The long-term goal of this research is to understand the mechanisms that control extracellular matrix assembly. This knowledge will allow future intervention in disease states where matrix deposition is excessive, a major problem in diabetes, where glomerulosclerosis and interstitial fibrosis contribute to renal failure. The use of dominant negative constructs has shown that syndecan-2 transmembrane heparan sulfate proteoglycan controls the assembly of extracellular matrix at the cell surface, the first stage in organized matrix deposition. Using cell biological, immunological, and molecular biology techniques, we will: 1) determine how syndecan-2 cytoplasmic domain controls matrix assembly, which regions of the cytoplasmic domain are involved, and whether this is regulated by phosphorylation events and/or binding to other cytoplasmic proteins; 2) determine how signaling through syndecan-2 occurs, whether the heparan sulfate glycosaminoglycans are involved or necessary, whether syndecan-2 activates the integrin family of matrix receptors and whether its acts via cytoskeletal organization; and 3) determine whether syndecan-2 protein levels are increased in diabetic nephropathy in concert with, or preceding, matrix deposition increases, whether protein and mRNA levels are elevated in response to mediators thought to promote diabetic nephropathy in vivo, such as transforming growth factor beta and high glucose, and whether transcription of the gene is under the control of similar mediators. We will directly test the hypothesis that syndecan-2 regulates matrix accumulation in kidney interstitial cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054605-04
Application #
6381259
Study Section
Special Emphasis Panel (ZDK1-GRB-4 (M1))
Program Officer
Hirschman, Gladys H
Project Start
1998-08-14
Project End
2003-04-30
Budget Start
2001-08-01
Budget End
2003-04-30
Support Year
4
Fiscal Year
2001
Total Cost
$217,197
Indirect Cost
Name
University of Alabama Birmingham
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Fears, Constance Y; Gladson, Candece L; Woods, Anne (2006) Syndecan-2 is expressed in the microvasculature of gliomas and regulates angiogenic processes in microvascular endothelial cells. J Biol Chem 281:14533-6
Fears, Constance Y; Woods, Anne (2006) The role of syndecans in disease and wound healing. Matrix Biol 25:443-56
Chen, Ligong; Klass, Carmen; Woods, Anne (2004) Syndecan-2 regulates transforming growth factor-beta signaling. J Biol Chem 279:15715-8
Chen, Ligong; Couchman, John R; Smith, Jacqueline et al. (2002) Molecular characterization of chicken syndecan-2 proteoglycan. Biochem J 366:481-90
Woods, A (2001) Syndecans: transmembrane modulators of adhesion and matrix assembly. J Clin Invest 107:935-41
Couchman, J R; Chen, L; Woods, A (2001) Syndecans and cell adhesion. Int Rev Cytol 207:113-50
Jeong, J; Han, I; Lim, Y et al. (2001) Rat embryo fibroblasts require both the cell-binding and the heparin-binding domains of fibronectin for survival. Biochem J 356:531-7
Woods, A; Couchman, J R (2001) Syndecan-4 and focal adhesion function. Curr Opin Cell Biol 13:578-83
Woods, A; Longley, R L; Tumova, S et al. (2000) Syndecan-4 binding to the high affinity heparin-binding domain of fibronectin drives focal adhesion formation in fibroblasts. Arch Biochem Biophys 374:66-72
Tumova, S; Woods, A; Couchman, J R (2000) Heparan sulfate proteoglycans on the cell surface: versatile coordinators of cellular functions. Int J Biochem Cell Biol 32:269-88

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