Research Centre for Modeling and Simulation, National University of Sciences and Technology, Islamabad, Pakistan.
PLoS One. 2012;7(3):e33532. doi: 10.1371/journal.pone.0033532. Epub 2012 Mar 30.
The discrete modeling formalism of René Thomas is a well known approach for the modeling and analysis of Biological Regulatory Networks (BRNs). This formalism uses a set of parameters which reflect the dynamics of the BRN under study. These parameters are initially unknown but may be deduced from the appropriately chosen observed dynamics of a BRN. The discrete model can be further enriched by using the model checking tool HyTech along with delay parameters. This paves the way to accurately analyse a BRN and to make predictions about critical trajectories which lead to a normal or diseased response. In this paper, we apply the formal discrete and hybrid (discrete and continuous) modeling approaches to characterize behavior of the BRN associated with MyD88-adapter-like (MAL)--a key protein involved with innate immune response to infections. In order to demonstrate the practical effectiveness of our current work, different trajectories and corresponding conditions that may lead to the development of cerebral malaria (CM) are identified. Our results suggest that the system converges towards hyperinflammation if Bruton's tyrosine kinase (BTK) remains constitutively active along with pre-existing high cytokine levels which may play an important role in CM pathogenesis.
雷内·托马斯的离散建模形式主义是一种用于建模和分析生物调控网络（BRN）的知名方法。该形式主义使用一组反映所研究的 BRN 动态的参数。这些参数最初是未知的，但可以从适当选择的 BRN 的观察到的动态中推断出来。离散模型可以通过使用模型检查工具 HyTech 以及延迟参数进一步丰富。这为准确分析 BRN 并对导致正常或疾病反应的关键轨迹做出预测铺平了道路。在本文中，我们应用正式的离散和混合（离散和连续）建模方法来描述与 MyD88 衔接蛋白样（MAL）相关的 BRN 的行为 - 一种与感染引起的先天免疫反应相关的关键蛋白。为了证明我们当前工作的实际效果，确定了可能导致脑型疟疾（CM）发展的不同轨迹和相应条件。我们的结果表明，如果布鲁顿酪氨酸激酶（BTK）保持组成型激活，同时存在预先存在的高水平细胞因子，系统会向过度炎症收敛，这可能在 CM 发病机制中发挥重要作用。
