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Interference of anthracyclines with cardiac energy signalling: implications for drugs, cardiotoxicity and oncogenic growth


Anthracyclines belong to the most efficient drugs of cancer chemotherapy. However, their use is limited by severe cardiotoxicity, whose molecular triggers are not fully understood. Our aim is to analyse novel aspects of cardiac response to anthracyclines, namely signalling pathways regulating cardiac energetics. The ability to respond to altered energy supply or demand is particularly important for heart to maintain its contractile performance. Our approach will integrate a non-biased global analysis of antracycline-induced changes in gene expression and proteome/phospho-proteome with a targeted analysis of the signaling pathway of AMP-activated protein kinase (AMPK).

AMPK is a key sensor and regulator of cellular energy state and the drug reduces basic AMPK phosphorylation as we showed recently. The multidisciplinary approach combining biophysical, biochemical, molecular and physiological state-of-the-art techniques will (i) apply different model systems as recombinant protein, cultured cardiomyocytes, isolated perfused rat heart, and cancer cells for comparison, (ii) explore regulatory cross-talk between the AMPK cascade and other signalling pathways or key regulators of cardiac energy metabolism (e.g. creatine kinase), (iii) screen a library of cardioprotective compounds.

In scientific terms, we will identify anthracycline-induced changes in the cardiac energetic network and other signalling pathways susceptible to mediate drug cardiotoxic, and possibly anticancer effects. This can provide potent means to modulate drugs toxic and therapeutic activity. In terms of training, fellows goal is to acquire expertise in different cardiac models and in integrative approach (from molecular to physiological) to cardiac bioenergetics and non-scientific skills in a leading medically oriented research environment to amend her multidisciplinary portfolio with the long-term goal to obtain a permanent, leading position in research, e.g. as professor or clinical researcher.

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