Stroke is one of the leading causes of death and disability in the U.S. New information regarding the mechanisms of ischemic neuronal death and new treatment strategies for stroke is urgently needed. Previous studies have indicated a key role of excessive poly (ADP-ribose) polymerase-1 (PARP-1) activation in oxidative cell death in cerebral ischemia and several other debilitating diseases. Recent studies by us and other laboratories have provided direct evidence demonstrating that PARP-1 induces cell death by depleting NAD+, which leads to mitochondria permeability transition (MPT) and nuclear translocation of apoptosis inducing factor. We have also provided the first evidence suggesting that poly(ADP-ribose) glycohydrolase (PARG), the sole catabolizing enzyme in poly(ADP-ribose) metabolism, is an important mediator of oxidative and excitotoxic neuronal death. Recent studies have further suggested that PARG and PARP-1 are promising therapeutic targets for decreasing ischemic neuronal death both in vivo and in vitro. However, in contrast to the rapidly growing information regarding PARP-1 in cell death, the mechanisms underlying the roles of PARG in cell death are unclear. The major objective of this study is to investigate the mechanisms underlying the PARG inhibition-produced neuroprotection. The information from this study may provide fundamental information regarding the downstream events mediating PARG/PARP-1 cytotoxicity, and suggest new strategies to decrease ischemic brain injury at delayed time points.
Specific aim 1 of this study is to test the hypothesis that PARG inhibition can decrease apoptotic changes of neurons and astrocytes induced by oxidative stress and other genotoxic agents by preventing NAD+ depletion;
and Specific aim 2 is to test the hypothesis that PARG inhibition can prevent genotoxic agent-induced mitochondrial permeability transition (MPT) of astrocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Small Research Grants (R03)
Project #
5R03NS051540-02
Application #
7068509
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Golanov, Eugene V
Project Start
2005-05-20
Project End
2007-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$80,561
Indirect Cost
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121