Researchers' Proposals

It is well known that reactive oxygen species (ROS) and peroxynitrite contribute to the cell damage in different disease, and that PARP inhibitors can protect cells from oxidative damages.  Mitochondria play a pivotal role in oxidative cell damages because oxidative damage can cause the release of cytochrome c or AIF from mitochondrial intermembrane space and can induce apoptotic cell death, or oxidant can inactivate respiratory complexes resulting in impaired energy metabolism and significant increase in mitochondrially produced ROS which eventually induce mitochondrial permeability transition and cell death. There are data showing that PARP inhibitors can inhibits ROS induced mitochondrial damages (1), raising the question that by which mechanism can PARP inhibitors modulate the functional integrity of mitochondria.

Our preliminary data indicate that oxidative stress-induced activation of MAP kinase system can be modulated by different type of PARP inhibitors, raising the possibility that the cytoplasmic protein kinase - phosphatase systems can transmit the protective effect of PARP inhibitors. The modulation of MAP kinase cascade by PARP inhibitors indicate a novel mechanism to explain the positive pharmacological effect of PARP inhibitors.

Specific aims.

1.  To understand the protective role of PARP inhibitors in ischemia-reperfusion induced myocardial damage with a specific concern for the functional integrity of mitochondria.

2.  To understand the mechanism by which PARP activation (and its inhibition) affects MAP kinases and other protein kinase cascades in perfused heart under ischemia and reperfusion.

3.  To reveal the effect of PARP inhibitors on signal transduction system and NF-κB activation in vivo in mice and in vitro in cell lines.

1.  Halmosi R, Berente Z, Osz E, Toth K, Literati-Nagy P, Sumegi B. (2001) Effect of Poly (ADP-Ribose) Polymerase Inhibitors on the Ischemia-Reperfusion Induced Oxidative Cell Damage and Mitochondrial Metabolism in  Langendorff Heart Perfusion System. Mol. Pharmacol. 59:1497-1505.