Lipoxygenases and cyclooxygenases are among the oxidative enzymes that contribute to the generation of reactive oxygen species (ROS) after stroke. While the cyclooxygenases COX-1 and COX-2 have been and are continuing to be extensively studied, little data is available on the contribution of lipoxygenases to ischemic brain cell death. Our preliminary results have shown that levels of 12-LOX, the major lipoxygenase isoform in mouse and rat brain, are elevated in a mouse model of focal ischemia, predominantly in neuronal cells of the cortex. 12-LOX knockout mice show significantly reduced infarction sizes, a finding that seems to be mimicked by treatment of wild-type mice with a 12-LOX inhibitor. In both rat primary neurons and a murine hippocampal cell line, we have confirmed and extended the findings of others that 12-LOX mediates oxidative stress-induced cell death, and neurons prepared from the 12-LOX knockout mice show enhanced resistance to this form of oxidative stress. We thus propose the following Specific Aims: 1. To investigate 12-LOX upregulation and changes in activity in mouse brain after ischemia with various times of reoxyenation and to correlate increased 12-LOX levels with the extent of brain damage; 2. To study the mechanisms by which 12-LOX contributes to the death of cultured neuronal cells, and to elucidate the degradative machinery responsible for executing cell death downstream of 12-LOX action; 3. To determine the consequences of inactivating 12-LOX by either genetic or pharmacological means on brain damage after focal ischemia in the mouse. With the knowledge gained from these studies we seek to establish 12-LOX as a novel therapeutic target in the treatment of stroke. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS049430-03
Application #
7225210
Study Section
Special Emphasis Panel (ZRG1-CDIN (01))
Program Officer
Golanov, Eugene V
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
3
Fiscal Year
2007
Total Cost
$335,478
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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