Stroke and other neurodegenerative disorders are a leading cause of death, disability and loss of quality of life. The importance of glutamate neurotoxicity in cerebral ischemia and neurodegenerative diseases is well documented. Both in vitro and in vivo administration of glutamate and its analogs effectively kill neurons via excitotoxic mechanisms. Poly(ADP-ribose) polymerase-1 (PARP-1) is pivotal in glutamate neurotoxicity and cerebral infarction. Prior studies indicate that NO, or peroxynitrite plays a prominent role in glutamate excitotoxicity and cerebral infarction. Amongst other responses NO, or peroxynitrite, can activate PARP-1, which leads to cell death through the formation of complex and branched poly(ADP-ribose) (PAR) polymer. Recently, apoptosis inducing factor (AIF) has been identified as key mediator of neurotoxicity triggered by glutamate, reactive oxygen species, DNA damage and PAR polymer. AIF resides in the mitochondria in normal healthy cells, but moves to the nucleus following a lethal stimulus in a PARP-1 dependent manner. Blocking AIF from entering the nucleus can spare cells from death. The proteins and the mechanisms that are involved in facilitating the release of AIF from the mitochondria following PARP-1 activation are not known. Accordingly, experiments are proposed to elucidate the underlying molecular mechanisms accounting for AIF release following PARP-1 activation and to investigate the role of PAR polymer in excitotoxic and stroke induced neuronal injury. We hope that understanding the mechanisms of PAR polymer induced cell death, the activation of AIF and the identification of additional components of the PAR/AIF signaling complex will lead to new methods to terminate the toxic actions of PAR polymer and AIF and offer innovative therapeutic approaches to treat neurodegenerative diseases and stroke.

Public Health Relevance

Stroke and other neurodegenerative disorders are a leading cause of death, disability and loss of quality of life. We hope that understanding the mechanisms of PAR polymer neurotoxic actions in stroke will lead to new methods to terminate the toxic actions of PAR polymer and offer innovative therapeutic approaches to treat neurodegenerative diseases and stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS067525-03
Application #
8213721
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Bosetti, Francesca
Project Start
2010-05-15
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$669,735
Indirect Cost
$261,359
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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