Dynamic Multiscale Regulation of Perfusion Recovery in Experimental Peripheral Arterial Disease: A Mechanistic Computational Model.
Dynamic Multiscale Regulation of Perfusion Recovery in Experimental Peripheral Arterial Disease: A Mechanistic Computational Model.
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DOI：
10.1016/j.jacbts.2021.10.014
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Popel AS
中科院分区：
文献类型：
--
作者：
Zhao C;Heuslein JL;Zhang Y;Annex BH;Popel AS
第一类系统生物学计算模型，描述了多尺度调节实验性外周动脉疾病的灌注恢复。多级模型校准和验证使实验性外周动脉疾病（小鼠HLI）的高分辨率模型模拟成为可能。一个综合的基于模型的机制表征的细胞内，细胞和组织水平的功能，关键的动态重建灌注以下不同模式的闭塞引起的缺血HLI的描述。使用基于模型的虚拟HLI小鼠群体，预测细胞坏死的药理学抑制作为具有高治疗潜力的改善灌注恢复的策略;在真实的HLI小鼠中，然后实验研究并证实这种新策略的积极影响。在外周动脉疾病（PAD）中，调节肢体肌肉血运重建的内源性能力的程度是腿部缺血管理的核心。为了表征PAD血运重建的多尺度和多细胞性质，我们开发了第一个计算系统生物学模型，该模型机械地结合了细胞内，细胞和组织水平的特征，这些特征对于闭塞诱导的缺血后灌注的动态重建至关重要。计算模型是专门为PAD（小鼠后肢缺血[HLI]）的临床前动物模型制定的，它已经通过了多级模型校准和验证，针对一组全面的实验数据，使其准确地捕捉复杂的细胞信号，细胞间通讯，和功能后HLI灌注恢复。例如，我们的模型模拟生成了HLI中时间依赖性光谱样巨噬细胞表型的高度详细描述，并且通过模型敏感性分析，我们确定了在PAD病理生理学中具有潜在治疗意义的关键细胞过程。此外，我们在基于模型的、数据驱动的虚拟小鼠群体中计算评估了不同靶向干预对HLI后组织灌注恢复的体内作用，并在真实的HLI小鼠中实验证实了新模型预测干预的治疗作用。这种新的多尺度模型开辟了一条新的途径，使用综合系统生物学建模，以促进转化研究在PAD。
A first-of-a-kind systems biology computational model is presented that describes multiscale regulation of perfusion recovery in experimental peripheral arterial disease. Multilevel model calibration and validation enable high-resolution model simulations for experimental peripheral arterial disease (mouse HLI). An integrative model-based mechanistic characterization of the intracellular, cellular, and tissue-level features critical for the dynamic reconstitution of perfusion following different patterns of occlusion-induced ischemia in HLI is described. Using a model-based virtual HLI mouse population, pharmacologic inhibition of cell necrosis is predicted as a strategy with high therapeutic potential to improve perfusion recovery; in real HLI mice, the positive impact of this new strategy is then experimentally studied and confirmed. In peripheral arterial disease (PAD), the degree of endogenous capacity to modulate revascularization of limb muscle is central to the management of leg ischemia. To characterize the multiscale and multicellular nature of revascularization in PAD, we have developed the first computational systems biology model that mechanistically incorporates intracellular, cellular, and tissue-level features critical for the dynamic reconstitution of perfusion after occlusion-induced ischemia. The computational model was specifically formulated for a preclinical animal model of PAD (mouse hindlimb ischemia [HLI]), and it has gone through multilevel model calibration and validation against a comprehensive set of experimental data so that it accurately captures the complex cellular signaling, cell–cell communication, and function during post-HLI perfusion recovery. As an example, our model simulations generated a highly detailed description of the time-dependent spectrum-like macrophage phenotypes in HLI, and through model sensitivity analysis we identified key cellular processes with potential therapeutic significance in the pathophysiology of PAD. Furthermore, we computationally evaluated the in vivo effects of different targeted interventions on post-HLI tissue perfusion recovery in a model-based, data-driven, virtual mouse population and experimentally confirmed the therapeutic effect of a novel model-predicted intervention in real HLI mice. This novel multiscale model opens up a new avenue to use integrative systems biology modeling to facilitate translational research in PAD.
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