Mhaskar Prashant, Hjortsø Martin A, Henson Michael A
Department of Chemical Engineering, Louisianna State University, Baton Rouge 70803-7303, USA.
Biotechnol Prog. 2002 Sep-Oct;18(5):1010-26. doi: 10.1021/bp020083i.
Saccharomyces cerevisiae is known to exhibit sustained oscillations in chemostats operated under aerobic and glucose-limited growth conditions. The oscillations are reflected both in intracellular and extracellular measurements. Our recent work has shown that unstructured cell population balance models are capable of generating sustained oscillations over an experimentally meaningful range of dilution rates. A disadvantage of such unstructured models is that they lack variables that can be compared directly to easily measured extracellular variables. Thus far, most of our work in model development has been aimed at achieving qualitative agreement with experimental data. In this paper, a segregated model with a simple structured description of the extracellular environment is developed and evaluated. The model accounts for the three most important metabolic pathways involved in cell growth with glucose substrate. As compared to completely unstructured models, the major advantage of the proposed model is that predictions of extracellular variables can be compared directly to experimental data. Consequently, the model structure is well suited for the application of estimation techniques aimed at determining unknown model parameters from available extracellular measurements. A steady-state parameter selection method developed in our group is extended to oscillatory dynamics to determine the parameters that can be estimated most reliably. The chosen parameters are estimated by solving a nonlinear programming problem formulated to minimize the difference between predictions and measurements of the extracellular variables. The efficiency of the parameter estimation scheme is demonstrated using simulated and experimental data.
已知酿酒酵母在有氧和葡萄糖限制生长条件下运行的恒化器中会表现出持续振荡。这种振荡在细胞内和细胞外测量中均有体现。我们最近的工作表明，非结构化细胞群体平衡模型能够在实验上有意义的稀释率范围内产生持续振荡。此类非结构化模型的一个缺点是它们缺乏可直接与易于测量的细胞外变量进行比较的变量。到目前为止，我们在模型开发方面的大部分工作旨在与实验数据达成定性一致。本文开发并评估了一个对细胞外环境具有简单结构化描述的分离模型。该模型考虑了以葡萄糖为底物的细胞生长过程中涉及的三个最重要的代谢途径。与完全非结构化模型相比，所提出模型的主要优点是细胞外变量的预测可以直接与实验数据进行比较。因此，该模型结构非常适合应用估计技术，旨在从可用的细胞外测量中确定未知的模型参数。我们团队开发的一种稳态参数选择方法被扩展到振荡动力学，以确定最可靠估计的参数。通过求解一个非线性规划问题来估计所选参数，该问题的制定是为了最小化细胞外变量预测值与测量值之间的差异。使用模拟和实验数据证明了参数估计方案 的效率。
