利用加权基因共表达网络分析评估肺纤维化

IF 3.6 Q2 TOXICOLOGY
Frontiers in toxicology Pub Date : 2024-10-24 eCollection Date: 2024-01-01 DOI:10.3389/ftox.2024.1465704
Christina Drake, Walter Zobl, Sylvia E Escher
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引用次数: 0

摘要

对于许多工业化学品来说,有关几个监管终点的毒理学数据非常稀少,因此对能够筛选这些化学品并确定其优先次序的 NAMs 的需求很高,而且往往得不到满足。在这项概念验证案例研究中,我们提出了化合物诱导肺纤维化能力的多基因生物标志物,并在体外演示了其应用。为了得出这些生物标志物,我们利用加权基因共表达网络分析重新分析了一项研究,该研究记录了博莱霉素治疗小鼠肺部基因表达的时间依赖性。我们确定了由 58 至 273 个基因组成的八个模块,这些基因在纤维化发展的不同阶段(炎症、急性和晚期纤维化)被特别激活。通过与 DisGenet 中已知的肺纤维化标志物进行比较,我们证实了这些模块与肺纤维化的关系。最后,我们基于对四种二酮类化合物的体外研究,展示了这些模块作为肺纤维化化学诱导剂生物标记的应用。根据之前提出的差异激活评分和模块中差异表达基因的比例,可以发现诱导肺纤维化的二酮类化合物和其他化合物在诱导模块激活的剂量依赖性增加方面存在明显差异。因此,本研究强调了复合生物标志物机理筛选在化合物诱导肺纤维化方面的潜在用途。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Assessment of pulmonary fibrosis using weighted gene co-expression network analysis.

For many industrial chemicals toxicological data is sparse regarding several regulatory endpoints, so there is a high and often unmet demand for NAMs that allow for screening and prioritization of these chemicals. In this proof of concept case study we propose multi-gene biomarkers of compounds' ability to induce lung fibrosis and demonstrate their application in vitro. For deriving these biomarkers we used weighted gene co-expression network analysis to reanalyze a study where the time-dependent pulmonary gene-expression in mice treated with bleomycin had been documented. We identified eight modules of 58 to 273 genes each which were particularly activated during the different phases (inflammatory; acute and late fibrotic) of the developing fibrosis. The modules' relation to lung fibrosis was substantiated by comparison to known markers of lung fibrosis from DisGenet. Finally, we show the modules' application as biomarkers of chemical inducers of lung fibrosis based on an in vitro study of four diketones. Clear differences could be found between the lung fibrosis inducing diketones and other compounds with regard to their tendency to induce dose-dependent increases of module activation as determined using a previously proposed differential activation score and the fraction of differentially expressed genes in the modules. Accordingly, this study highlights the potential use of composite biomarkers mechanistic screening for compound-induced lung fibrosis.

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来源期刊
CiteScore
3.80
自引率
0.00%
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审稿时长
13 weeks
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