: The overall aim of this application is to elucidate the biochemical events leading from PARP and PARG activation to cell death, and to investigate potential interventions that could abrogate this cell death. Poly (ADP-ribose) polymerase-1 (PARP1) generates ADP-ribose polymers on many target proteins when activated by single-strand DNA breaks. PARP 1 is now well established as a mediator of cell death under conditions that lead to extensive or sustained activation. In particular, PARP1 gene disruption and PARP inhibitors have been shown to reduce brain infarction after cerebral ischemia. However, the intervening biochemical steps between PARP activation and cell death are not well understood. Our preliminary results and previously published reports suggest the involvement of secondary oxidative stress and impaired substrate delivery to mitochondria as key intermediate steps in PARP 1-mediated cell death. Providing cells with antioxidants or with TCA cycle substrates at time points after PARP 1 activation improves cell survival. Poly(ADP-ribose) glycohydrolase (PARG) binds to the (ADP-ribose) polymers produced by PARP1 and rapidly hydrolyzes them to mono(ADP-ribose). Our preliminary results also suggest that PARG is of equal importance as PARP1 in mediating oxidative and excitotoxic cell death. The studies proposed will employ cortical cultures from wild type and PARP-/- mice, neuroblastoma cells, and a mouse model of cerebral ischemia to investigate the biochemical mechanisms by which PARP and PARG activation lead to cell death. These studies will also explore interventions for reducing cell death at time points after PARP 1 activation. A better understanding of these processes could lead to neuroprotective approaches aimed at downstream events in the evolution of cell death after ischemia and other insults.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041421-03
Application #
6685157
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Jacobs, Tom P
Project Start
2001-12-15
Project End
2005-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
3
Fiscal Year
2004
Total Cost
$318,488
Indirect Cost
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121
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