Systems Understanding of Microbial Oxygen-Dependent and Independent Catabolism (SUMO2)

在这个项目中，一个由分子生物学家、生物化学家、数学家和计算机科学家组成的多学科科学家团队将共同努力，利用系统生物学来研究细菌对环境中氧气的反应。这种细菌就是大肠杆菌，它是一种主要的模式生物，对它的研究提供了我们目前基本分子生物学的大部分知识，并继续成为生物技术部门的主力。系统生物学的研究方法是一个相对较新的研究领域，它试图了解整个生物过程或系统(如有机体及其行为)，而不仅仅是系统的组件(如原子、分子和个别反应)。实际上，系统生物学试图“把矮子重新组合在一起”。系统生物学可以用来模拟生物过程并预测干扰系统的结果，甚至在实验进行之前就可以了。这种预测能力导致了更有意义的实验的设计。我们的目标是获得对这种细菌新陈代谢的完整、定量的描述，即了解碳食物是如何被分解并在发酵和呼吸过程中产生能量的。预期结果如下。(1)复杂的实验结果，描述了：(A)从发酵到厌氧(即无氧)呼吸生长过程中基因表达的动态；(B)对氧化剂(氧气和与化学相关的分子)脉冲的响应动态；(C)在特定的好氧条件下(即在空气中)底物运输过程的突变对生理的影响；(D)突变和碳源转换对中央新陈代谢的影响；(E)分支呼吸链在条件变化时的适应作用。(2)多尺度、多层次数学模型，描述：(A)厌氧培养扰动期间基因调控网络的动态；(B)基因调控过程复杂网络内动态的调控后果；(C)基因启动子的调控机制；(D)食物从进入细胞到能量产生的分解(分解)，包括厌氧途径；(E)替代呼吸链的调控和作用；(F)单细胞动力学和不稳定条件下的细胞行为。(3)建立一个可预测的、定量的、经实验验证的大肠杆菌综合代谢子系统的模型，以及这些子系统如何对内部和外部信号的变化作出反应。

In this project, a multidisciplinary team of scientists, comprising molecular biologists, biochemists, mathematicians and computer scientists will work together and use Systems Biology to study the response of a bacterium to oxygen in its environment. The bacterium is E. coli, a major model organism, study of which has provided much of our current knowledge of basic molecular biology and continues to be the workhorse of the biotechnology sector. The Systems Biology approach to research is a relatively new area of investigation that tries to understand entire biological processes or systems (such as an organism and its behaviour), rather than merely the components of the system (such as atoms, molecules, and individual reactions). In effect, Systems Biology attempts to 'put Humpty Dumpty together again'. Systems Biology can be used to simulate biological processes and predict the outcome of perturbing the system, even before experiments are carried out. This ability to predict leads to the design of more meaningful experiments. We aim to obtain a complete, quantitative description of the metabolism of this bacterium, i.e. understand how carbon foodstuffs are broken down and used to generate energy in fermentation and respiration. The expected results are as follows. (1) Complex experimental results describing: (a) the dynamics of gene expression during the change from fermentative to anaerobic (i.e. without oxygen) respiratory growth; (b) the dynamics of responses to pulses of oxidants (oxygen and chemically related molecules); (c) the effects of mutation of substrate transport processes on physiology under defined aerobiosis conditions (i.e. in air); (d) effects of perturbation of central metabolism by mutation and by switching carbon source; (e) the role of a branched respiratory chain in adapting when conditions change. (2) Multi-scale, multi-level mathematical models describing: (a) the dynamics of gene regulatory networks during perturbations of anaerobic cultures; (b) the regulatory consequences of dynamics within complex networks of gene regulation processes; (c) the regulatory mechanisms of gene promoters; (d) catabolism (break-down) of foodstuffs from their entry into the cell right through to energy generation, including anaerobic pathways; (e) the regulation and action of alternative respiratory chains; (f) single-cell dynamics and cell behaviour in unstable conditions. (3) The formulation of a predictive, quantitative, experimentally validated model of the integrated metabolic sub-systems of E. coli and how these respond to changes in internal and external signals.