Vascular disease is the major cause of morbidity and mortality in the elderly. The deposition of nonenzymatically glycated proteins, advanced glycosylation endproducts (AGEs), in the vasculature is thought to promote vascular dysfunction: AGEs increase endothelial cell (EC) monolayer permeability, thrombogenicity, and enhance proliferation, as well as having the capacity to attract mononuclear phagocytes (MPs) into the vessel wall and lead to their activation. Since the presence of AGEs has been correlated with aging, and is accelerated by concomitant glucose intolerance, a not infrequent clinical finding in the elderly, I propose to examine the role of AGEs in the pathogenesis of vascular disease. My recent work has led to the purification and cloning of a new member of the immunoglobulin superfamily of cell surface receptors, termed Receptor for AGEs or RAGE, which has a central role in the interaction of AGEs with ECS and MPs in culture, and appears to mediate AGE intravascular clearance in vivo. The hypothesis motivating this proposal is that the interaction of AGE& with RAGE on ECs and MPs is an important initiating event in the pathogenesis of vascular disease.
The specific aims of my work are (i) to assess AGE-cellular interactions and AGE-induced gene activation, in vitro and in vivo, focussing on the role of RAGE; (ii) to understand regulation of RAGE expression in cultured cells and a murine model; (iii) to determine the role of AGEs in the pathogenesis of atherosclerosis in a hamster model using immunologic reagents to detect AGEs and RAGE, and agents which blocked AGE-RAGE interaction; and (iv) to assess regulation of RAGE expression in MPs from elderly patients, and individuals with glucose intolerance.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AG000602-03
Application #
2048406
Study Section
Biological and Clinical Aging Review Committee (BCA)
Program Officer
Finkelstein, David B
Project Start
1993-07-01
Project End
1998-06-30
Budget Start
1995-07-01
Budget End
1996-06-30
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032