QSB: Computing Life and the Kinetics of the Cell

Arnold 0425762本研究的主要目标是实现和验证一种新的方法，对定量功能基因组学，被称为计算生命范式，它集成了国家的最先进的实验探针的时间依赖性细胞内动力学与最近提出的基于整体的动力学建模技术。它的起点是定量RNA和蛋白质分析实验，以监测细胞对受控外部扰动的反应，如基因敲除、蛋白质抑制和各种依赖时间的外部食物来源和饥饿时间表。集成建模技术，然后利用这样的时间依赖性的实验数据，不仅约束的拓扑结构和参数空间的遗传网络模型（S）的研究，但也进行定量预测，最重要的是，提供定量标准的合理设计的“最大信息的下一个实验”。因此，计算生命范例的完全实现导致工作流循环，其中合理设计的新实验进一步约束“模型集合”，而模型集合在其预测能力方面变得越来越精细和有区别。这种方法的最初应用将集中在真菌生物中的两个先前已充分探索的遗传模型系统，特别是在粗糙脉孢菌中，它们表现出截然不同的动力学行为：奎尼酸（qa）基因簇，参与细胞碳代谢的瞬时响应;和生物钟，振荡系统的原型。

Arnold0425762The main goal of this research is to implement and validate a novel approach towards quantitative functional genomics, referred to as the computing life paradigm, which integrates state-of-the-art experimental probes of the time-dependent intra-cellular kinetics with a recently proposed ensemble-based kinetics modeling technique. Its starting point are quantitative RNA and protein profiling experiments to monitor the cell's responses to controlled external perturbations such as gene knock-outs, protein inhibition and various time-dependent schedules of external food sources and starvation. The ensemble modeling technique then utilizes such time-dependent experimental data to not only constrain the topology and the parameter space of the genetic network model(s) under study; but also to make quantitative predictions and, most importantly, to provide quantitative criteria for the rational design of a "maximally informative next experiment". The full implementation of the computing life paradigm thus results in a workflow cycle wherein rationally designed new experiments further constrain the "ensemble of models" while the model ensemble becomes more and more refined and discriminating in its predictive capabilities. The initial applications of this approach will focus on two previously well explored genetic model systems in fungal organisms, specifically in Neurospora crassa, exhibiting widely different dynamical behavior: the quinic acid (qa) gene cluster, involved in transient responses of the cell's carbon metabolism; and the biological clock, the proto-type of an oscillatory system.