缺氧诱导因子-1 α（HIF -1α）在单细胞和三维细胞培养系统中的动力学建模
Modeling the dynamics of hypoxia inducible factor-1α (HIF-1α) within single cells and 3D cell culture systems
摘要：
缺氧诱导因子（Hypoxia Inducible Factor，HIF）是一种氧调节的转录因子，介导细胞内缺氧反应。越来越多的证据表明，细胞信号转导途径编码时间信息，因此细胞命运可能由蛋白质水平的动态决定。我们建立了一个数学模型来描述缺氧休克单细胞中HIF-1α蛋白的瞬时动态变化。这些数据的基本特征用描述HIF-1α和脯氨酰羟化酶（PHD）氧传感器之间的反馈抑制的微分方程系统建模。通过模型中的参数变化来解释单细胞数据中的异质性。我们以前确定PHD 2亚型是负责控制HIF-1α瞬时反应的主要PHD，并在此对反复低氧脉冲下HIF-1α动力学进行了可检验的预测。该模型被进一步开发以描述HIF-1α在培养为3D球体的细胞中的动力学，其中氧动力学使用球体内氧的实验测量来参数化。我们发现，HIF-1α的动力学和HIF-1α的转录靶点显示出对氧动力学的非单调响应。具体来说，我们证明了HIF-1α的动态瞬时行为导致转录靶点的差异动力学。
英文摘要：
HIF (Hypoxia Inducible Factor) is an oxygen-regulated transcription factor that mediates the intracellular response to hypoxia in human cells. There is increasing evidence that cell signaling pathways encode temporal information, and thus cell fate may be determined by the dynamics of protein levels. We have developed a mathematical model to describe the transient dynamics of the HIF-1α protein measured in single cells subjected to hypoxic shock. The essential characteristics of these data are modeled with a system of differential equations describing the feedback inhibition between HIF-1α and Prolyl Hydroxylases (PHD) oxygen sensors. Heterogeneity in the single-cell data is accounted for through parameter variation in the model. We previously identified the PHD2 isoform as the main PHD responsible for controlling the HIF-1α transient response, and make here testable predictions regarding HIF-1α dynamics subject to repetitive hypoxic pulses. The model is further developed to describe the dynamics of HIF-1α in cells cultured as 3D spheroids, with oxygen dynamics parameterized using experimental measurements of oxygen within spheroids. We show that the dynamics of HIF-1α and transcriptional targets of HIF-1α display a non-monotone response to the oxygen dynamics. Specifically we demonstrate that the dynamic transient behavior of HIF-1α results in differential dynamics in transcriptional targets.
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