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

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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.