Oxidative stress and expression of the vascular cell adhesion molecule-1 (VCAM-1) on vascular endothelial cells are early features in the pathogenesis of atherosclerosis and other inflammatory diseases. We have recently demonstrated a linkage between oxidation-reduction (redox) sensitive regulatory mechanisms and the expression of vascular endothelial cell genes, such as VCAM-1, that are involved in the early inflammatory processes characteristic of atherosclerosis. To explore the molecular determinants of atherogenesis, this proposal will characterize the molecular regulatory mechanisms through which modified low density lipoprotein (LDL) regulates VCAM-1 gene expression in human vascular endothelial cells and to identify the specific oxidation-reduction sensitive transcriptional regulatory factor(s) that mediate this effect. Using an integrated immunological, biochemical, cellular, and molecular biological approach in cultured human vascular endothelial cells, the regulatory effects of modified LDLs, both oxidized and glycated, as primary regulators and as modulators of cytokine activation of VCAM-1, ICAM-1, and E-selectin will be defined. This combined approach will be used to define the specific oxidant compounds within modified LDL that regulate VCAM-1 expression. Using these defined oxidants, an in vitro """"""""knockout"""""""" approach is proposed, using synthetic oligonucleotides, to define the role of specific, endogenously expressed transcriptional regulatory factor(s) in the regulation of endogenous VCAM-1 gene expression.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL003137-03
Application #
2609169
Study Section
Special Emphasis Panel (ZHL1-CCT-L (O1))
Project Start
1995-04-01
Project End
2001-05-30
Budget Start
1997-12-01
Budget End
1999-05-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322