Molecular pathophysiology of cystic fibrosis based on the rescued knockout mouse model
Molecular pathophysiology of cystic fibrosis based on the rescued knockout mouse model
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DOI：
10.1006/mgme.1998.2683
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发表时间：
1998-06-01
影响因子：
3.8
通讯作者：
Larson, JE
中科院分区：
文献类型：
--
作者：
Cohen, JC;Morrow, SL;Larson, JE
囊性纤维化跨膜传导调节因子（cftr）基因突变被认为是由于蛋白质的氯离子通道的缺失而导致囊性纤维化。最近，cftr敲除小鼠中的致死性肠阻塞被子宫内单剂量的含有人cftr基因的重组腺病毒逆转。这些动物的救援不需要该基因的持续表达，并且环磷酸腺苷依赖性氯离子通道也没有永久恢复。这些数据表明cftr是肠道正常发育所必需的，但不是成年器官正常功能所必需的。子宫内cftr基因敲除小鼠和杂合子小鼠的肠和肺的表型变化表明，诱导了发育的改变。未经处理的基因敲除小鼠的肠道显示出细胞内钙和UTP受体都缺乏。这两种缺陷在拯救的敲除小鼠中得到部分纠正，而杂合子动物的治疗破坏了这些标记的正常模式。用凝集素对基因敲除cftr（-/-）小鼠的肺进行检查，发现与对照杂合子相比，分泌的含有α（2，6）-唾液酸和岩藻糖的糖缀合物增加。子宫内处理的敲除也显示这种物质的增加，但它包含在细胞内囊泡中。这些组织的电子显微镜证实了肺中分泌细胞分化的发育改变。这些数据表明，cftr是肺和肠中分泌细胞群正常分化所必需的，如果没有cftr，这些细胞就不能产生特性。(C)北京：科学出版社.
Cystic fibrosis transmembrane conductance regulator (cftr) gene mutations are thought to result in cystic fibrosis due to an absence of the protein's chloride channel, Recently; the lethal intestinal blockage in the cftr knockout mouse was reversed by a single in utero dose of a recombinant adenovirus containing the human cftr gene. The rescue of these animals did not require continuous expression of the gene and the cAMP-dependent chloride channel was not permanently restored. These data suggested that cftr was required for normal development of the intestine but not for normal function of the adult organ. Phenotypic changes in the intestines and lungs of in utero cftr-treated knockout and heterozygous mice revealed that altered development was induced. The intestines of the untreated knockout mice were shown to be deficient in both intracellular calcium and UTP receptors. Both of these deficiencies were partially corrected in the rescued knockout mice, whereas treatment of heterozygous animals disrupted the normal pattern of these markers. Examination of the lungs of knockout cftr (-/-) mice with lectins showed an increase in secreted glycoconjugates containing alpha(2,6)-sialic acid and fucose as compared with control heterozygotes. The in utero-treated knockouts showed an increase in this material as well, but it was contained in intracellular vesicles. Electron microscopy of these tissues confirmed the developmental alteration of secretory cell differentiation in the lungs. These data show that cftr is required in both the lung and intestines for normal differentiation of a secretory cell population and that in its absence these cells fail to develop property. (C) 1998 Academic Press.