THE "REDOX TRIANGLE" - COMMUNICATION BETWEEN PEROXISOMES, THE ENDOPLASMIC RETICULUM AND MITOCHONDRIA IN HEALTH AND DISEASE

为了生存和茁壮成长，群居动物需要有效地交流和合作，这样当作为一个整体来看，一个个体的社区大于它的各个部分的总和。“在人类(以及动物)的漫长历史中，那些学会最有效地合作和即兴发挥的人占了上风”(查尔斯·达尔文，1809-1882)。这一普遍概念也适用于人类细胞不同部分之间的通信。使用的“语言”可能有所不同，细胞隔间交换化学信号以指示环境的变化，而不是动物之间发出的警告危险的声音，但潜在的前提是相同的。我的研究旨在探索细胞内不同的隔间是如何沟通的，以及当这种沟通中断时会发生什么。从概念上讲，人类细胞可以细分为单独的隔间(细胞器)，这些隔间(细胞器)是更广泛的网络或生产线的一部分。每个细胞器都有自己特定的工作要做，但也广泛依赖网络中的其他单位。例如，脂肪(脂)等食物通常先在一个细胞器中进行部分加工，然后再移交给另一个细胞器进行进一步加工。这种协调也是产生能量、产生构建神经细胞膜所需的脂类以及激活细胞循环系统所必需的。细胞器需要聚集在一起在细胞反应中进行交流和合作的想法是细胞生物学中的一个新兴领域，我们对所涉及的因素以及这种交流何时发生仍然知之甚少。然而，由于相关机制的缺陷，细胞器通讯的故障已被认为与阿尔茨海默氏症、帕金森氏症以及代谢紊乱等疾病有关。此外，随着细胞老化，它们的新陈代谢效率降低，协调危险废物解毒的能力减弱，这可能是通讯中断的结果，导致导致老化过程的渐进性损害。在我的研究中，我将使用哺乳动物细胞来研究内质网、过氧化物体和线粒体这三个细胞器是如何沟通的。这些细胞器是细胞中的主要中心，参与脂质交换以及以活性氧物种的形式产生和解毒废物。我将评估这些细胞器如何以及何时进行通信，以及涉及哪些组成部分。由于活性氧的积累与衰老有关，我将研究细胞器之间的信号交换是如何分担负荷和协调解毒的。我将发现代谢开关，这些开关可以开启和关闭不同的途径和系统，并产生新的工具和系统，也可以被该领域的其他研究人员使用，从而加快这一领域的研究。这项工作的第一阶段将提供基础知识和工具，然后在第二阶段利用这些知识和工具来评估细胞器相互作用中的缺陷是如何与疾病联系在一起的。我将研究细胞器之间的相互作用如何随着时间的推移而变化，作为衰老的模型，我还将评估当通讯出错时细胞中的脂质平衡会发生什么。最后，我的目标是恢复有缺陷的沟通渠道，以确定这是否可以成为一种可能的治疗方法。这个新颖而极其令人兴奋的细胞生物学领域有望提供对细胞中细胞器相互作用事件的基本见解，并确定这如何适应更广泛的细胞信号网络，以及沟通障碍可能如何与疾病联系在一起。

In order to survive and thrive, social animals need to communicate and collaborate effectively so that when taken as a whole, a community of individuals is greater than the sum of its parts. "It is the long history of humankind (and animal kind, too) that those who learned to collaborate and improvise most effectively have prevailed" (Charles Darwin, 1809 - 1882). This general concept is also true for communication between different parts of the human cell. The "language" used may differ, instead of vocal calls between animals as a warning of danger, cellular compartments exchange chemical signals to indicate a change in environment, but the underlying premise is shared. My research aims to explore how different compartments inside cells communicate and what happens when this communication breaks down. Conceptually, the human cell can be sub-divided into separate compartments (organelles) which are a part of wider networks or production lines. Each organelle has its own particular job to perform but also relies extensively on other units within the network. For example, foods such as fats (lipids) are often partially processed in one organelle before being handed over to a different organelle for further processing. Such coordination is also required for the generation of energy, the production of lipids required to build nerve cell membranes, and the activation of the cells recycling systems. The idea that organelles need to come together to communicate and collaborate in cellular reactions is an emerging field in cell biology and we still know relatively little about the factors involved and when this communication takes place. However, a breakdown in organelle communication, due to defects in the machinery involved, has been implicated in diseases such as Alzheimer's and Parkinson's as well as metabolic disorders. Furthermore, as cells age their metabolic efficiency is reduced and the ability to coordinate detoxification of dangerous waste products is diminished, perhaps as a result of communication breakdown, resulting in progressive damage which contributes to the ageing process. In my research I will use mammalian cells to investigate how three organelles, the endoplasmic reticulum, peroxisomes and mitochondria communicate. These organelles are the major centres in the cell which are involved in both lipid exchange and the production and detoxification of waste products in the form of reactive oxygen species. I will assess how and when these organelles communicate and what components are involved. As the accumulation of reactive oxygen species is associated with ageing I will investigate how signal exchange between the organelles works to share the load and coordinate detoxification. I will uncover the metabolic switches which turn different pathways and systems on and off and generate new tools and systems which can also be used by other researchers in the field, accelerating research in this area. The first phase of the work will provide the underpinning knowledge and tools which will then be leveraged in the second phase to assess how defects in organelle interactions are linked to disease. I will investigate how interactions between organelles can change over time as a model for ageing and will also assess what happens to the lipid balance in cells when communication goes wrong. Finally, I aim to restore defective communication channels to determine if this can be a possible therapeutic approach. This novel and extremely exciting area of cell biology promises to deliver fundamental insights into organelle interactions events in cells and also establish how this fits into the broader cellular signalling network and how failure to communicate may be linked to disease.