灌流细胞培养实验中GnRH信号转导的数学模型
Mathematical Modeling of Perifusion Cell Culture Experiments on GnRH Signaling
摘要：
使用灌注细胞培养物研究了脉冲式GnRH刺激对垂体前叶细胞的影响，其中在固定化细胞上不断移动的培养基允许间歇性GnRH递送。流出培养基的LH含量用作细胞中GnRH信号通路激活的读数。挑战在于将离开腔室的培养基的LH含量与产生LH分泌的细胞过程相关联。为了研究这种关系，我们开发和分析了一个数学模型组成的耦合偏微分方程描述LH分泌在灌流细胞培养。我们将数学模型与三个不同的数据集相匹配，并给出解释数据的细胞机制。我们的模型说明了负反馈在信号通路和受体脱敏中的重要性。我们表明，不同的LH结果催产素和GnRH刺激可能源于不同的受体动力学和浓度。我们分析了模型，以了解参数的影响，如介质流速或部分收集时间，对LH结果。我们发现，低速度导致高LH的结果。此外，我们表明，馏分收集时间，不划分GnRH脉冲周期均匀，导致数据的不规则性。我们研究了GnRH的结合和解离速率对GnRH向下移动的影响。我们的模型作为一个重要的工具，可以帮助灌注实验的设计和结果的解释。
英文摘要：
The effects of pulsatile GnRH stimulation on anterior pituitary cells are studied using perifusion cell cultures, where constantly moving medium over the immo- bilized cells allows intermittent GnRH delivery. The LH content of the outgoing medium serves as a readout of the GnRH signaling pathway activation in the cells. The challenge lies in relating the LH content of the medium leaving the chamber to the cellular processes producing LH secretion. To investigate this relation we developed and analyzed a mathematical model consisting of coupled partial differential equations describing LH secretion in a perifusion cell culture. We match the mathematical model to three different data sets and give cellular mechanisms that explain the data. Our model illustrates the importance of the negative feedback in the signaling pathway and receptor desensitization. We demonstrate that different LH outcomes in oxytocin and GnRH stimulations might originate from different receptor dynamics and concentration. We ana- lyze the model to understand the influence of parameters, like the velocity of the medium flow or the fraction collection time, on the LH outcomes. We show that slow velocities lead to high LH outcomes. Also, we show that fraction collection times, which do not divide the GnRH pulse period evenly, lead to irregularities in the data. We examine the influence of the rate of binding and dissociation of GnRH on the GnRH movement down the chamber. Our model serves as an important tool that can help in the design of perifusion experiments and the interpretation of results.
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