Our long-term goal is to decipher the extracellular signals that communicate across compartments to synchronize 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 functions in all phases, not only initiating post-wound contraction, but also triggering the resolving phase and 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 cell transplantation 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 probed in wounds. 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 and upper dermal 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 t promote normal wound healing and limit scarring.
Failure to properly heal wounds results in significant morbidity and mortality in many patients, particularly those with diabetes, neuropathies, trauma and even those just advanced in years. Incomplete wound resolution predisposes to ulcers and skin disruption, while excessive repair results in scarring which impairs use and function. These investigations will define key extracellular and intracellular molecules that are potential targets for rationally designed interventions to promote normal wound healing and limit scarring.
|Jamison, Joshua; Wang, James H-C; Wells, Alan (2014) PKC? regulates force signaling during VEGF/CXCL4 induced dissociation of endothelial tubes. PLoS One 9:e93968|
|Stenger, Elizabeth O; Rosborough, Brian R; Mathews, Lisa R et al. (2014) IL-12hi rapamycin-conditioned dendritic cells mediate IFN-ýý-dependent apoptosis of alloreactive CD4+ T cells in vitro and reduce lethal graft-versus-host disease. Biol Blood Marrow Transplant 20:192-201|
|Grahovac, Jelena; Wells, Alan (2014) Matrikine and matricellular regulators of EGF receptor signaling on cancer cell migration and invasion. Lab Invest 94:31-40|
|Rodrigues, Melanie; Blair, Harry; Stockdale, Linda et al. (2013) Surface tethered epidermal growth factor protects proliferating and differentiating multipotential stromal cells from FasL-induced apoptosis. Stem Cells 31:104-16|
|Grahovac, Jelena; Becker, Dorothea; Wells, Alan (2013) Melanoma cell invasiveness is promoted at least in part by the epidermal growth factor-like repeats of tenascin-C. J Invest Dermatol 133:210-20|
|Wells, Alan; Grahovac, Jelena; Wheeler, Sarah et al. (2013) Targeting tumor cell motility as a strategy against invasion and metastasis. Trends Pharmacol Sci 34:283-9|
|Stenger, Elizabeth O; Turnquist, H?th R; Mapara, Markus Y et al. (2012) Dendritic cells and regulation of graft-versus-host disease and graft-versus-leukemia activity. Blood 119:5088-103|
|Leloup, Ludovic; Wells, Alan (2011) Calpains as potential anti-cancer targets. Expert Opin Ther Targets 15:309-23|
|Tamama, Kenichi; Kawasaki, Haruhisa; Wells, Alan (2010) Epidermal growth factor (EGF) treatment on multipotential stromal cells (MSCs). Possible enhancement of therapeutic potential of MSC. J Biomed Biotechnol 2010:795385|
|Yates, Cecelia C; Whaley, Diana; Hooda, Shveta et al. (2009) Delayed reepithelialization and basement membrane regeneration after wounding in mice lacking CXCR3. Wound Repair Regen 17:34-41|
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