"Anthracyclines, in particular doxorubicin, are the most effective anticancer drugs. However, their serious side effect is a cardiotoxicity, which is not entirely understood. We propose a novel hypothesis, namely that anthracycline-induced cardiac damage is related to impaired cellular responses to energy depletion, and possibly also to other forms of stress (oxidative, genotoxic), inducing a “catastrophe”, fatal for cardiac (and cancer) cells. The aim of the project is to verify this hypothesis in different models: perfused heart, cultured cardiomyocytes, and an in vivo model of cardiotoxicity newly established in our group, the doxorubicin-treated rat. Our project will integrate: (i) a non-biased phosphoproteomic approach extending our transcriptomic study and aiming at the identification of new phosphorylation events mediating response to doxorubicin; (ii) a targeted approach focusing on pathways identified by our targeted and non-biased in vitro studies, as e.g. signaling by LKB1-AMPK-mTOR, MAPK, HIF, VEGF, and NDPK, a metabolic kinase that we have recently identified as doxorubicin target. We will analyse the effects of doxorubicin on these pathways (including gene and protein expression, phosphorylation, activity) and their consequences for cardiac function, energy state, apoptotic status, and response to an additional stress (ischemia). This multidisciplinary project will combine biophysical, biochemical, molecular, physiological and systems biology (phosphoproteomics, modeling) state-of-the-art approaches. We expect to identify new signaling pathways mediating doxorubicin cardiotoxic action. Further integration of the fellow with the host will allow full valorisation of projects initiated during the present Marie-Curie Fellowship, further supervision of PhD and master students, and access to a permanent position in Grenoble at the group leader level. This would enable the fellow to pursue a dual academic career with her spouse at the same geographic location."