Accelerated atherosclerosis and microvascular complications account for the greatest numbers of deaths and hospitalizations in diabetic patients. However, the molecular mechanisms responsible for these complications remain poorly understood. As a result of our work on the project supported for 3 years by a K01 award from NIDDK, we recently reported that the expression of thrombospondin-1 (TSP-1) is strikingly elevated in large vessels of Zucker rats, an animal model of type 2 diabetes, both in basal conditions and in response to injury, suggesting a role for this protein in the accelerated atherosclerosis and increased restenosis in this animal model and diabetic patients. TSP-1 has a number of well-documented proatherogenic properties including genetic and biochemical evidence. This protein is also one of the most potent anti-angiogenic agents, a function directly relevant to diabetic complications. Our preliminary data indicated that TSP-1 expression is regulated by glucose at the transcriptional level and suggested a new direction for the applicant - use of a mouse model of atherosclerosis. The applicant is submitting a competing renewal of the grant to support her training in a new experimental approach - mouse model of atherosclerosis. The overall goal of the proposed program, which represents a competing renewal application, is to elucidate specific transcriptional mechanisms responsible for the upregulation of TSP-1 expression by glucose in major cell types of large blood vessels and to test the hypothesis that increased expression of TSP-1 in the vascular wall of a mouse model contributes to the development of atherosclerotic lesions and neointima formation. The long-term objective of the project is to uncover the hyperglycemia-induced molecular mechanisms that lead to development of diabetic vascular complications.
The Specific Aims are: 1. To identify the promoter region of the TSP-1 gene and nuclear factors responsible for the transcriptional up-regulation of TSP-1 expression by glucose and wounding; 2. To demonstrate directly in the transgenic mouse model that increased expression of TSP-1 in the vascular wall contributes to the development of atherosclerotic lesions and neointima formation in response to injury. The results of these experiments will: 1) identify targets for the regulation of expression of TSP-1, a potent anti-angiogenic and pro-atherogenic protein that may contribute to vascular diabetic complications; 2) provide additional information about the molecular mechanisms for the effects of glucose in vascular cells; and 3) demonstrate directly that TSP-1 may serve as a link between diabetes and vascular 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 #
2K01DK062128-04
Application #
6983331
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2005-08-01
Budget End
2006-06-30
Support Year
4
Fiscal Year
2005
Total Cost
$105,586
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Raman, Priya; Harry, Christy; Weber, Malory et al. (2011) A novel transcriptional mechanism of cell type-specific regulation of vascular gene expression by glucose. Arterioscler Thromb Vasc Biol 31:634-42
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
Pothoulakis, C; Gilbert, R J; Cladaras, C et al. (1996) Rabbit sucrase-isomaltase contains a functional intestinal receptor for Clostridium difficile toxin A. J Clin Invest 98:641-9