pGlcNAc stimulates wound healing and defensin expression via AKT1

pGlcNAc 通过 AKT1 刺激伤口愈合和防御素表达

• 批准号: 8471013
• 负责人: Amanda Haley Buff Lindner
• 金额: $ 4.8万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8471013
• 关键词: AKT1 gene; Acute; Animals; Biological Assay; Blocking Antibodies; Chronic; Computer Simulation; Cutaneous; Data; Defensins; Dental Clinics; Diatoms; Endothelial Cells; Fibroblasts; Future; Gene Expression; Growth Factor; Healed; Hemostatic function; Immunohistochemistry; Impaired wound healing; In Vitro; Inflammation; Integrins; Interleukin-1; Kinetics; Knockout Mice; Knowledge; Laboratory Research; Lead; Marines; Methods; Modeling; Natural Immunity; Neutrophil Infiltration; Oral cavity; Pathway interactions; Patients; Peptides; Phase; Phenotype; Polysaccharides; Process; Promoter Regions; Publishing; Recombinant Growth Factor; Regulation; Research; Research Training; Role; Site; Training; Transcriptional Regulation; Up-Regulation; Wound Healing; angiogenesis; antimicrobial; cell motility; cell type; cytokine; experience; healing; in vivo; knockout animal; nanofiber; novel; poly-N-acetyl glucosamine; promoter; response; transcription factor

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.

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。伤口愈合的经典模型可分为连续但重叠的阶段：止血、炎症、增殖以及重塑和成熟。已经进行了集中的努力来增加急性和慢性伤口中的伤口愈合，例如使用重组生长因子或内皮细胞前体，然而，这些方法具有低功效。最近的研究结果表明，用聚-N-乙酰葡糖胺（pGlcNAc）纳米纤维（一种源自海洋硅藻的新型多糖材料）治疗皮肤伤口，导致伤口愈合的动力学增加，这部分归因于血管生成的显著增加。我们已发表的数据表明，治疗的原代内皮细胞（EC）与此ESTA的结果在增加细胞迁移，这是由于整合素依赖性上调的Ets 1转录因子。我们表明，pGlcNAc刺激Ets 1的结果从Akt 1的激活这些纳米纤维。纳米纤维治疗EC导致参与先天免疫和细胞募集的基因表达增加，例如IL-1（已知的Ets 1靶点）和几种防御素（23，11，14和15），最近显示小的抗微生物肽也可作为化学引诱剂。在体外，这些分子的转录诱导依赖于Akt 1。事实上，野生型和Akt 1缺失动物的pGlcNAc纳米纤维处理也表明Akt 1在体内防御素表达中发挥作用。总之，这些发现表明pGlcNAc纳米纤维刺激Akt 1活化导致防御素表达和愈合伤口中的细胞募集的假设。虽然本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。使用pGlcNAc纳米纤维来增强伤口愈合的未来方向将包括其在口腔中的使用。提出的培训和研究计划将使我获得在口腔中进行转化伤口愈合研究所需的知识和技术经验。能够使用实验室研究并将其直接应用于患者需求至关重要。