An Integrative Multi-Level Systems Biology Approach to Understanding Enterobacterial Responses to Oxygen

在“分子时代”，生物学家通过详细分析组织、细胞、亚细胞碎片和分子等个体组成部分，研究了生命背后的机制。这种方法非常有效，但现在新的方法和技术使科学家能够看到“大局”，并试图理解所有这些部分是如何协同工作的。细菌细胞为这种分析提供了理想的材料，因为它们（相对）小而简单，我们对它们的组成分子了解很多。在这个项目中，我们将尝试重新组装一幅图片，展示一种众所周知的细菌，大肠杆菌，是如何对它经常遇到的压力做出反应的，特别是在它的双重生活方式中，在动物（包括人类）肠道和外部世界之间交替。在前者中，细菌的环境在很大程度上是无氧的，生物体必须通过基因调节、蛋白质合成和代谢控制来适应其生理机能，以利用其他（无氧）可呼吸的底物。当大肠杆菌离开大肠时，它突然面临一个更冷、更富氧但营养更不令人满意的环境，必须对基因调控、蛋白质合成和代谢过程做出迅速而重大的改变。我们将进行仔细的实验室实验，在可复制的条件下培养细菌，对细胞遇到不同水平的氧气时发生的变化进行分类。然后，将尝试对这些过程进行数学模拟（或模型），其中我们试图将分子和途径的数据整合到“大局”中（系统生物学）。希望这个模型能揭示细胞反应的新方面，更重要的是，强调我们仍需要收集的事实，以完善模拟。这项工作的结果将更好地理解一个简单的细胞是如何对危及生命的压力作出反应的，并可能告诉我们控制这种细菌和其他细菌在疾病中的生存的方法，以及在商业生物过程中优化这种有机体的生长。此外，该项目将促进英国、荷兰和德国的生物学和数学/计算科学家之间的合作，促进系统生物学新领域的协同研究活动。

In the 'molecular age', biologists have investigated the mechanisms underlying life by analysing individual components in great detail / tissues, cells, subcellular bits and pieces, and molecules. This approach has been highly productive but new methods and technology now allow scientists to look at the 'big picture' and attempt to understand how all these pieces work together. Bacterial cells provide ideal material for this kind of analysis since they are (relatively) small and simple and we understand a lot about their component molecules. In this project we will attempt to reassemble a picture of how a well-understood bacterium, Escherichia coli, responds to a stress that it will frequently encounter, particularly in its dual lifestyle, alternating between the animal (including human) gut and the outside world. In the former, the bacterium's environment is largely oxygen-free and the organism must adapt its physiology via gene regulation, protein synthesis and metabolic control to utilise other (non-oxygen) respirable substrates. When E. coli leaves the large intestine, it is suddenly faced with a colder, more oxygen-rich but nutritionally less satisfying environment and must make rapid and major changes to gene regulation, protein synthesis and metabolic processes. We will perform careful laboratory experiments in which the bacterium is cultivated under reproducible conditions, cataloguing the changes that occur in the cell when it encounters various levels of oxygen. Then a mathematical simulation (or model) of these processes will be attempted in which we try to integrate the data on molecules and pathways into the 'big picture' (Systems Biology). It is hoped that the model will reveal new aspects of the cell's response and, importantly, highlight those facts that we still need to gather to refine the simulation. The results of this work will be a much better understanding of how a simple cell responds to life-threatening stresses and may inform our approaches to controlling the survival of this and other bacteria in disease, as well as optimising the growth of this organism in commercial bioprocesses. Moreover, the project will stimulate cooperation between biological and mathematical/computing scientists in the UK, the Netherlands and Germany, promoting a concerted research activity in the new area of Systems Biology.