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首页> 外文期刊>Molecular medicine. >Pharmacological Rescue of the Mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Detected by Use of a Novel Fluorescence Platform
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Pharmacological Rescue of the Mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Detected by Use of a Novel Fluorescence Platform

机译：通过使用新型荧光平台检测到的突变囊性纤维化跨膜电导调节剂（CFTR）的药理救援。

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摘要

Numerous human diseases arise because of defects in protein folding, leading to their degradation in the endoplasmic reticu-lum. Among them is cystic fibrosis (CF), caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), an epithelial anion channel. The most common mutation, F508del, disrupts CFTR folding, which blocks its trafficking to the plasma membrane. We developed a fluorescence detection platform using fluorogen-activating proteins (FAPs) to directly detect FAP-CFTR trafficking to the cell surface using a cell-impermeant probe. By using this approach, we determined the efficacy of new corrector compounds, both alone and in combination, to rescue F508del-CFTR to the plasma membrane, Combinations of correctors produced additive or synergistic effects, improving the density of mutant CFTR at the cell surface up to ninefold over a single-compound treatment. The results correlated closely with assays of stimulated anion transport performed in polarized human bronchial epithelia that endogenously express F508del-CFTR.These findings indicate that the FAP-tagged constructs faithfully report mutant CFTR correction activity and that this approach should be useful as a screening assay in diseases that impair protein trafficking to the cell surface.
机译：由于蛋白质折叠缺陷而导致许多人类疾病，导致其在内质网中降解。其中的一种是囊性纤维化（CF），是由编码CF跨膜电导调节剂（CFTR）（一种上皮阴离子通道）的基因突变引起的。最常见的突变F508del破坏CFTR折叠，阻止其转运到质膜。我们开发了一种使用氟激活蛋白（FAP）的荧光检测平台，以使用细胞不透过性探针直接检测FAP-CFTR转运到细胞表面。通过使用这种方法，我们确定了单独使用和组合使用新校正剂化合物将F508del-CFTR拯救到质膜的功效，校正剂的组合产生了累加或协同作用，提高了细胞表面向上突变体CFTR的密度。到单一化合物处理的九倍。该结果与在内源性表达F508del-CFTR的极化人支气管上皮细胞中刺激的阴离子转运测定密切相关。阻碍蛋白质向细胞表面运输的疾病。

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