pGlcNAc stimulates wound healing and defensin expression via AKT1

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DESCRIPTION (provided by applicant): Wound healing is an intricate process involving interactions between different cell types, cytokines, and growth factors. The classic model of wound healing can be divided into sequential, but overlapping phases: hemostasis, inflammation, proliferation, and remodeling and maturation. Concentrated efforts have been made to increase wound healing in both acute and chronic wounds such as with the use of recombinant growth factors or endothelial cell precursors, however, these methods have low efficacy. Recent findings show that treatment of cutaneous wounds with poly-N-acetyl-glucosamine (pGlcNAc) nanofibers, a novel polysaccharide material derived from a marine diatom, results in an increased kinetics of wound healing that can be attributed, in part, by a marked increase in angiogenesis. Our published data suggests that treatment of primary endothelial cells (EC) with this nanofiber results in an increased cell migration, which is due to an integrin-dependent up-regulation of the Ets1 transcription factor. We show that pGlcNAc stimulation of Ets1 results from the activation of Akt1 by these nanofibers. Nanofiber treatment of EC results in increased expression of genes involved in innate immunity and cellular recruitment, such as IL-1 (a known Ets1 target) and several defensins (23, 11, 14, and 15), small anti-microbial peptides recently shown to also act as chemo attractants. The nanofiber induction of these molecules is dependent on Akt1 in vitro. Indeed, pGlcNAc nanofiber treatment of wild type and Akt1 null animals indicates a role for Akt1 in defensin expression in vivo as well. Taken together these findings suggest the hypothesis that pGlcNAc nanofibers stimulate Akt1 activation resulting in defensin expression and cellular recruitment in a healing wound. While this training application deals with the mechanisms of cutaneous wound healing, many of these mechanisms will be applicable to healing in the dental clinic. Future directions using pGlcNAc nanofibers to enhance wound healing will include its use in the oral cavity. The training and research plan set forth will allow me to acquire knowledge and technical experience necessary for pursuing translational wound healing research in the oral cavity. Being able to use laboratory research and apply this directly to patient needs is of utmost importance.