Progressive atherosclerosis and restenosis following angioplasty are more common and occur at an earlier age in diabetic than in nondiabetic patients, and the consequences of atherosclerosis (stroke, coronary artery and peripheral vascular disease) are the primary causes of mortality in the diabetic population. The thrombospondins (TSPs) are a family of multifunctional proteins that interact with numerous matrix proteins and cell surface receptors. Only very limited information had linked the TSPs with diabetes and atherosclerosis. This has changed with the recent completion of a large scale genetic association study (GeneQuest) which found that single nucleotide polymorphisms (SNP) in TSP-1, TSP-2 and TSP-4 were not only associated with premature coronary artery disease, but were the only three of more than 80 SNP analyzed that were highly correlated with disease. These observations prompted us to assess the effects of high glucose on TSP release from vascular cells, and a significant increase was observed. Based upon these findings, we hypothesize that changes in TSP production by vascular cells exposed to high glucose may lead to the accelerated development of atherosclerotic lesions in diabetes. Now, by studying the functional differences between the variants, insights can be gained into the mechanisms by which the TSPs may induce atherosclerotic lesions in diabetes. Accordingly, the overall goal of this project is to elucidate the role of the TSPs in the accelerated development of atherosclerotic lesions in diabetes and to identify the molecular basis for the proatherogenic effects of the variant forms of TSP.
The Specific Aims are: 1. To establish the mechanism by which glucose regulates TSP expression in vascular cells. 2. To characterize the expression of TSPs in the vascular wall, heart and brain of diabetic Zucker rats and to establish differences between diabetic and control Zucker rats in TSP expression patterns in response to vascular injury. 3. To identify the molecular mechanisms and the structural basis for the proatherogenic effects of the SNP in the coding regions of the TSPs. The mentored Research Scientist Development Award would greatly assist Dr. Olga I. Stenina in making a successful transition to an independent researcher in the field of diabetes and its cardiovascular complications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK062128-02
Application #
6605832
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2002-07-01
Project End
2004-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$93,172
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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Dabir, Pankaj; Marinic, Tina E; Krukovets, Irene et al. (2008) Aryl hydrocarbon receptor is activated by glucose and regulates the thrombospondin-1 gene promoter in endothelial cells. Circ Res 102:1558-65
Bhattacharyya, Sanghamitra; Marinic, Tina E; Krukovets, Irene et al. (2008) Cell type-specific post-transcriptional regulation of production of the potent antiangiogenic and proatherogenic protein thrombospondin-1 by high glucose. J Biol Chem 283:5699-707
Stenina, Olga I; Topol, Eric J; Plow, Edward F (2007) Thrombospondins, their polymorphisms, and cardiovascular disease. Arterioscler Thromb Vasc Biol 27:1886-94
Raman, Priya; Krukovets, Irene; Marinic, Tina E et al. (2007) Glycosylation mediates up-regulation of a potent antiangiogenic and proatherogenic protein, thrombospondin-1, by glucose in vascular smooth muscle cells. J Biol Chem 282:5704-14
Stenina, Olga I; Ustinov, Valentin; Krukovets, Irene et al. (2005) Polymorphisms A387P in thrombospondin-4 and N700S in thrombospondin-1 perturb calcium binding sites. FASEB J 19:1893-5
Pluskota, Elzbieta; Stenina, Olga I; Krukovets, Irene et al. (2005) Mechanism and effect of thrombospondin-4 polymorphisms on neutrophil function. Blood 106:3970-8
Stenina, Olga I; Desai, Shailesh Y; Krukovets, Irene et al. (2003) Thrombospondin-4 and its variants: expression and differential effects on endothelial cells. Circulation 108:1514-9
Stenina, Olga I; Krukovets, Irene; Wang, Kai et al. (2003) Increased expression of thrombospondin-1 in vessel wall of diabetic Zucker rat. Circulation 107:3209-15
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