Targeting new redox-signalling mechanisms as a therapeutic target to prevent age-associated diseases

活性氧(ROS)引起细胞损伤，是许多与年龄相关的疾病的主要诱因，包括癌症、神经退行性疾病和心血管疾病。然而，在过去的15年里，我们对如何限制这种损害的看法已经发生了革命性的变化。在此之前，人们发现低水平的ROS具有重要的、积极的信号传递功能；启动保护性反应，维持细胞活力/机体健康。尽管越来越多的证据表明局部ROS增加可能是有益的，但这些ROS信号被转导以防止衰老/与年龄相关的组织功能/疾病丧失的机制仍然知之甚少。这名学生将是一个多学科团队的一员，该团队结合了一系列遗传学、生化和计算方法，为这一基本问题提供答案。监管人员已经确定了几种在健康和疾病中具有重要作用的信号蛋白作为候选ROS目标。该项目的目标是使用一系列分子生物学和生化技术(包括基因组编辑、RNAi、免疫印迹共聚焦显微镜和蛋白质组学)来研究ROS诱导的这些信号蛋白中半胱氨酸的氧化如何在细胞(酵母)和动物(无脊椎动物秀丽线虫)模型中促进ROS的积极作用。通过阐明调节ROS和新陈代谢影响的新信号机制，该项目将向从治疗上增强ROS诱导的保护性反应的目标迈出重要的第一步，以对抗衰老的影响。工业植入将使学生能够使用网络药理学来确定转化这些发现的下一步。

Reactive oxygen species (ROS) cause cell damage that is a major contributor to many age-associated diseases, including cancer, neurodegenerative and cardiovascular diseases. However, over the last 15 years, our view of how to limit this damage has been revolutionised. This follows the discovery that low levels of ROS have important, positive, signalling functions; initiating protective responses that maintain cell viability/organismal health. Despite, the increasing evidence that localised ROS increases can be beneficial, the mechanisms by which these ROS signals are transduced to protect against ageing/age-associated loss of tissue function/disease remain poorly understood. The student will be part of a multidisciplinary team combining a range of genetic, biochemical and computational approaches to provide answers to this fundamental question. The supervisors have identified several signalling proteins with important roles in health and disease as candidate ROS targets. The goal of this project will be to use a range of molecular biological and biochemical techniques (including genome editing, RNAi, immunoblotting confocal microscopy and proteomics) to investigate how ROS-induced oxidation of cysteines in these signalling proteins contribute to the positive effects of ROS in cell (yeast) and animal (the invertebrate Caenorhabditis elegans) models. By elucidating new signalling mechanisms that mediate effects of ROS and metabolism, this project will provide an essential initial step towards the goal of therapeutically enhancing ROS-induced protective responses, to counter the effects of ageing. The industrial placement will enable the student to use network pharmacology to identify the next step towards translating these discoveries.