MATRIX REGULATION OF CELL FUNCTION DURING WOUND HEALING

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Wound scarring and contracture is an important clinical problem with potentially serious consequences for the surgical patient, including impairment of normal tissue regeneration and neighboring tissue function. The scarring that is a hallmark of the wound healing process in adults occurs as a consequence of complex and finely regulated interactions between cytokines, growth factors, proteases, extracellular matrix molecules and fibroblasts. Our long term goal is to understand the regulatory mechanisms governing fibroblast activation and to develop new therapies to control fibroplasia. The fibronectins (FNs), are extracellular matrix proteins that mediate important functions, in vitro, such as cell activation, proliferation and migration. A dramatic increase in the levels of FNs occurs at wound sites, first by extravasation of plasma FN from blood, and then from synthesis by wound cells. An alternatively spliced segment (termed ED-A or EIIIA) is included in a FN variant synthesized prominently in healing wounds in a characteristic spatial and temporal pattern. Although present transiently in normal healing wounds, EIIIA+FNs persist during fibroplasia. When tested in vitro, EIIIA+FNs, together with TGF-beta, activate fibroblasts to express increased levels of SMC alpha-actin. The hypothesis of the present proposal states that the EIIIA segment of FN promotes the TGF-beta-dependent activation of fibroblasts and thereby regulates fibroplasia. Two specific aims are proposed to test this hypothesis: (1) Demonstrate inhibition of fibroplasia, in vivo; (2) Determine the mechanisms by which EIIIA+FNs and TGF- beta activate fibroblasts. Findings obtained from the proposed work will support our overall objective to develop new therapeutic strategies that will control the extent to which injured tissues scar and contract.