Project 3: Resolution of Surgical Injury

项目总结/摘要 通过手术或物理创伤破坏皮肤屏障会使下层组织暴露于环境中 并可能导致感染。一个强大的炎症反应，以打击外源性病原体在受伤 组织，并与修复过程紧密相连。长期或过度的炎症会阻碍组织 修复，表明炎症的迅速消退控制着这种转变。的关系 对炎症的消退和组织修复还不完全了解。Resolvins是一个脂质家族， 由免疫细胞产生的介质，促进炎症的消退并增强宿主防御。 我们最近的证据表明，消退素和相关的促消退介质也发挥重要作用， 组织修复本项目的项目3将测试假设，D系列resolvins和他们的新- 经鉴定的硫代缀合物（SC）促进皮肤组织修复并对抗外科手术后的感染 切除伤为了检验这一假设，将实现以下具体目标：1）评估 皮肤再上皮化中的消退素。我们将确定消退素是否促进上皮再生 用项目1和2确定其与炎症消退的关系; 2）阐明颞叶 D-系列消退素的生物合成关系和内源性作用， 损伤修复反应的重塑阶段。通过与Cores B & C以及项目1和2的互动， 我们将确定D系列消退素的生物合成及其SC在消退过程中是如何调节的， 组织修复我们将确定RvD 1和RvD 2的促消退受体如何影响上皮再生， 皮肤外科损伤; 3）建立消退素促进上皮再形成的机制。使用 在二维和三维培养的原代角质形成细胞，我们将确定如何resolvins调节分化，迁移 和增殖的受体依赖性的方式;和4）确定是否resolvins恢复有缺陷的重新， 通过对抗细菌感染来上皮化。在这里，我们将研究如何感染皮肤病原体， 金黄色葡萄球菌，影响局部消退素生物合成以及消退素是否促进细菌生长 遏制和重建表皮屏障功能。总体而言，项目3将提供基本的新 关于消退素在组织修复中的作用的知识，这可以导致新的治疗方法的开发， 增强组织修复和宿主防御的方法。

Project Summary/Abstract Disruption of the cutaneous barrier by surgery or physical trauma exposes underlying tissue to the environment and can lead to infection. A robust inflammatory response serves to combat exogenous pathogens in injured tissue and is tightly coupled to the process of repair. Prolonged or excessive inflammation can impede tissue repair, suggesting that prompt resolution of inflammation governs this transition. The relationship between resolution of inflammation and tissue repair is incompletely understood. Resolvins are a family of lipid mediators generated by immune cells that promote resolution of inflammation and also enhance host defense. Our recent evidence indicates that resolvins and related pro-resolving mediators also play an important role in tissue repair. Project 3 of this Program Project will test the hypothesis that D-series resolvins and their newly- identified sulfido-conjugates (SC) promote cutaneous tissue repair and combat infection following surgical excisional injury. To test this hypothesis, the following specific aims will be carried out: 1) Assess the role of resolvins in cutaneous re-epithelialization. We will determine whether resolvins promote re-epithelialization and determine its relationship to the resolution of inflammation with Projects 1 & 2; 2) Elucidate the temporal biosynthetic relationships and endogenous roles of D-series resolvins during the inflammatory, proliferative and remodeling phases of the injury-repair response. Through interactions with Cores B & C and Projects 1 & 2, we will determine how biosynthesis of D-series resolvins and their SC are regulated during resolution and tissue repair. We will determine how pro-resolving receptors for RvD1 and RvD2 impact re-epithelialization in cutaneous surgical injury; 3) Establish the mechanisms whereby resolvins promote re-epithelialization. Using primary keratinocytes cultured in 2D and 3D, we will determine how resolvins regulate differentiation, migration and proliferation in a receptor-dependent manner; and 4) Determine whether resolvins restore defective re- epithelialization by combating bacterial infection. Here, we will examine how infection with skin pathogen, Staphylococcus aureus, impacts local resolvin biosynthesis and whether resolvins promote bacterial containment and re-establish epidermal barrier function. Collectively, Project 3 will provide fundamental new knowledge about the roles of resolvins in tissue repair, which can lead to the development of new therapeutic approaches for enhancing tissue repair and host defense.