ANTHRAPLUS · Doxorubicin-induced impairment of metabolic and stress signaling: a culprit of cardiotoxic action of the drug?
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2010-01-01 → 2012-12-31
- Финансиране от ЕС
- 45 000 €
- Участници
- 1
- Схема
- MC-ERG
Линиите свързват координатора с партньорите.
Накратко на български
Лекарството доксорубицин, използвано при рак, уврежда сърцето чрез нарушаване на енергийния обмен и сигналите между протеините. Разбирането на тези процеси помага да се обясни защо се появяват странични ефекти като сърдечна дисфункция и разстройство на мускулните влакна.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Doxorubicin-induced impairment of metabolic and stress signaling: A culprit of cardiotoxic action of the drug?
Anthracyclines, in particular doxorubicin, are the most effective anticancer drugs. However, their serious side effect is a cardiotoxicity, which is not entirely understood. In this project we have addressed doxorubicin-induced changes in cell signalling (mainly energy-related signalling) as a novel potential mediator of doxorubicin cardiotoxicity. Our approach was two-fold: 1. non-biased phosphoproteomic approach aiming at the identification of new phosphorylation events mediating response to doxorubicin 2. a targeted approach focusing on pathways identified by our previous studies, as signalling by LKB1, AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Akt and mitogen-activated protein kinases (MAPK). We have used two doxorubicin cardiotoxicity models: Langendorff perfused rat heart and an in vivo treated rat. The phosphoproteomic approach identified 22 proteins with a significantly changed phosphorylation status. Identified proteins were mainly involved in energy metabolism (e.g. pyruvate dehydrogenase and acyl-CoA dehydrogenase), sarcomere structure and function (e.g. desmin) or chaperone-like activities (e.g. alpha-crystallin B chain and prohibitin). These changes might be relevant for main symptoms of cardiac dysfunction related to doxorubicin treatment, namely energy imbalance and myofibrillar disorganisation. Using targeted analysis we have shown that in the doxorubicin-challenged heart, a combined energetic, oxidative, and genotoxic stress elicits a specific, hierarchical response where the key cellular energy sensor and regulator, AMPK, is inhibited at least partially by the known negative cross-talk with Akt and MAPK pathways. Such response is largely triggered by deoxyribonucleic acid (DNA) damage signalling. Protective effects of creatine and phosphocreatine were demonstrated and potential contributing mechanisms were suggested.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
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.
Оригинален текст от CORDIS (на английски).
Участници
- UNIVERSITE JOSEPH FOURIER GRENOBLE 1 · GRENOBLEКоординаторФранция
Връзки
Данни: CORDIS, © Европейски съюз