Cluster Gauss-Newton and CellNOpt Parameter Estimation in a Small Protein Signaling Network of Vorinostat and Bortezomib Pharmacodynamics.
Cluster Gauss-Newton and CellNOpt Parameter Estimation in a Small Protein Signaling Network of Vorinostat and Bortezomib Pharmacodynamics.
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伏立诺他和硼替佐米药效学的小蛋白信号网络中的聚类高斯-牛顿和CellNOpt参数估计。
DOI：
10.1208/s12248-021-00640-7
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发表时间：
2021-10-07
期刊：
影响因子：
--
通讯作者：
Mager DE
中科院分区：
文献类型：
--
作者：
Niu J;Nguyen VA;Ghasemi M;Chen T;Mager DE
基于常微分方程(ODE)的信号转导模型通常包含实验数据无法识别或无法测量的参数，因此将这些模型校准到数据仍然具有挑战性。在这里，两种有效的参数估计方法，集群高斯-牛顿(CGN)和细胞NOpt(CNO)，被用来拟合U266多发性骨髓瘤细胞的信号网络模型，以响应关键蛋白的活性动态响应威力诺和/或波特佐米。构建了一个基于逻辑的网络模型，并将其转换为17个ODE，其中79个参数估计在生物学上可信的大范围内。两种方法得到的前10%最佳拟合度参数具有较高的不确定度，大多数参数的变异系数为50%。两种方法的均方根和预测误差具有可比性，无统计学差异。尽管参数估计不确定，但对硼替佐米和恒涡器序贯组合后蛋白质动力学的预测具有相当的准确性和精确度。偏相关系数和Sobol敏感性的全局敏感性分析表明，诱导细胞凋亡对控制蛋白酶体-JNK-caspase-8轴活性的参数最为敏感。模拟显示，波特佐米和伏立诺坦之间的药效药物相互作用在caspase-9、AKT和bc l-2发生了最大幅度的相互作用。在电子计算机上探索了两种顺序组合，结果与基于细胞活性的药效相互作用的经验评估定性地匹配。总体而言，CGN和CNO算法在这一基于ODE的网络模型校准中的表现相似，校准后的模型为响应药理学扰动的细胞信号机制提供了有意义的见解。
Ordinary differential equation (ODE) based models of signal transduction pathways often contain parameters that are unidentifiable or unmeasurable by experimental data, and calibrating such models to data remains challenging. Here, two efficient parameter estimation methods, Cluster Gauss-Newton (CGN) and CellNOpt (CNO), were applied to fit a signaling network model of U266 multiple myeloma cells to the activity dynamics of key proteins in response to vorinostat and/or bortezomib. A logic-based network model was constructed and transformed to 17 ODEs with 79 parameters estimated within broad ranges of biologically plausible values. The top 10% best-fit parameters by both methods had high uncertainties with CV > 50% for the majority of parameters. The root mean square and prediction errors were comparable without statistically significant differences between the two methods. Despite uncertain parameter estimation, prediction of protein dynamics after the sequential combination of bortezomib and vorinostat was predicted with reasonable accuracy and precision. Global sensitivity analyses of partial rank correlation coefficients and Sobol sensitivity demonstrated that apoptosis induction was most sensitive to parameters governing the activity of the proteasome-JNK-caspase-8 axis. Simulations revealed that the greatest magnitude of pharmacodynamic drug interactions between bortezomib and vorinostat occurred at caspase-9, AKT, and Bcl-2. Two sequential combinations were explored in silico, and the outcome matched qualitatively with an empirical evaluation of the pharmacodynamic interaction based on cell viability. Overall, the CGN and CNO algorithms performed similarly for this ODE-based network model calibration, and the calibrated model provided meaningful insights into cellular signaling mechanisms in response to pharmacological perturbations.
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影响因子：
3
作者：
Krumsiek J;Pölsterl S;Wittmann DM;Theis FJ
通讯作者：
Theis FJ
DOI：
10.1002/psp4.12246
发表时间：
2017-11
期刊：
CPT: pharmacometrics & systems pharmacology
影响因子：
--
作者：
Nanavati C;Ruszaj D;Mager DE
通讯作者：
Mager DE
影响因子：
6.7
作者：
Niu, Jin;Straubinger, Robert M.;Mager, Donald E.
通讯作者：
Mager, Donald E.
影响因子：
9.9
作者：
Eduati, Federica;Jaaks, Patricia;Saez-Rodriguez, Julio
通讯作者：
Saez-Rodriguez, Julio
影响因子：
9.9
作者：
Chen, William W.;Schoeberl, Birgit;Jasper, Paul J.;Niepel, Mario;Nielsen, Ulrik B.;Lauffenburger, Douglas A.;Sorger, Peter K.
通讯作者：
Sorger, Peter K.