pGlcNAc stimulates wound healing and defensin expression via AKT1

描述(由申请人提供)：伤口愈合是一个复杂的过程，涉及不同细胞类型、细胞因子和生长因子之间的相互作用。经典的伤口愈合模型可分为连续但重叠的阶段：止血、炎症、增殖、重塑和成熟。对于急慢性创面，如使用重组生长因子或血管内皮细胞前体，人们已经集中精力促进创面愈合，然而，这些方法的效果很低。最近的研究结果表明，用聚N-乙酰-氨基葡萄糖(PGlcNAc)纳米纤维(一种从海洋硅藻中提取的新型多糖材料)治疗皮肤伤口，可以提高伤口愈合的动力学，这在一定程度上可以归因于显著增加血管生成。我们发表的数据表明，用这种纳米纤维处理原代内皮细胞(EC)后，细胞迁移增加，这是由于整合素依赖的Ets1转录因子上调所致。我们表明，pGlcNAc对Ets1的刺激是这些纳米纤维激活Akt1的结果。EC的纳米纤维处理导致参与先天性免疫和细胞募集的基因表达增加，例如IL-1(已知的Ets1靶标)和几种防御素(23，11，14和15)，这些小的抗菌肽最近被证明也可以作为化学引诱剂。在体外，这些分子的纳米纤维诱导依赖于Akt1。事实上，野生型和Akt1缺失动物的pGlcNAc纳米纤维处理表明Akt1在体内的防御素表达中也起到了作用。综上所述，这些发现表明，pGlcNAc纳米纤维刺激Akt1激活，导致愈合伤口中防御素的表达和细胞募集。虽然这一培训应用程序涉及皮肤伤口愈合的机制，但其中许多机制将适用于牙科诊所的愈合。未来使用pGlcNAc纳米纤维促进伤口愈合的方向将包括将其用于口腔。制定的培训和研究计划将使我获得从事口腔转化性伤口愈合研究所需的知识和技术经验。能够利用实验室研究并将其直接应用于患者的需求是至关重要的。

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.