Department of Medical Bioinformatics, University Medical Center Göttingen, Goldschmidtstraße 1, 37077 Göttingen, Germany.
Clinic for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
Int J Mol Sci. 2021 Jul 15;22(14):7590. doi: 10.3390/ijms22147590.
Different causative therapeutics for CF patients have been developed. There are still no mutation-specific therapeutics for some patients, especially those with rare CFTR mutations. For this purpose, high-throughput screens have been performed which result in various candidate compounds, with mostly unclear modes of action. In order to elucidate the mechanism of action for promising candidate substances and to be able to predict possible synergistic effects of substance combinations, we used a systems biology approach to create a model of the CFTR maturation pathway in cells in a standardized, human- and machine-readable format. It is composed of a core map, manually curated from small-scale experiments in human cells, and a coarse map including interactors identified in large-scale efforts. The manually curated core map includes 170 different molecular entities and 156 reactions from 221 publications. The coarse map encompasses 1384 unique proteins from four publications. The overlap between the two data sources amounts to 46 proteins. The CFTR Lifecycle Map can be used to support the identification of potential targets inside the cell and elucidate the mode of action for candidate substances. It thereby provides a backbone to structure available data as well as a tool to develop hypotheses regarding novel therapeutics.
已经开发出针对 CF 患者的不同病因治疗方法。对于某些患者，特别是那些 CFTR 突变罕见的患者，仍然没有特定突变的治疗方法。为此，已经进行了高通量筛选，产生了各种候选化合物，其中大多数作用机制尚不清楚。为了阐明有前途的候选物质的作用机制，并能够预测物质组合的可能协同效应，我们使用系统生物学方法以标准化、人类可读和机器可读的格式在细胞中创建 CFTR 成熟途径的模型。它由一个核心图组成，该核心图是从人类细胞的小规模实验中手动整理的，以及一个包括在大规模研究中鉴定的相互作用物的粗图。手动整理的核心图包括来自 221 篇出版物的 170 种不同分子实体和 156 种反应。来自四个出版物的 1384 种独特蛋白质组成粗图。两个数据源之间的重叠数量为 46 个蛋白质。CFTR 生命周期图可用于支持识别细胞内的潜在靶标，并阐明候选物质的作用机制。它为组织可用数据提供了一个主干，并为开发关于新型治疗方法的假设提供了一个工具。
