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Analysing and Modulating Apoptosis Sensitisation and Resistance in Cultured and Patient-Derived Cardiac Cells by Quantitative Biochemistry and Computational Systems Biology Implications to Cardiotoxicity and Differentiation.
Deregulated apoptosis resulting in a loss of cardiomyocytes has been implicated in malignant cardiac remodelling after exposure with the chemotherapeutic doxorubicin (DOX), resulting in cardiac impairment later in life. While differentiated primary cells such as cardiomyocytes are usually very robust to apoptosis, evidence has been provided that their toxic exposure may make them susceptible to further injury. We therefore ask here if cardiomyoblasts that are differentiated to a cardiomyocyte-like phenotype, and that are likely more robust to apoptosis, may lose this specific protection after toxic exposure and become apoptosis sensitive. Availing of a systems biology technique that allows us to predict apoptosis likelihood from protein expressions, we want to address the following fundamental questions that relate cardiac cell physiology to toxic derangement of programmed cell death (apoptosis): I) Do we find increased apoptosis robustness when H9C2.1 cardiomyoblasts are differentiated into a cardiomyocyte-like phenotype? II) Do we find higher apoptosis sensitivity in H9C2.1 cells that were pre-exposed to mild DOX when a secondary DOX stimulus is used? III) Can we explain changes of apoptosis susceptibility in I) and II) by systems models that analyse changes in apoptosis protein expressions during differentiation and toxic exposure? IV) Can we exploit the approach of III) to computationally predict and experimentally test molecular strategies to reverse pre-exposed H9C2.1 cells back to a more apoptosis resistant phenotype.
Date:1 Oct 2015 → 30 Sep 2016
Keywords:Systems Biology, Cardiomyocytes, Doxorubicin, Cardiotocicity, Quantitative Biochemistry
Disciplines:Cardiac and vascular medicine