Mechanisms of PARP and PARG mediated cell death

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DESCRIPTION (provided by applicant): The DNA repair enzyme, PARP-1, has emerged as a critical determinant of neuronal death in brain ischemia and other conditions. Work supported by this grant in the prior funding period elucidated the mechanism and role of bioenergetic failure in PARP-1 - mediated acute cell death, and identified several mechanisms by which PARP-1 activity is regulated. In the course of these studies we also identified a dominant role for PARP-1 in regulating microglial activation, MMP-9 release, and microglial-induced neuronal death. PARP-1 inhibitors are currently entering clinical trials for the treatment of stroke, myocardial ischemia, and other conditions as both cytoprotective and anti-inflammatory agents. Minocycline is also a PARP-1 inhibitor, and has also entered clinical trials for CNS disorders. However, the mechanism by which these compounds influence the inflammatory response remains poorly understood. This is an important translational question, because inflammation has beneficial as well as deleterious effects on brain recovery from stroke, with some aspects of the inflammatory response required for normal brain recovery after injury. A second, related question concerns the long-term consequences of PARP-1 inhibition. Given that PARP-1 is involved in DNA repair, and that PARP-1 deficient mice have an accelerated rate of mutagenesis, there is the possibility that treatment with PARP-1 inhibitors could increase DNA mutations in surviving cells, particularly in the setting of oxidative stress. Accumulated mutations could impact neuronal function and long term survival. The studies proposed here will address these related questions through three specific aims. Aim 1 will establish the effect of PARP inhibitors on specific aspects of post-ischemic brain inflammation and recovery, Aim 2 will identify the mechanisms by which PARP-1 and PARG influence microglial activation, and Aim 3 will establish the effects of PARP and PARG inhibitors on DNA mutations induced by oxidative stress and stroke. Success with these studies will increase our understanding of regulatory processes in brain inflammation, the mechanisms by which PARP-1 and PARG inhibitors suppress brain inflammation, and the mutagenic potential of these agents when used in the post-ischemic setting. PUBLIC HEALTH RELEVANCE: Stroke is a major cause of death and disability in the United States and throughout the world. Studies proposed here will evaluate an approach to suppressing inflammation in brain after stroke as a means of improving recovery from stroke. These studies will also establish a way to evaluate DNA mutations in brain caused by stroke and by post-stroke inflammation.