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.
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