The process of repair and regeneration following traumatic or surgical injuries represents a fundamental protection of an organism against its environment. Thus, cutaneous wound healing is not only one of the most important research subjects, but also a challenging one due to the complex nature of skin. The general features of wound healing have been described (Peacock, E. E. 1984.), however, the exact mechanisms of healing remain undefined. The long term objective of the research plan is to understand the cellular and biochemical mechanisms underlying fibroplasia in wound repair. The information gained from this study will uncover important details of biological events essential in fibroblast-fibrin interactions and possibly lead to the treatment of keloid and hypertrophic scars and other pathologic skin conditions. During the five years of the proposed project, research will focus on the interactions between skin fibroblasts and fibrin and their influence on matrix remodeling using an in vitro 3-dimensional fibrin gel culture system. The following specific aims will be systematically studied. I. Characterization and purification of fibrinogen receptor on fibroblasts. We will study the binding characteristic of fibrin to fibroblasts, and use antibodies and adhesion peptides to investigate the adhesion function of fibroblasts on fibrinogen substratum and in fibrin gels and use the methods of chemical crosslinking and affinity chromatography to isolate the receptor. I. Study the effect of fibroblast types, age, and density on fibroblast contraction of fibrin gels. We will culture papillary and reticular fibroblasts separately from dermis and study their interactions with fibrin gels in gel contraction and degradation. III. Study the effect of TGF-beta on fibroblast contraction of fibrin gels. A preliminary study has indicated that TGF-beta enhanced gel contraction and prevented fibrinolysis under serum free condition. We will further investigate the mechanism of the effect regarding fibrin matrix contraction and degradation by fibroblasts. IV. Study collagen synthesis by fibroblasts cultured in fibrin gels and the effect of TGF-beta on the process. First, we will study the collagen synthesized by fibroblasts in fibrin gels and compare to monolayer and collagen gel cultures; second, the effect of fibrinolysis on collagen synthesis and the enzyme that involved in the lytic process; and third, the effect of TGF-beta on collagen synthesis and examine its regulatory mechanisms on both fibrin degradation and collagen synthesis by fibroblasts. V. To study the behavior of fibroblasts isolated from keloids and hypertrophic scars in fibrin gel contraction and collagen production and the effect of TGF-beta on the process. We will use fibroblasts isolated from papillary and reticular dermis separately in the studies and investigate the possible pathologic mechanism involved in the tissue fibrosis.
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