Accumulation of oxidative DNA damage in the human brain is implicated in the etiology of posttraumatic and age associated declines in brain function. In neurons, because of their high metabolic rate and prolonged life span, exposure to reactive oxygen species (ROS) is extensive and the risk for accumulation of nuclear and mitochondria! DNA damage is amplified. Although recent studies demonstrate that neurons are equipped to repair nuclear and mitochondrial oxidative DNA damage via the base excision repair (BER) pathway, the capacity for repair and the impact of repair on preservation of neurons are not well defined. With the support of this grant we have demonstrated that in a rat model of respiratory hypoxia, oxidative DNA damage is formed and repaired in the brain. We have shown that expression levels and excision activities of BER enzymes vary in a brain region-specific manner and are differentially modulated by hypoxia. Our main objective is to identify mechanisms that determine the capacity for repair of oxidative DNA damage, and how the repair process is augmented in vivo, in the brain. The Central Hypothesis of this proposal is that neurons are equipped to repair oxidative DNA damage via BER and that nuclear and mitochondrial BER is a component of a neuroprotective response, which varies in a brain region-specific manner. To test this hypothesis we have planned in vivo and in vitro studies with the following Specific Aims: 1) To characterize the transcriptional component in hypoxia-induced DNA repair in the rat brain. 2) To determine brain region-specific, hypoxia-induced changes in excision rates of mitochondrial and nuclear BER enzymes. 3) To identify functional consequences of post-translational modifications of BER enzymes in vitro and in vivo, in the brain. 4) To test in vitro the hypothesis that the base excision repair pathway is a component of the adaptive response to oxidative stress; modulation of BER enzymes in primary neurons. We expect that gaining a better understanding of molecular mechanisms underlying augmentation of DNA repair via the BER pathway will present an opportunity for novel drug development to protect the brain from adverse consequences of disrupted oxygen supply under pathologic conditions including, cerebral ischemia, stroke and trauma as well as in advance of invasive clinical procedures, which generate a heavy oxidative burden in the brain. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS039449-05A1
Application #
7029799
Study Section
Special Emphasis Panel (ZRG1-BDCN-L (90))
Program Officer
Golanov, Eugene V
Project Start
1999-12-01
Project End
2010-12-31
Budget Start
2006-01-15
Budget End
2006-12-31
Support Year
5
Fiscal Year
2006
Total Cost
$339,750
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Surgery
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
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