This proposal studies how hyaluronan (HA) influences the wound repair process in the adult and fetus. While typically effective, repair resulting in a scar can have devastating consequences, as demonstrated by hypertrophic scars, peri-tendon adhesions, and scar contractures. Indeed, scarring and fibrosis are responsible for disease in virtually all areas of medicine. Maintaining HA levels in wounds promotes fetal-like scarless repair, while removing HA from a fetal wound induces adult-like scarring. The core hypothesis is; differential binding of HA cell surface receptors dictates the organization of collagen in the resulting repair. There are at least 3 ways HA interacts with the cell surface: 1. CD44 receptor; 2. RHAMM (Receptor for HA Mediated Motility); and 3. HA Synthase. HA breakdown requires binding to the surface, endocytosis and lysosomal enzyme digestion. Increased binding of HA to CD44 receptor is proposed to enhance the breakdown of HA, promoting repair by scarring. RHAMM-HA interaction has been associated with increased fibroblast locomotion. It is proposed that the RHAMM-HA complex modulates the fibroblast s ability to organize collagen fibers in the ECM. Increased levels of the RHAMM-HA complex on the cell surface promote scarless repair. HA is synthesized by HA Synthase, a cell surface enzyme. Newly synthesized HA projects from the cell surface directly into the ECM. HA synthesis has been shown to enhance cell proliferation. It is proposed that inhibiting HA Synthase will reduce cell proliferation and impede wound repair. Both in vitro and in vivo models will be used to substantiate the core hypothesis: fetal mouse organ cultures; adult mouse sponge implants; and mouse-derived fibroblasts in culture.
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