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

在“分子时代”，生物学家通过非常详细地分析个体成分（组织、细胞、亚细胞碎片和分子）来研究生命的基本机制。这种方法已经非常富有成效，但新的方法和技术现在允许科学家们看到“大局”，并试图了解所有这些部分如何协同工作。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有很多了解。在这个项目中，我们将试图重新组装一幅图片，了解一种众所周知的细菌，大肠杆菌，如何应对它经常遇到的压力，特别是在其双重生活方式中，在动物（包括人类）肠道和外部世界之间交替。在前者中，细菌的环境基本上是无氧的，生物体必须通过基因调控、蛋白质合成和代谢控制来适应其生理学，以利用其他（非氧）可呼吸基质。当E.当大肠杆菌离开大肠时，它突然面临一个更冷、更富氧但营养不太满意的环境，必须对基因调控、蛋白质合成和代谢过程进行快速和重大的改变。我们将进行仔细的实验室实验，在可重复的条件下培养细菌，编目细胞中发生的变化时，它遇到不同水平的氧气。然后将尝试对这些过程进行数学模拟（或模型），我们试图将分子和途径的数据整合到“大局”（系统生物学）中。希望该模型将揭示细胞反应的新方面，重要的是，突出那些我们仍然需要收集以完善模拟的事实。这项工作的结果将更好地了解简单细胞如何应对危及生命的压力，并可能为我们控制这种细菌和其他细菌在疾病中的生存以及优化这种生物体在商业生物过程中的生长提供信息。此外，该项目将促进英国、荷兰和德国的生物和数学/计算科学家之间的合作，促进系统生物学新领域的协调研究活动。

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.