Integrated systems biology approach identifies gene targets for endothelial dysfunction.
Integrated systems biology approach identifies gene targets for endothelial dysfunction.
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综合系统生物学方法确定内皮功能障碍的基因靶点。
DOI：
10.15252/msb.202211462
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发表时间：
2023-12-06
影响因子：
9.9
通讯作者：
Krieger, Jose Eduardo
中科院分区：
文献类型：
--
作者：
Pinheiro-de-Sousa, Iguaracy;Fonseca-Alaniz, Miriam Helena;Giudice, Girolamo;Valadao, Iuri Cordeiro;Modestia, Silvestre Massimo;Mattioli, Sarah Viana;Rosa Junior, Ricardo;Zalmas, Lykourgos-Panagiotis;Fang, Yun;Petsalaki, Evangelia;Krieger, Jose Eduardo
内皮功能障碍(Ed)在心血管(CV)疾病的发生和发展中起着关键作用，但由于对其潜在分子机制的了解有限，目前对其有效的治疗靶点仍不明确。为了解决这一差距，我们采用了系统生物学的方法来确定ED的潜在靶点。我们的研究结合了多组学数据集成、siRNA筛选、高含量成像和网络分析，以确定关键的ED基因的优先顺序，并确定支持和反对ED的网络。我们发现26个基因在沉默后加剧了所测试的ED表型，网络传播发现了一个与炎症反应相关的功能丰富的前ED网络。相反，31个基因改善了ED的表型，指向了潜在的ED靶点，各自的抗ED网络在缺氧、血管生成和癌症相关过程中得到了丰富。一项包含17种药物的独立筛查发现，与我们siRNA筛查的趋势基本一致，并进一步强调DUSP1、IL6和CCL2是靶向ED的潜在候选药物。总体而言，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的疾病特异性候选药物靶点方面的潜力。多组学数据集成、遗传和药理学干扰以及对内皮细胞的网络分析相结合，以识别内皮功能障碍网络特征并优先选择候选治疗靶点。
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. Multi‐omics data integration, genetic and pharmacological perturbations, and network analysis on endothelial cells are combined to identify endothelial dysfunction network signatures and prioritise candidate therapeutic targets.
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影响因子：
5.8
作者：
Fang, Yun;Wu, David;Birukov, Konstantin G.
通讯作者：
Birukov, Konstantin G.
影响因子：
4.4
作者：
Abe H;Semba H;Takeda N
通讯作者：
Takeda N
影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
4.1
作者：
Coutinho, Agnes E.;Chapman, Karen E.
通讯作者：
Chapman, Karen E.
内皮健康和疾病中整合素依赖性细胞粘附。
影响因子：
20.1
作者：
Aman, Jurjan;Margadant, Coert
通讯作者：
Margadant, Coert