Advanced glycosylation endproducts (AGEs) are nonenzymatically glycated proteins present in plasma and in tissues, and which accumulate in the vasculature at an accelerated rate in diabetes. Exposure of cultured endothelial cells to AGEs increases monolayer permeability, alters cellular proliferation and thrombogenicity. The presence of AGEs in the basal lamina can promote monocyte migration, followed by monocyte interaction with AGEs, thereby leading to cell activation with cytokine and growth factor release. The basis for these perturbations of monocyte and endothelial functions in vitro, which could set the stage for the development of vascular lesions in vivo, results from the interaction of AGEs with specific cellular binding proteins. The central hypothesis of this work is that AGEs contribute to the pathogenesis of vascular lesions via their interactions with cellular receptors central in the pathogenesis.
The specific aims of our application are to assess endothelial expression of AGE receptors and deposition of AGEs in a hamster model of hyperglycemia, hypercholesterolemia, and hyperglycemia + hypercholesterolemia. These studies will utilize antibodies raised to cellular AGE receptors and antibodies to AGEs in order to localize these molecules in vascular lesions, and to determine the effect of blocking AGE- cellular interactions on lesion formation/progression. The experiments outlined in this application should provide insights into an additional ligand-receptor interaction, the binding of AGEs to their receptors, which is likely to contribute to the pathogenesis of atherosclerotic vascular lesions.

Agency
National Institute of Health (NIH)
Institute
Fogarty International Center (FIC)
Type
Small Research Grants (R03)
Project #
1R03TW000118-01
Application #
3432549
Study Section
Special Emphasis Panel (SRC)
Project Start
1992-08-15
Project End
1995-08-14
Budget Start
1992-08-15
Budget End
1993-08-14
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027