Liver disorders in mice lacking transcription factors

缺乏转录因子的小鼠的肝脏疾病

基本信息

批准号：
09470047
负责人：
TAKIGUCHI Masaki
金额：
$ 7.04万
依托单位：
Chiba University (1998-1999)Kumamoto University (1997)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470047/
关键词：
transcription factor gene disrupted mice metabolic disorder CCAAT enhancer-binding protein C EBP ornithine cycle hyperammonemia hypoglycemia 肝臓アンモニア

项目摘要

Gene disruption studies have produced a number of transcription factor-deficient mice, some of which are useful as model animals for human disorders. Recently, mice lacking members of the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors were shown to exhibit a variety of liver disorders. To investigate pathophysiology and to develop therapy for these disorders, we examined abnormalities in expression of genes for ornithine cycle enzymes which detoxify ammonia in the liver.Pathophysiology of C/EBPα-deficient mice- It has been reported that C/EBPα-deficient mice die within several hours after birth because of hypoglycemia resulting from insufficiency of expression of genes for gluconeogenic enzymes in the liver. We showed that the mice also exhibit hyperammonemia resulting from insufficiency of genes for ornithine cycle enzymes. Now we are examining whether induction of other members such as C/EBPβ by administration of glucocorticoids and cAMP can compensate C/EBPα-deficiency or not. In addition, we are investigating organ-specificity of the defficiency by examining whether expression of the gene for arginase, the last enzyme of the ornithine cycle, in salivary glands is affected or not.Defects in hormone responsiveness of genes for ornithine cycle enzymes in C/EBPβ-deficient mice- We showed that in primary-cultured hepatocytes derived from C/EBPβ-deficient mice induction of genes for two enzymes of the cycle by glucocorticoids and glucagon are almost completely lost. Now we are examining whether the induction of genes for the enzymes in vivo is affected or not in fasting which augments effects of glucocorticoids and glucagon.

基因破坏研究产生了许多转录因子缺陷小鼠，其中一些小鼠可作为人类疾病的模型动物。最近，缺乏CCAAT/增强子结合蛋白（C/EBP）转录因子家族的小鼠表现出各种肝病。 To investigate pathophysiology and to develop therapy for these disorders, we examined abnormalities in expression of genes for ornithine cycle enzymes which detoxify ammonia in the liver.Pathophysiology of C/EBPα-deficient mice- It has been reported that C/EBPα-deficient mice die within several hours after birth because of hypoglycemia resulting from expression of genes for glutoneogenic enzymes在肝脏中。我们表明，小鼠还暴露了鸟氨酸循环酶基因不足导致的催眠症。现在，我们正在研究通过糖皮质激素和cAMP给予其他成员（例如C/EBPβ）的诱导是否可以补偿C/EBPα缺陷。此外，我们正在研究缺乏的器官特异性，通过研究精氨酸基因的表达是唾液腺中鸟氨酸周期的最后一个酶是否受到影响。 C/EBPβ缺乏症小鼠中鸟氨酸循环酶的激素反应性缺陷 - 我们表明，在原培养的肝细胞中，在C/EBPβ缺陷型小鼠的基因中诱导了两种循环的基因诱导基因，几乎完全损失了葡萄糖皮质激素和葡萄糖皮质激素。现在，我们正在研究酶在体内的诱导是否受到禁食的影响，从而增强了糖皮质激素和胰高血糖素的影响。