Elucidating new redox-signalling mechanisms mediating responses to reactive oxygen species (ROS)

BACKGROUND: Reactive oxygen species (ROS) are natural products of aerobic metabolism but also encountered following exposure to irradiation, drugs/xenobiotics. Oxidative damage caused by ROS is a significant cause of cell death and loss of tissue function during many diseases, and in ageing. Hence, a better understanding of ROS-defence mechanisms and how they are regulated is vital to prevent oxidative damage associated with ageing, as well as to improve the targeting of cancer cells or fungal pathogens with cytotoxic drugs. The goal of this project is to elucidate new mechanisms by which cells sense and respond to ROS. PROJECT: Yeast and human cells are able to buffer their intracellular environment against low levels of hydrogen peroxide, using specific sensor proteins to activate protective responses that limit damage and maintain optimal conditions. Using a novel proteomic approach we have identified many candidate sensors for mediating these protective responses. These include a conserved kinase that protects cancer cells against treatment with irradiation. In this project the student will use an integrated approach, involving 2 model systems [1] a yeast that is a well-established model for studies of hydrogen peroxide responses, cell division and ageing and [2] cultured human cell models that are ideal for studies of circadian regulation, cell division and senescence. They will use a wide range of molecular and cellular techniques in these model systems (including microscopy and methods to examine whether specific proteins are oxidised) to determine how this kinase is regulated in response to increases in hydrogen peroxide. The data from these studies will be used to inform a mathematical model representing how redox-regulation of this kinase and other signalling proteins, protects cells/organisms against oxidative stress. We expect knowledge obtained from this systems approach to allow the future design of new, improved strategies to target senescent or cancer cells in animals, or fungal pathogens within their host.
This is a basic science proposal that fits well with 'Healthy ageing across the lifecourse' a major strategic objective of the BBSRC. Ageing and many diseases of old age are associated with increases in oxidative cell damage. Despite increasing evidence that low levels of reactive oxygen species trigger mechanisms that protect against ageing, the pathways mediating these pro-longevity effects remain unknown. The identification and characterisation of new pathways that respond to changes in H2O2 is expected to have a significant impact on ageing research by identifying new candidate targets for therapeutic interventions. The student will receive training in state of the art molecular genetic approaches to analysis gene function in yeast and human cells as well as redox-signalling methodologies. This will increase capacity in the growing area of redox signal transduction/protein oxidation which has many academic, medical and industrial applications. The mathematical modelling component of the project fits with the BBSRC strategic investment in methods/training exploiting New Ways of Working and systems approaches to tackle research questions.