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首页> 外文期刊>BMC Systems Biology >Computational analysis reveals the coupling between bistability and the sign of a feedback loop in a TGF-β1 activation model
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Computational analysis reveals the coupling between bistability and the sign of a feedback loop in a TGF-β1 activation model

机译：计算分析揭示了双稳态和TGF-β1激活模型中反馈回路的符号之间的耦合

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Bistable behaviors are prevalent in cell signaling and can be modeled by ordinary differential equations (ODEs) with kinetic parameters. A bistable switch has recently been found to regulate the activation of transforming growth factor-β1 (TGF-β1) in the context of liver fibrosis, and an ordinary differential equation (ODE) model was published showing that the net activation of TGF-β1 depends on the balance between two antagonistic sub-pathways. Through modeling the effects of perturbations that affect both sub-pathways, we revealed that bistability is coupled with the signs of feedback loops in the model. We extended the model to include calcium and Krüppel-like factor 2 (KLF2), both regulators of Thrombospondin-1 (TSP1) and Plasmin (PLS). Increased levels of extracellular calcium, which alters the TSP1-PLS balance, would cause high levels of TGF-β1, resembling a fibrotic state. KLF2, which suppresses production of TSP1 and plasminogen activator inhibitor-1 (PAI1), would eradicate bistability and preclude the fibrotic steady-state. Finally, the loop PLS???TGF-β1???PAI1 had previously been reported as negative feedback, but the model suggested a stronger indirect effect of PLS down-regulating PAI1 to produce positive (double-negative) feedback in a fibrotic state. Further simulations showed that activation of KLF2 was able to restore negative feedback in the PLS???TGF-β1???PAI1 loop. Using the TGF-β1 activation model as a case study, we showed that external factors such as calcium or KLF2 can induce or eradicate bistability, accompanied by a switch in the sign of a feedback loop (PLS???TGF-β1???PAI1) in the model. The coupling between bistability and positiveegative feedback suggests an alternative way of characterizing a dynamical system and its biological implications.
机译：双稳态行为在细胞信号传导中很普遍，可以用具有动力学参数的常微分方程（ODE）进行建模。最近发现，在肝纤维化的背景下，双稳态开关可调节转化生长因子-β1（TGF-β1）的激活，并发表了一个常微分方程（ODE）模型，表明TGF-β1的净激活取决于在两个对立子路径之间的平衡。通过对影响两个子路径的摄动的影响进行建模，我们揭示了双稳态与模型中反馈回路的征兆相关。我们将模型扩展到包括钙和克虏伯样因子2（KLF2），它们都是血小板反应蛋白1（TSP1）和纤溶酶（PLS）的调节剂。增加的细胞外钙水平改变了TSP1-PLS的平衡，将导致高水平的TGF-β1，类似于纤维化状态。 KLF2抑制TSP1和纤溶酶原激活物抑制剂1（PAI1）的产生，将消除双稳态并排除纤维化稳态。最后，环路PLS ???TGF-β1??? PAI1先前曾被报道为负反馈，但是该模型表明PLS下调PAI1产生更强的间接作用，在纤维化状态下产生正（双负）反馈。 。进一步的模拟表明，激活KLF2能够恢复PLS-TGF-β1-PAI1环中的负反馈。使用TGF-β1激活模型作为案例研究，我们表明，诸如钙或KLF2之类的外部因素可以诱导或消除双稳态，同时伴随着反馈回路符号的切换（PLS ???TGF-β1???）。 PAI1）。双稳态和正/负反馈之间的耦合提示了表征动力学系统及其生物学含义的另一种方法。

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