Our overall goal is to understand how the dermal and epidermal compartments communicate during wound repair. Wound healing requires orchestrated repopulation and regeneration of the lost tissue, a process deficient in normal aging, after large traumatic or burn wounds, and in numerous chronic diseases. In skin wounds, fibroblasts are recruited to regenerate the dermal layer, and keratinocytes from the margins to re-epithelialize the initial clot. Orchestration of repair is conducted by signals from successive waves of growth factor, chemokines, and matrix fragments. A central question is how cells in the different compartments communicate or sense the status of the healing. For instance, how does a dermal fibroblast 'know' that re-epithelialization is complete and thus must switch to the resolving phase functions of contraction and collagen remodeling? Soluble peptide factors play major roles in signaling cell proliferation and migration into the wound and differentiation functions including wound contraction and epidermal stratification. Prominent during all stages of wound repair are epidermal growth factor receptor ligands that induce fibroblast and keratinocyte motility and proliferation. However, the equally important 'stop' and differentiation signals have not been fully elucidated. We have posited a novel model in which ELR- CXC chemokines (PF4, IP-10, MIG and IP-9) are elaborated to limit or modulate the responses to growth factors. Our previous studies determined that these chemokines negatively regulate fibroblast repopulation and steer these cells to more reparative phase contraction. Recently, we found that, surprisingly, these same chemokines promote proliferation and migration of mesenchymally-transitioned keratinocytes, the differentiation state that is responsible for re-epithelialization. We hypothesize that during wound repair, the dermal compartment is synchronized to re-epithelialization status by IP-9. The following hypotheses will test this model: I. That 1P-9 is a wound-response factor produced during re-epithelialization. We will identify the source and stimulus for IP-9 production and whether re-epithelialization is prerequisite for production. II. That 1P-9 is a keratinocyte-derived factor that alters fibroblast and keratinocyte repopulation. We will identify the intracellular signaling pathways it evokes in fibroblasts and keratinocytes. Ill. That IP-9 and 1P-10 alter fibroblast and keratinocyte functioning and differentiation state. This will be determined in vitro and then verified in targeted transgenic mice. The completion of these investigations will yield a model of dermal skin repair in which key extracellular and intracellular molecules are identified that can be targeted to either increase healing or limit scarring.
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