"Perturbations in cellular redox status are implicated in many human diseases, yet there is an extreme lack of knowledge about the effects of oxidative stress in vivo, mainly due to difficulties in measuring reactive oxygen species (ROS) in vivo and the absence of experimental models. REDOX will use novel transgenic technologies to develop mouse models that report on ROS in vivo, allowing spatio-temporal monitoring of different types of oxidative stress, ultimately simultaneously in a complex reporter line, and clarifying its role in the aetiology of disease and pathways of drug & chemical toxicity. These models will reveal oxidative stress as a primary cause, or a consequence, of the disease process. Reporters will be driven by endogenous genes regulated by different forms of oxidative stress and, uniquely, we will exploit the sophisticated redox sensing systems in bacteria to discern different types of ROS. In a sophisticated system we will express 3 reporters from the same stress regulated promotor, generating a polycistronic mRNA by use of the FMDV 2A sequence, which cleaves the nascent polypeptide to yield the endogenous gene product and individual reporters. LacZ will be used as an in situ reporter, luciferase for imaging, and a secreted protein, eg hCG, as a non-invasive biomarker in blood or urine. The in vivo role of oxidative stress in disease aetiology, and the potential of novel anti-oxidants to prevent such diseases, will be evaluated in these models. A further novel aspect will be to generate ES cells from the reporter lines, and create genetically-driven disease models which reflect inherited human diseases. REDOX combines ambitious experimental systems with sophisticated novel technologies to create models to define the role of oxidative stress in human disease, offering a new approach in defining and testing of disease prevention and therapeutic interventions while reducing the number of animals required."
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