DERMAL-EPIDERMAL COMMUNICATION DURING WOUND HEALING Our long-term goal is to decipher the extracellular signals that communicate across compartments to synchronize the phenotypes of the key cells in the wound repair process. Healing requires orchestrated repopulation, regeneration, and maturation remodeling of the lost tissue, a process deficient in normal aging and numerous clinical situations including chronic ulcers and diabetes. Many of these defects occur due to failure of the wound to mature during the resolving phase. Key to this maturation is reversion of the exuberant fibroplasia and vascularity needed to heal the wounds, though the signals and mechanisms driving this are unknown. Soluble peptide factors, in addition to matrix components and other signaling elements, play major roles in wound bed signaling. During the current initial funding period, we found production late in the wound repair process of CXCR3 ligands (the ELR-negative chemokines IP-9/CXCL11 and IP-10/CXCL10). These blocked fibroblast motility by preventing rear release, thereby channeling the phenotype towards matrix contraction, and stopped endothelial cells from migrating and forming tubes in vitro and vasculature in vivo. We hypothesize that during wound repair, the CXCR3 signaling network not only initiates the resolving phase, but also triggers the involution of the neovasculature and loss of fibroblasts necessary to form the mature, pauci-cellular dermis. We propose to test the following hypotheses, supported by initial experiments, to define the molecular mechanisms of these processes: I. That CXCR3 ligands are required for wound matrix maturation. We will use defined knockout mice and primary dermal fibroblasts to examine wound bed matrix maturation. II. That CXCR3 signaling leads to vascular involution. The inductive role of IP-10 in vascular involution will be tested in animals, and the intracellular molecular basis will be defined in primary endothelial cells. III. CXCR3 signaling reduces dermal cellularity. The molecular mode by which regenerative fibroplasia is reverted during the resolving phase will be defined in vitro and in vivo. IV. Specific CXCR3 ligands dictate distinct aspects of repair. An IP-9-devoid mouse model will determine the role of CXCR3 on basement membrane regeneration and a PF4-deficient mouse model will probe the basis of skin contraction that happens immediately upon wounding. These investigations will define key extracellular and intracellular molecules for wound resolution. These are potential targets for rationally designed interventions to promote normal wound healing and limit scarring.
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