综合系统生物学方法确定内皮功能障碍的基因靶标。

IF 8.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Molecular Systems Biology Pub Date : 2023-12-06 Epub Date: 2023-11-30 DOI:10.15252/msb.202211462
Iguaracy Pinheiro-de-Sousa, Miriam Helena Fonseca-Alaniz, Girolamo Giudice, Iuri Cordeiro Valadão, Silvestre Massimo Modestia, Sarah Viana Mattioli, Ricardo Rosa Junior, Lykourgos-Panagiotis Zalmas, Yun Fang, Evangelia Petsalaki, José Eduardo Krieger
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引用次数: 0

摘要

内皮功能障碍(ED)在心血管(CV)疾病的发生和进展中至关重要,但由于对其潜在分子机制的了解有限,ED的有效治疗靶点仍然难以捉摸。为了解决这一问题,我们采用了系统生物学方法来确定ED的潜在靶点。我们的研究结合了多组学数据整合、siRNA筛选、高含量成像和网络分析来确定关键ED基因的优先级,并确定了一个支持和反对ED的网络。我们发现26个基因在沉默后会加重ED表型,并且网络传播发现了一个与炎症反应相关功能丰富的促ED网络。相反,31个基因改善了ED表型,指出了潜在的ED靶点,并且各自的抗ED网络在缺氧,血管生成和癌症相关过程中富集。17种药物的独立筛选结果与我们的siRNA筛选结果普遍一致,并进一步突出了DUSP1、IL6和CCL2作为ED靶向的潜在候选药物。总的来说,我们的结果证明了综合系统生物学方法在发现内皮功能障碍疾病特异性候选药物靶点方面的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Integrated systems biology approach identifies gene targets for endothelial dysfunction.

Endothelial dysfunction (ED) is critical in the development and progression of cardiovascular (CV) disorders, yet effective therapeutic targets for ED remain elusive due to limited understanding of its underlying molecular mechanisms. To address this gap, we employed a systems biology approach to identify potential targets for ED. Our study combined multi omics data integration, with siRNA screening, high content imaging and network analysis to prioritise key ED genes and identify a pro- and anti-ED network. We found 26 genes that, upon silencing, exacerbated the ED phenotypes tested, and network propagation identified a pro-ED network enriched in functions associated with inflammatory responses. Conversely, 31 genes ameliorated ED phenotypes, pointing to potential ED targets, and the respective anti-ED network was enriched in hypoxia, angiogenesis and cancer-related processes. An independent screen with 17 drugs found general agreement with the trends from our siRNA screen and further highlighted DUSP1, IL6 and CCL2 as potential candidates for targeting ED. Overall, our results demonstrate the potential of integrated system biology approaches in discovering disease-specific candidate drug targets for endothelial dysfunction.

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来源期刊
Molecular Systems Biology
Molecular Systems Biology 生物-生化与分子生物学
CiteScore
18.50
自引率
1.00%
发文量
62
审稿时长
6-12 weeks
期刊介绍: Systems biology is a field that aims to understand complex biological systems by studying their components and how they interact. It is an integrative discipline that seeks to explain the properties and behavior of these systems. Molecular Systems Biology is a scholarly journal that publishes top-notch research in the areas of systems biology, synthetic biology, and systems medicine. It is an open access journal, meaning that its content is freely available to readers, and it is peer-reviewed to ensure the quality of the published work.
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