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Identification of p38 MAPK partners in the response of endothelium to oxidative stress and ionizing radiation. Impact in cancer radiotherapy (p38RADOX)
Date du début: 1 août 2013, Date de fin: 31 juil. 2015 PROJET  TERMINÉ 

Cancer is a leading cause of death in Europe. Therefore, improving the efficacy of curative treatments remains a major goal to achieve. Today, with more than 60% of European cancer patients treated with radiotherapy, understanding the biology underlying the cellular response to ionizing radiation (IR) is an ongoing challenge to ameliorate efficacy of this treatment. Basic concepts in tumor radiobiology have evolved. Endothelium irrigating tissues exposed to radiation and signaling events initiated at the plasma membrane are now considered as key issues. Thus, the membrane sphingolipid ceramide, reactive oxygen species (ROS) and importantly p38 MAPK proteins have been identified as critical molecular actors of the membrane initiated-response of the endothelium to IR.This project aims at characterizing the p38 MAPK pathway in the response of tumor endothelium to oxidative stress/IR and will address the following issues: What are the partners of p38 MAPK (p38-Partns) in IR/oxidative stress/ceramide pathway? Which IR-endothelial dysfunctions are associated with this p38 MAPK/p38-Partns pathway? The outgoing phase will characterize the ceramide/p38 MAPK pathway in endothelial cells exposed to oxidative stress. The methodological approach will rely on mass spectroscopy identification of p38-Partns. Role of p38-Partns in endothelial functions, notably in cell migration and adhesion by supra-resolution TIRF microscopy, will then be investigated. The return phase will explore this p38 MAPK pathway in vitro in endothelium exposed to IR and in vivo in human samples of irradiated tumor microenvironment.This project will yield new insights in life sciences from fundamental radiobiology and oxidative stress biology to identification of potential new targets for improvement of radiotherapeutical benefit.This proposal will provide scientific expertise and additional training (people management, ethics, translational research) that will impact the fellow’s career development