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，像人类这样典型的多细胞生物是由数百万个这样的积木组成的。在每个细胞内，成千上万的化学反应发生，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裹在细胞周围的膜中。一组这样的化学反应形成了这项研究计划的重点，并涉及到一系列重要化合物的制造，这些化合物被称为多胺。多胺是一种小分子，在细胞健康和活力中起着至关重要的作用，没有它们，生命将无法维持。多胺水平的变化会导致细胞死亡或癌症，以及像斯奈德-罗宾逊综合征这样的人类遗传疾病。多胺有助于支持一系列对生存至关重要的过程。例如，它们帮助DNA被正确地包装和折叠。在这样做的过程中，它们帮助DNA中编码的基因被正确地打开和关闭，或“表达”。多胺还能帮助另一种叫做RNA的聚合物正确折叠，RNA在基因表达中也起着核心作用。最后一个例子是，多胺有助于保护细胞内的膜，使其免受细胞在产生能量时意外产生的氧化化学物质的损害；因此，多胺的作用与维生素C非常相似，维生素C是一种重要的抗氧化剂，存在于我们的饮食中。在工厂或化工厂里，化学反应总是受到严密的控制，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，以确保反应可以开启或关闭，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作出反应的能力，实际上，在某些情况下，生命系统将无法生存。对有效、严格控制的要求导致许多细胞化学反应，包括多胺合成反应，受到复杂、多重和连锁的控制。了解对多胺合成的控制是如何在活细胞中运作的，这种控制有多强大，以及在什么情况下这种控制可能会失效，例如在癌症或Snyder-Robinson综合征等疾病状态下，这是一个只能通过系统生物学的新领域来解决的问题。在系统生物学中，生物学家在多学科团队中与物理科学家（如控制工程师）合作，试图了解生物控制过程如何相互作用以实现鲁棒控制。这种跨学科的方法是需要的，因为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的直接反应。在本提案中，生物学家和控制工程师将在一个跨学科的团队中一起工作，对多胺合成途径进行系统生物学分析。生物化学反应的数学模型将被开发、测试并用于测试关于该途径如何发挥作用的假设。目的是了解多胺的制造是如何控制的，了解人类疾病状态下的控制过程出了什么问题，并了解多胺控制是如何强大的，即，尽管细胞生物化学发生了变化，但控制是如何成功维持的。该研究项目将揭示在健康细胞中对这一关键代谢过程的控制是如何发挥作用的，以及在不同的疾病状态下这种控制是如何出错的。

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.