Shedding light on oxidative stress: Identifying factors modulating the redox balance in the endoplasmic reticulum of Caenorhabditis elegans.

活性氧(ROS)、氧化应激和氧化还原平衡在生物体的许多不同过程中起着关键作用。这些因素的重要性反映在疾病的数量和它们发挥主要作用的条件上，包括炎症(包括关节炎)、癌症、心脏病和中风，以及在老龄化过程中。除了参与疾病外，氧化还原和ROS在关键的正常细胞功能中起着至关重要的作用。蛋白质在分泌前折叠和组装的细胞室称为内质网(ER)。ER蛋白质折叠的关键步骤是形成二硫键，这是一种对氧化还原环境高度敏感的事件。如果ER太还原，那么二硫化物还不会形成，如果它太氧化，那么非自然形式变得非常稳定，导致错误折叠，这一事件可能导致疾病。控制这种微妙的平衡以允许正确的二硫化物形成和防止内质网中的氧化应激的许多因素仍有待确定。在这个项目中，我们将结合我们在遗传学、生物化学和细胞生物学方面的不同但互补的专业知识，全面剖析如何在一种名为秀丽线虫的小型模式生物的内质网中维持氧化还原平衡。我们已经开发了一种线虫，它发出一种特定的光信号，这种光信号依赖于内质网中的氧化还原环境，我们建议将其作为一种实验工具，以揭示该细胞器中参与氧化还原平衡的基因。这些实验将用于在哺乳动物细胞中提供信息和指导实验，并将对人类细胞生物学、人类疾病状态、衰老和蛋白质的生物技术生产产生直接影响。

Reactive oxygen species (ROS), oxidative stress and the reduction-oxidation (redox) balance play key roles in many different processes in living organisms. The importance of these are reflected in the number of diseases and conditions where they play a major role, including, inflammation (including arthritis), in cancer, heart disease and stroke, and in the ageing process. In addition to involvement in disease, redox and ROS play essential roles in key normal cellular functions. The cellular compartment where proteins are folded and assembled prior to secretion is called the endoplasmic reticulum (ER). A critical step in ER protein folding is the formation of disulphide bonds, an event that is highly sensitive to the redox environment. If the ER is too reducing then disulphides will not form yet if it is too oxidising then non-native forms become very stable leading to misfolding, an event that may lead to disease. Many of the factors involved in controlling this delicate balance to allow correct disulphide formation and to prevent oxidative stress in the ER remain to be identified. In this project we will combine our diverse but complementary expertise in genetics, biochemistry and cell biology to fully dissect how the redox balance is maintained in the ER of a small model organism called Caenorhabditis elegans. We have developed a strain of C. elegans that emits a specific light signal that is dependent on the redox environment in the ER and we propose to use this as an experimental tool to uncover the genes involved in redox balance in this organelle. These experiments will be used to inform and direct experiments in mammalian cells and will have a direct bearing on human cell biology, human disease states, ageing and the biotechnological production of proteins.