CHO细胞中M$_{2}$受体依赖性联合信号和次级信使网络的建模和数学分析。

IF 0.8 4区 数学 Q4 BIOLOGY
Benjamin Engelhardt, Janine Holze, Christina Elliott, George S Baillie, Maik Kschischo, Holger Fröhlich
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引用次数: 0

摘要

毒蕈碱M${2}$受体是GPCR家族的重要成员,与心脏疾病密切相关。最近发表的实验研究探讨了中国仓鼠卵巢(CHO)细胞对iperoxo诱导的M${2}$受体刺激的细胞反应。为了更好地理解这些反应,我们模拟并分析了毒蕈碱M$_{2}$受体依赖的信号通路,并利用质量作用结合了相关的次级信使分子。在我们基于文献的联合信号传导和次级信使模型中,所有结合和磷酸化事件都被明确考虑在内,以便进行后续的化学计量矩阵分析。我们提出约束通量采样(CFS)作为表征稳态反应通量分布因已知cAMP产量和PDE4活化量而产生的预期位移的方法。CFS正确地预测了实验观察到的对细胞骨架结构(以肌动蛋白和微管蛋白为标志)的影响,并因此改变了细胞的光密度。第二步,我们使用CFS来模拟生物系统内敲除实验的效果,从而对单个分子对观察到的光细胞密度变化的影响进行排序。特别是,我们确认了RGS14蛋白的相关性,这得到了现有文献的支持。结合CFS和基本通量模式分析使我们能够确定可能的潜在机制。我们的分析表明,为代谢网络分析开发的数学工具也可以应用于混合次级信使和信号模型。如果参数未知,这将非常有助于进行模型检查并为进一步研究生成假设。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Modelling and mathematical analysis of the M$_{2}$ receptor-dependent joint signalling and secondary messenger network in CHO cells.

The muscarinic M$_{2}$ receptor is a prominent member of the GPCR family and strongly involved in heart diseases. Recently published experimental work explored the cellular response to iperoxo-induced M$_{2}$ receptor stimulation in Chinese hamster ovary (CHO) cells. To better understand these responses, we modelled and analysed the muscarinic M$_{2}$ receptor-dependent signalling pathway combined with relevant secondary messenger molecules using mass action. In our literature-based joint signalling and secondary messenger model, all binding and phosphorylation events are explicitly taken into account in order to enable subsequent stoichiometric matrix analysis. We propose constraint flux sampling (CFS) as a method to characterize the expected shift of the steady state reaction flux distribution due to the known amount of cAMP production and PDE4 activation. CFS correctly predicts an experimentally observable influence on the cytoskeleton structure (marked by actin and tubulin) and in consequence a change of the optical density of cells. In a second step, we use CFS to simulate the effect of knock-out experiments within our biological system, and thus to rank the influence of individual molecules on the observed change of the optical cell density. In particular, we confirm the relevance of the protein RGS14, which is supported by current literature. A combination of CFS with Elementary Flux Mode analysis enabled us to determine the possible underlying mechanism. Our analysis suggests that mathematical tools developed for metabolic network analysis can also be applied to mixed secondary messenger and signalling models. This could be very helpful to perform model checking with little effort and to generate hypotheses for further research if parameters are not known.

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来源期刊
CiteScore
2.20
自引率
0.00%
发文量
15
审稿时长
>12 weeks
期刊介绍: Formerly the IMA Journal of Mathematics Applied in Medicine and Biology. Mathematical Medicine and Biology publishes original articles with a significant mathematical content addressing topics in medicine and biology. Papers exploiting modern developments in applied mathematics are particularly welcome. The biomedical relevance of mathematical models should be demonstrated clearly and validation by comparison against experiment is strongly encouraged. The journal welcomes contributions relevant to any area of the life sciences including: -biomechanics- biophysics- cell biology- developmental biology- ecology and the environment- epidemiology- immunology- infectious diseases- neuroscience- pharmacology- physiology- population biology
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