R117H-CFTR 的功能和对 VX-770 的反应与肠道类器官中的 mRNA 和蛋白表达相关。
R117H-CFTR function and response to VX-770 correlate with mRNA and protein expression in intestinal organoids.
机构信息
Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center, Utrecht University, Utrecht, the Netherlands, member of ERN-LUNG.
Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center, Utrecht University, Utrecht, the Netherlands, member of ERN-LUNG; Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht, the Netherlands.
出版信息
J Cyst Fibros. 2020 Sep;19(5):728-732. doi: 10.1016/j.jcf.2020.02.001. Epub 2020 Feb 13.
INTRODUCTION
Variability in disease severity and CFTR modulator responses exists between patients with identical CFTR genotypes. Here, we characterized transcription, translation and function of R117H-CFTR using intestinal organoids and correlated them with in vitro responses to ivacaftor (VX-770).
METHODS
Organoids were generated from individuals possessing at least one R117H-CFTR allele. The forskolin-induced swelling (FIS) assay was used to measure CFTR function and response to VX-770 treatment. R117H-CFTR protein and mRNA expression levels were determined in parallel and Pearson's correlation coefficients were assessed.
RESULTS
Variability in R117H-CFTR FIS responses was observed and correlated significantly with mRNA and protein expression. Response to VX-770 treatment in organoids correlated with mRNA and protein expression as well.
CONCLUSIONS
Our results indicate that gene expression, protein expression and CFTR function are strongly correlated in organoids from people with CFTR-R117H-7T/9T, which may suggest that CFTR gene expression may have consequences for CF diagnosis, prognosis and therapeutic benefit.
简介
具有相同 CFTR 基因型的患者之间，疾病严重程度和 CFTR 调节剂反应存在差异。本研究使用肠类器官对 R117H-CFTR 的转录、翻译和功能进行了表征，并将其与体外对 ivacaftor（VX-770）的反应相关联。
方法
从至少携带一个 R117H-CFTR 等位基因的个体中生成类器官。使用福司可林诱导肿胀（FIS）测定法来测量 CFTR 功能和对 VX-770 治疗的反应。同时测定 R117H-CFTR 蛋白和 mRNA 表达水平，并评估 Pearson 相关系数。
结果
观察到 R117H-CFTR FIS 反应的变异性，并且与 mRNA 和蛋白表达显著相关。类器官中对 VX-770 治疗的反应与 mRNA 和蛋白表达也相关。
结论
我们的研究结果表明，CFTR-R117H-7T/9T 个体的类器官中基因表达、蛋白表达和 CFTR 功能密切相关，这可能表明 CFTR 基因表达可能对 CF 的诊断、预后和治疗效果有影响。
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