Center for Computational Biology (CBIO), Mines Paris-PSL, 75006, Paris, France.
Institut Curie, Université PSL, 75005, Paris, France.
BMC Genomics. 2024 Sep 28;25(1):892. doi: 10.1186/s12864-024-10752-x.
Cystic Fibrosis (CF) is a monogenic disease caused by mutations in the gene coding the Cystic Fibrosis Transmembrane Regulator (CFTR) protein, but its overall physio-pathology cannot be solely explained by the loss of the CFTR chloride channel function. Indeed, CFTR belongs to a yet not fully deciphered network of proteins participating in various signalling pathways.
We propose a systems biology approach to study how the absence of the CFTR protein at the membrane leads to perturbation of these pathways, resulting in a panel of deleterious CF cellular phenotypes.
Based on publicly available transcriptomic datasets, we built and analyzed a CF network that recapitulates signalling dysregulations. The CF network topology and its resulting phenotypes were found to be consistent with CF pathology.
Analysis of the network topology highlighted a few proteins that may initiate the propagation of dysregulations, those that trigger CF cellular phenotypes, and suggested several candidate therapeutic targets. Although our research is focused on CF, the global approach proposed in the present paper could also be followed to study other rare monogenic diseases.
囊性纤维化（CF）是一种由编码囊性纤维化跨膜转导调节蛋白（CFTR）的基因突变引起的单基因疾病，但 CFTR 氯离子通道功能的丧失并不能完全解释其整体生理病理学。事实上，CFTR 属于一个尚未完全破译的蛋白质网络，参与各种信号通路。
我们提出了一种系统生物学方法来研究细胞膜上 CFTR 蛋白的缺失如何导致这些通路的紊乱，从而导致一系列有害的 CF 细胞表型。
基于公开的转录组数据集，我们构建并分析了一个能够重现信号转导紊乱的 CF 网络。CF 网络的拓扑结构及其产生的表型与 CF 病理学一致。
对网络拓扑结构的分析突出了几个可能引发紊乱传播的蛋白质，这些蛋白质触发 CF 细胞表型，并提出了几个候选治疗靶点。虽然我们的研究集中在 CF 上，但本文提出的全局方法也可用于研究其他罕见的单基因疾病。
