Wound healing mechanisms modulated by novel antimicrobial Peptides

描述：伤口愈合是一个复杂的过程，遵循一系列确定的事件，包括 上皮细胞的炎症、增殖和迁移以使伤口重新上皮化，以及 重塑/分化。37 kDa阳离子抗菌蛋白(CAP37)属于天然免疫 它最初是基于其强大的抗菌作用而被识别的。后来发现它能诱导 培养的角膜上皮细胞的迁移、黏附和增殖，转化为更快的角膜复张 体内上皮化。CAP37的结构-功能研究是以长期目标为基础的 该蛋白的抗菌域和创面修复域可产生临床治疗多肽 使用。我们的实验室最近发现了两个CAP37衍生的多肽类似物，它们具有很强的抗菌活性， 甚至对抗生素耐药或多重耐药菌株，以及伤口愈合活动。这些类比有很强的 具有促进角膜复明双重作用的新型眼科治疗方法 上皮化和预防或清除细菌感染。 全长CAP37及其衍生产物介导创面愈合的分子机制 类比是未知的。这项建议的目标是确定膜和细胞内的介质 被这些细胞外配体激活，诱导永生化的角膜上皮细胞和角膜迁移 小鼠的再上皮化。根据我们实验室以前的研究，我们假设CAP37和派生的 类似物作为细胞外配体，与角膜上皮细胞上的G蛋白偶联受体(GPCR)结合 激活细胞内信号通路，包括信号转导蛋白PKCδ和PKCθ，从而 促进伤口愈合效果。提出了两个具体目标。(1)确定介导血管紧张素转换酶的受体(S CAP37配体对人角膜上皮细胞迁移和角膜伤口愈合的影响(2)至 识别介导角膜上皮细胞迁移和角膜损伤的下游信号通路(S) 修复对CAP37配体的反应。这一新知识将在这一研究领域开辟新天地。 因为CAP37的受体将自30年前被发现以来首次被发现。这是一项新的 知识也将是开发和优化CAP37衍生多肽类似物成为创新的关键 具有杀灭耐药病原体和促进伤口愈合双重作用的治疗药物。

DESCRIPTION: Wound healing is a complex process that follows a defined sequence of events consisting of inflammation, proliferation and migration of epithelial cells to re-epithelialize the wound, and remodeling/differentiation. The cationic antimicrobial protein of 37 kDa (CAP37) belongs to the innate immune system and was originally identified based on its powerful antimicrobial effect. It was later found to induce migration, adhesion and proliferation of cultured corneal epithelial cells, which translated into faster corneal re- epithelialization in vivo. Structure-function studies of CAP37 were initiated with the long-term goal to identify the antimicrobial and the wound healing domains of the protein to generate therapeutic peptides for clinical use. Our lab recently identified two CAP37-derived peptide analogs that carry a strong antimicrobial activity, even on antibiotic resistant or multiresistant strains, and a wound healing activity. These analogs have strong potential to be used as innovative ocular treatments with the dual effects of promoting corneal re- epithelialization and preventing or clearing bacterial infections. The molecular mechanisms mediating the wound healing effects of the full length CAP37 and the two derived analogs are unknown. The objective of this proposal is to identify the membrane and intracellular mediators activated by these extracellular ligands to induce migration of immortalized corneal epithelial cells and corneal re-epithelialization in mouse. Based on previous studies in our lab, we hypothesize that CAP37 and derived analogs act as extracellular ligands, binding a G protein-coupled receptor (GPCR) on corneal epithelial cells to activate intracellular signaling pathways, including the signal transduction proteins PKCδ and PKCθ, thus promoting wound healing effects. Two specific aims are proposed. (1) To identify the receptor(s) mediating the migration of human corneal epithelial cells and corneal wound healing in response to CAP37 ligands. (2) To identify the downstream signaling pathway(s) mediating corneal epithelial cell migration and corneal wound healing in response to CAP37 ligands. This new knowledge will break new grounds in this field of research because a receptor for CAP37 will be identified for the first time since its discovery 30 years ago. This new knowledge will also be key to developing and optimizing CAP37-derived peptide analogs into innovative therapeutics with the dual effects of killing resistant pathogens and promoting wound healing.