Nearly 80 percent of all strokes are ischemic episodes arising from atherosclerosis. The pathogenesis of atherosclerosis rests on abnormalities in lipid metabolism leading to the development of atherosclerotic plaques. Despite current treatments for stroke, this and other diseases effected by atherosclerosis remain a problem. Study of the group VIA calcium-independent phospholipase A2 (iPLA2) may offer novel therapeutic approaches to treat atherosclerosis. iPLA2, a lipid hydrolase that catabolizes glycerophospholipids, releases polyunsaturated fatty acids (PUFA) from the glycerol backbone. Reports suggest that PUFA may modulate cholesterol metabolism by blocking the processing and/or expression of sterol regulatory element binding proteins (SREBP), transcription factors inducing key genes involved in the metabolism of cholesterol and fatty acids. Thus, iPLA2 could modulate atherogenesis through its indirect effects on gene expression. iPLA2 may also contribute to plaque rupture and thrombus formation resulting from death of macrophage-derived foam cells, a major component of atherosclerotic plaques. Disruption of the free cholesterol (FC):phospholipid (PL) ratio, a characteristic of foam-cells following excess LDL uptake, results in foam-cell death. iPLA2-mediated PL catabolism may potentiate foam-cell death by further decreasing the FC:PL ratio. Overexpression, chemical inhibition, and siRNA to regulate iPLA2 will be used to determine if iPLA2 can influence SREBP processing/transcriptional activity and foam-cell viability.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS051090-01A1
Application #
6937459
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Golanov, Eugene V
Project Start
2005-04-11
Project End
2008-04-10
Budget Start
2005-04-11
Budget End
2006-04-10
Support Year
1
Fiscal Year
2005
Total Cost
$30,546
Indirect Cost
Name
Virginia Commonwealth University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298