Parameter-free methods distinguish Wnt pathway models and guide design of experiments
Parameter-free methods distinguish Wnt pathway models and guide design of experiments
复制标题
DOI：
10.1073/pnas.1416655112
复制
发表时间：
2015-03-03
影响因子：
11.1
通讯作者：
Harrington, Heather A.
中科院分区：
文献类型：
--
作者：
MacLean, Adam L.;Rosen, Zvi;Harrington, Heather A.
典型的Wnt信号通路由β-连环蛋白介导，在发育、成人干细胞组织的维持以及包括癌症在内的一系列疾病中起着至关重要的作用。我们分析了现有的WNT的数学模型，并将它们与一种新的以空间定位为目标的WNT信号模型进行比较；我们的目的是区分这两种模型，并从它们中提取生物学见解。使用贝叶斯方法，我们从哺乳动物Wnt信号数据中推断出每个模型的参数，并发现所有模型都可以拟合这一时间过程。我们呼吁使用代数方法(来自化学反应网络理论和拟阵理论的概念)来分析模型，而不求助于特定的参数值。这些方法提供了对Wnt调控的各个方面的洞察：新的模型通过控制穿梭和降解参数，允许在分化层次中对应于干细胞样和承诺的细胞状态的多个稳定稳定状态。我们的分析还确定了应该测量的变量组，以充分表征和区分竞争模型，从而作为执行模型比较的最小实验的指南。
The canonical Wnt signaling pathway, mediated by beta-catenin, is crucially involved in development, adult stem cell tissue maintenance, and a host of diseases including cancer. We analyze existing mathematical models of Wnt and compare them to a new Wnt signaling model that targets spatial localization; our aim is to distinguish between the models and distill biological insight from them. Using Bayesian methods we infer parameters for each model from mammalian Wnt signaling data and find that all models can fit this time course. We appeal to algebraic methods (concepts from chemical reaction network theory and matroid theory) to analyze the models without recourse to specific parameter values. These approaches provide insight into aspects of Wnt regulation: the new model, via control of shuttling and degradation parameters, permits multiple stable steady states corresponding to stem-like vs. committed cell states in the differentiation hierarchy. Our analysis also identifies groups of variables that should be measured to fully characterize and discriminate between competing models, and thus serves as a guide for performing minimal experiments for model comparison.