(Verbatim) This investigation seeks to understand how proteoglycans act to control cell communication in the skin through their influence on growth factor activity and the expression of leukocyte binding molecules. Proteoglycans (PG) and glycosaminoglycans (GAG) are induced and released after injury in a specific pattern. This expression is linked to innate immunity through our prior finding that antimicrobial peptides stimulate expression of specific PG. In addition wound derived GAGs, namely, dermatan sulfate, are responsible for activation of the growth factor FGF-2. In addition, dermatan sulfate and hyaluronic acid also activate endothelial cells to increase the expression of leukocyte adhesion molecules such as ICAM-1. These findings, taken in context with the link to antimicrobial peptides in the wound environment, suggest that PGs and GAGs in the extracellular environment are important components of the cutaneous innate defense and repair system. The overall goals of this investigation are to increase our understanding of this newly recognized process. Specifically, the aims of this project are to: 1. Identify the skin proteoglycans and component GAGs that facilitate growth factor activity by identifying the core proteins and glycosaminoglycan structural components responsible for binding and activation of FGF-2 and FGF-7. 2. Define which skin proteoglycans and GAGs activate endothelial cells and if this response is specific to endothelia. Purified GAG and PGs derived from specific aim 1 will be used to determine which components are active in stimulation of dermal endothelial cells. Cellular responsiveness will be evaluated in vitro and in vivo in a murine model. 3. Investigate the mechanisms of cellular response to skin GAGs by identifying how endothelial cells are activated by dermatan sulfate and hyaluronic acid. The GAG ligand(s) responsible for activation will be sought and gene expression profiles investigated. Successful completion of these aims will reveal fundamental events in wound repair and may suggest new approaches to wound therapy.
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