Targeting redox-active cysteine residues in protein kinases as a new therapeutic approach to ageing and age-associated diseases

背景：活性氧(ROS)可引起细胞损伤，是许多与年龄相关的疾病的主要诱因，包括神经退行性疾病和心血管疾病。然而，在过去的10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，包括启动保护反应，以维持细胞存活/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丧失的机制仍然知之甚少。这个项目涉及一个多学科的指导团队，使学生能够结合一系列遗传学、生化和计算方法来为这个基本问题提供答案。项目：监管人员已经成功地使用高通量基因筛选和蛋白质组学方法相结合的方法来识别几个候选的ROS调节的激酶。本项目将使用标准和尖端的分子生物学和生化技术(包括基因组编辑、RNAi、免疫印迹和共聚焦显微镜)来研究ROS诱导的半胱氨酸在细胞(哺乳动物)和动物(秀丽线虫)模型中的氧化是否介导了ROS的积极作用。通过阐明介导ROS效应的新的信号机制，该项目将向从治疗上增强ROS诱导的保护性反应以抵消衰老影响的目标迈出重要的一步。在Conlon博士的监督下，工业植入将使网络药理学能够被用作转化这些发现的前奏。该项目正好属于BBSRC挑战领域‘终身健康’-了解健康的生物学机制，长期目标是在整个生命过程中保持和提高心理和身体健康的质量。

Background: Reactive oxygen species (ROS) cause cell damage that is a major contributor to a number of age-related conditions including neurodegenerative disorders and cardiovascular diseases. However, over the last 10 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, that include 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 remain poorly understood. This project involves a multidisciplinary supervisorial team, enabling the student to combine a range of genetic, biochemical and computational approaches to provide answers to this fundamental question. Project: The supervisors have successfully used a combination of high throughput genetic screening and proteomic approaches to identify several candidate ROS-regulated kinases. This project will use standard and cutting-edge molecular biological and biochemical techniques (including genome editing, RNAi, immunoblotting and confocal microscopy) to investigate, whether ROS-induced oxidation of cysteines in these kinases mediates the positive effects of ROS in cell (mammalian), and animal (Caenorhabditis elegans) models. By elucidating new signalling mechanisms that mediated effects of ROS, this project will provide an essential step towards the goal of therapeutically enhancing ROS-induced protective responses to counteract the effects of ageing. The industrial placement, supervised by Dr Conlon, will enable network pharmacology to be used as a prelude to translating these discoveries.This project falls squarely under the BBSRC challenge area 'Lifelong Health' - understanding the biological mechanisms of healthspan, with the long-term objective of maintaining and enhancing the quality of mental and physical health throughout the life-course.