Post-transcriptional feedback control of polyamine metabolism in yeast: an integrated modelling and experimental investigation

细胞是生命的基本单位，一个典型的多细胞生物体，如人类，是由数百万个这样的积木组成的。在每个细胞内，发生数千种化学反应，控制着从能量产生到DNA制造的一切。所有这些化学反应都被包围在细胞膜内。其中一组这样的化学反应形成了这项研究计划的重点，并参与了一系列称为多胺的重要化合物的制造。多胺是在细胞健康和生存能力中起关键作用的小分子，没有它们，生命将无法维持。多胺水平的变化可能导致细胞死亡或癌症，以及人类遗传疾病，如精神发育迟滞疾病斯奈德-罗宾逊综合征。多胺有助于支持一系列对可行性至关重要的过程。例如，它们帮助DNA正确包装和折叠。在这样做的过程中，它们帮助DNA中编码的基因正确地打开和关闭，或“表达”。多胺还帮助另一种叫做RNA的聚合物正确折叠，同样，RNA在基因表达中起着核心作用。作为最后一个例子，多胺有助于保护细胞膜免受能量产生时细胞中意外产生的氧化化学物质的损害;因此，多胺与维生素C（我们饮食中发现的重要抗氧化剂）起着非常相似的作用。在工厂或化工厂中，化学反应总是受到严格控制，在这方面，细胞也不例外。它的化学反应也受到一系列在进化过程中完善的制衡，以确保反应可以打开或关闭，因为需要或多或少的产品。如果没有这种控制，生命系统就不会表现出对环境变化做出反应的能力，甚至在某些情况下，生命系统将不再有活力。对有效、严格控制的要求导致许多细胞化学反应，包括多胺合成的那些反应，受到复杂、多重和连锁的控制。了解多胺合成的控制如何在活细胞中运作，这种控制有多强大，以及在什么情况下控制可能会崩溃，例如在癌症或Snyder-Robinson综合征等疾病状态下，这是一个只能由系统生物学新领域解决的问题。在系统生物学中，生物学家与控制工程师等物理科学家组成多学科团队，试图了解生物控制过程如何相互作用，以实现强大的控制。这种跨学科的方法是需要作为一个直接响应的多胺控制机制的复杂性正在研究，这使得标准的生物学研究方法不足。在这项提案中，生物学家和控制工程师将在一个跨学科的团队中共同努力，对多胺合成途径进行系统生物学分析。生化反应的数学模型将被开发，测试和使用来测试关于途径如何发挥作用的假设。目的是了解多胺的生产是如何控制的，了解在人类疾病状态下控制过程中出现了什么问题，并了解多胺控制的稳健性，即尽管细胞生物化学发生了变化，但控制效果如何。该研究项目将揭示如何在健康细胞中控制这一关键代谢过程，以及这种控制在不同疾病状态下如何出错。

The cell is the basic unit of life, and a typical multi-celled organism like a human is made up of literally millions of such building blocks. Within each cell, thousands of chemical reactions take place, controlling everything from energy generation to DNA manufacture. All these chemical reactions are enclosed within the membrane that surrounds the cell. One set of such chemical reactions forms the focus of this research proposal, and is involved in the manufacture of a series of important compounds called polyamines. Polyamines are small molecules that play a crucial role in cell health and viability, and without them, life would be unsupportable. Changes in the levels of polyamines can cause cell death or cancer, as well as human genetic disease like the mental retardation disorder Snyder-Robinson Syndrome. Polyamines help support a range of processes central for viability. For instance, they help DNA to be correctly packaged and folded. In doing so, they help the genes encoded in the DNA to be correctly switched on and off, or 'expressed'. Polyamines also help another polymer called RNA to fold correctly, and again, RNA plays a central role in gene expression. As a final example, polyamines help protect the membrane in the cell from damage by the oxidising chemicals generated accidentally in the cell when energy is generated; as such, polyamines play a very similar role to vitamin C, an important anti-oxidant found in our diet. In a factory or chemical plant, chemical reactions are always carefully controlled, and in this respect, the cell is no different. Its chemical reactions are also subject to a series of checks and balances perfected over the course of evolution to make sure the reactions can be turned on, or off, as more or less product is required. Without this control, living systems would not exhibit the ability to respond to changes in the environment, and indeed, in some cases, would cease to be viable. The requirement for effective, tight control has resulted in many cellular chemical reactions, including those of polyamine synthesis, being subject to complex, multiple and interlocking controls. Understanding how control over polyamine synthesis operates in a living cell, how robust that control is, and under what circumstances the control might break down, for example in a disease state like cancer or Snyder-Robinson Syndrome, is a problem that can only be addressed by the new field of systems biology. In systems biology, biologists work in multi-disciplinary teams with physical scientists such as control engineers to try and understand how biological control processes interact to enable robust control to be exerted. This interdisciplinary approach is required as a direct response to the complexity of the polyamine control mechanisms being studied, which renders standard biological research approaches inadequate. In this proposal, biologists and control engineers will be working together in an interdisciplinary team to subject the polyamine synthesis pathway to a systems biology analysis. Mathematical models of the biochemical reactions will be developed, tested and employed to test hypotheses about how the pathway functions. The aim is to understand how polyamine manufacture is controlled, to understand what goes wrong with the control processes in human disease states, and to understand how robust polyamine control is i.e. how successfully is control maintained despite changes in cell biochemistry. The research project will reveal how control over this key metabolic process is exerted in a healthy cell, and how that control goes wrong in different disease states.