat brain revealed by non-radioisotopic in situ hybridization"Mol. Brain Res.. 53. 1-12 (1998)
[Publications] Braissant, O., et al.: "Hyperammonemia: regulation of argininosuccinate synthetase and argininosuccinate lyase genes in aggregating cell cultures of fetal rat brain"Neurosci. Lett.. 266. 89-92 (1999)
[Publications] Sugahara, K., et al.: "Differential expression of CCAAT enhancer binding protein family in rat alveolar epithelial cell proliferation and acute lung injury"Cell Tissue Res.. 297. 261-270 (1999)
[Publications] Zhang, W. I., et al.: "Expression of citrulline-nitric oxide cycle in lipopolysaccharide and cytokine-stimulated rat astroglioma C6 cells"Brain Res.. 849. 78-84 (1999)
[Publications] Yanai, K., et al.: "Regulated expression of human angiotensinogen gene by hepatocyte nuclear factor 4 and chicken ovalbumin upstream promoter-transcription factor"J. Biol. Chem.. 274. 34605-34612 (1999)
[Publications] Iwase, K., et al.: "Induction of endothelial nitric oxide synthase in rat brain astrocytes by systemic lipopolysaccharide treatment"J. Biol. Chem.. 275(in press). (2000)

1999 Fiscal Year Annual Research Report

転写因子遺伝子標的破壊マウスにおける肝機能障害に関する研究

Principal Investigator

滝口 正樹 千葉大学, 医学部, 教授 (40179578)

Research Products

[Publications] Tomomura, M., et al.: "Suppressed expression of the urea cycle enzyme genes in the liver of carnitine-deficient juvenile visceral steatosis (JVS) mice in infancy and during starvation in adulthood"J. Biochem.. 121. 172-177 (1997)

[Publications] Yoshida, E., et al.: "Functional association between CBP and HNF4 in trans-activation"Biochem. Biophys. Res. Commun.. 241. 664-699 (1997)

[Publications] Sonoki, T., et al.: "Coinduction of nitric-oxide synthase and arginase I in cultured rat peritoneal macrophages and rat tissues in vivo by lipopolysaccharide"J. Biol. Chem.. 272. 3689-3693 (1997)

[Publications] Osada,S., et al.: "Identification of an extended half-site motif required for the function of peroxisome proliferator-activated receptor α"Genes to Cells. 2. 315-327 (1997)

[Publications] Gotoh, T., et al.: "The glucocorticoid-responsive gene cascade: activation of the rat arginase gene through induction of C/EBPβ"J. Biol. Chem.. 272. 3694-3698 (1997)

[Publications] Yamaguchi, Y., et al.: "Mechanisms of transcription in eosinophils: GATA-1, but not GATA-2, transactivates the promoter of the eosinophil granule major basic protein gene"Blood. 91. 3447-3458 (1998)

[Publications] Takiguchi, M., et al.: "The C/EBP family of transcription factors in the liver and other organs (Review)"Int. J. Exp. Pathol.. 79. 369-391 (1998)

[Publications] Kimura, T., et al.: "Hypoglycemia-associated hyperammonemia caused by impaired expression of ornithine cycle enzyme genes in C/EBPα knockout mice"J. Biol. Chem.. 273. 27505-27510 (1998)

[Publications] Miyanaka, K., et al.: "Immunohistochemical localization of arginase II and other enzymes of arginine metabolism in rat kidney and liver"Histochem. J.. 30. 741-751 (1998)

[Publications] Mori, M., et al.: "Regulation of the urea cycle enzyme genes in nitric oxide synthesis (Review)"J. inherit. Metab. Dis.. 21. 59-71 (1998)

[Publications] Iwase, K., et al.: "Precise distribution of neuronal nitric oxide synthase mRNA in the rat brain revealed by non-radioisotopic in situ hybridization"Mol. Brain Res.. 53. 1-12 (1998)

[Publications] Braissant, O., et al.: "Hyperammonemia: regulation of argininosuccinate synthetase and argininosuccinate lyase genes in aggregating cell cultures of fetal rat brain"Neurosci. Lett.. 266. 89-92 (1999)

[Publications] Sugahara, K., et al.: "Differential expression of CCAAT enhancer binding protein family in rat alveolar epithelial cell proliferation and acute lung injury"Cell Tissue Res.. 297. 261-270 (1999)

[Publications] Zhang, W. I., et al.: "Expression of citrulline-nitric oxide cycle in lipopolysaccharide and cytokine-stimulated rat astroglioma C6 cells"Brain Res.. 849. 78-84 (1999)

[Publications] Yanai, K., et al.: "Regulated expression of human angiotensinogen gene by hepatocyte nuclear factor 4 and chicken ovalbumin upstream promoter-transcription factor"J. Biol. Chem.. 274. 34605-34612 (1999)

[Publications] Iwase, K., et al.: "Induction of endothelial nitric oxide synthase in rat brain astrocytes by systemic lipopolysaccharide treatment"J. Biol. Chem.. 275(in press). (2000)

滝口正樹千葉大学, 医学部, 教授 (40179578)