To explain how capillaries form, as well as the organization of fibroblasts and keratinocytes in response to cutaneous injury, recent emphasis has been placed on the extracellular matrix and its ability to control morphogenic processes. It is now recognized that cells are capable of integrating both chemical and mechanical signals from the matrix which directly influences the expression of differentiation and growth specific genes. Cell locomotion, as an essential component of endothelial and mesenchymal repair and regenerative processes, requires the coordinated interaction between cell surface adhesion receptors and specific extracellular matrix (ECM) molecules. Therefore, identification of molecules which regulate the process of cell migration is important for the development of new targeted therapies for accelerating impaired dermal wound healing or enhancing repair processes in the high-risk wound. Fundamentally, the pericellular composition and concentration of surrounding matrix components has a direct effect on cell speed, in part, by controlling the adhesive strength of the cell-substrate interaction through the level and availability of bound legends for cell adhesion receptors. Typically, low cell speed occurs on ligand densities which yield either very weak or extremely strong levels f adhesive strength. Within this framework both the levels of specific glycoprotein and proteoglycan synthesis, as well as their degradation by proteases or other factors will influence adhesive ligand availability. However, mediation of these effects requires ligand interaction with specialized adhesive contacts on the cell surface which integrate and coordinate the environmental signals responsible for cell movement. In addition to containing integrin receptors, a recently cloned transmembrane heparin sulphate proteoglycan (HSPG), syndecan-4, has also been localized to these adhesive complexes.
Specific Aim 1 : Define the role of syndecan-4 in modulating cell migration in relation to substrate ligand density and its correspondence with effects on overall cell/substrate adhesiveness.
Specific Aim 2 : Characterize the spatiotemporal expression pattern of syndecan-4 in migrating keratinocytes, dermal endothelial cells, and fibroblasts, as well as in a model of cutaneous injury.
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