Ischemic stroke is a significant threat to human health. Currently, there is a lack of effective treatments for stroke, and progress in new neuron-centered drug target development is relatively slow. On the other hand, studies have demonstrated that brain microvascular endothelial cells (BMECs) are crucial components of the neurovascular unit and play pivotal roles in ischemic stroke progression. To better understand the complex multifaceted roles of BMECs in the regulation of ischemic stroke pathophysiology and facilitate BMEC-based drug target discovery, we utilized a transcriptomics-informed systems biology modeling approach and constructed a mechanism-based computational multipathway model to systematically investigate BMEC function and its modulatory potential. Extensive multilevel data regarding complex BMEC pathway signal transduction and biomarker expression under various pathophysiological conditions were used for quantitative model calibration and validation, and we generated dynamic BMEC phenotype maps in response to various stroke-related stimuli to identify potential determinants of BMEC fate under stress conditions. Through high-throughput model sensitivity analyses and virtual target perturbations in model-based single cells, our model predicted that targeting succinate could effectively reverse the detrimental cell phenotype of BMECs under oxygen and glucose deprivation/reoxygenation, a condition that mimics stroke pathogenesis, and we experimentally validated the utility of this new target in terms of regulating inflammatory factor production, free radical generation and tight junction protection in vitro and in vivo. Our work is the first that complementarily couples transcriptomic analysis with mechanistic systems-level pathway modeling in the study of BMEC function and endothelium-based therapeutic targets in ischemic stroke.

中文翻译：

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脑微血管内皮细胞信号传导的机制系统生物学模型揭示了基于动态通路的脑缺血治疗靶点


缺血性中风对人类健康构成重大威胁。目前，缺乏针对中风的有效治疗方法，并且以神经元为中心的新药物靶点开发进展相对较慢。另一方面，研究表明，脑微血管内皮细胞 （BMECs） 是神经血管单位的重要组成部分，在缺血性中风进展中起着关键作用。为了更好地了解 BMECs 在缺血性卒中病理生理学调节中复杂的多方面作用并促进基于 BMEC 的药物靶点发现，我们利用转录组学信息系统生物学建模方法并构建了基于机制的计算多途径模型来系统研究 BMEC 功能及其调节潜力。有关各种病理生理条件下复杂 BMEC 通路信号转导和生物标志物表达的大量多层次数据用于定量模型校准和验证，我们生成了动态 BMEC 表型图以响应各种与中风相关的刺激，以确定压力条件下 BMEC 命运的潜在决定因素。通过基于模型的单细胞中的高通量模型敏感性分析和虚拟靶点扰动，我们的模型预测靶向琥珀酸盐可以有效逆转 BMECs 在氧和葡萄糖剥夺/再氧合（一种模拟中风发病机制的情况下）的有害细胞表型，并且我们实验验证了这个新靶点在调节炎症因子产生方面的效用， 体外和体内自由基的产生和紧密连接保护。 我们的工作是首次将转录组学分析与机制系统水平通路建模互补耦合，用于研究缺血性中风中 BMEC 功能和基于内皮的治疗靶点。