Scar and fibrosis are the end result of tissue injury and disease. They are a major health problem because scarring does not replace lost function at the site of tissue injury, and no proven therapy for scarring exists. Remarkably, fetal full-thickness skin wounds heal with restoration of normal epidermal and dermal architecture and not with scar formation. The biology responsible for scarless wound healing, a paradigm for ideal tissue repair, is poorly understood. Although the fetal dermal fibroblast repairs wounds without collagen scar formation, the influence of the fetal keratinocyte during repair is unknown. During adult repair keratinocytes express cytokines (e.g. transforming growth factor-betas, TGFbeta) that regulate fibroblast function. Conversely, adult fibroblasts express cytokines (e.g. keratinocyte growth factor-1 and -2) that influence keratinocyte function. Similar epithelial-mesenchymal cell interactions likely occur during scarless fetal repair and may influence TGF-beta ligand, receptor, and signaling molecule expression. However, the biology of the interaction of the primary cells responsible for scarless repair, the fetal keratinocyte and fibroblast, is not known. The central hypothesis to be tested in this proposal is that fetal keratinocytes interact with fetal fibroblasts in promoting scarless repair. Furthermore, we hypothesize that this interaction involves differential expression of cytokines (e.g. the TGF-betas) and other genes associated with cellular proliferation, matrix production, and cellular differentiation. We will examine the interactions of the fetal keratinocyte and fetal fibroblast compared to their adult counterparts, as well as scarless and scarring wounds, for differential genome-wide expression changes. This proposal will continue our long-term goal of developing innovative treatment for scarless healing.
The specific aims of this proposal are: (1) to gain an improved understanding of the biology of scarless fetal wound repair by characterizing the influence of keratinocyte-fibroblast interactions on TGF-b expression; and to test the influence of TGF-beta on scarless and scarring fetal wounds; (2) to perform genome-wide expression analysis of fetal and adult keratinocytes and fibroblasts; (3) to perform genome-wide expression analysis of fetal and adult skin, and fetal (scarless) and adult (scarring) wounds. We are uniquely qualified to complete this proposal due to our long history of fetal wound healing research and our successful use of the cellular and molecular techniques described herein.
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