A mechanistic systems biology model of brain microvascular endothelial cell signaling reveals dynamic pathway-based therapeutic targets for brain ischemia

作者：Geli Li, Yuchen Ma, Sujie Zhang, Wen Lin, X. Y. Yao, Yating Zhou, Yanyong Zhao, Qi Rao, Yue-jin Qu, Yuan Gao, Lianmin Chen, Yu Zhang, Feng Han, Meiling Sun, Chen Zhao · 发表于：Redox Biology · 年份：2024 · DOI：10.1016/j.redox.2024.103415 · 被引用次数：5 · 研究领域：Axon Guidance and Neuronal Signaling、Kruppel-like factors research、Barrier Structure and Function Studies

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...