Epithelial-connective tissue interactions: Influence on scar formation

描述（由申请人提供）：瘢痕形成仍然是一个重要的临床问题，治疗不足。 临床观察和实验研究支持粘膜比皮肤愈合更快且瘢痕形成更少的观点。 这些观察结果强烈表明：1）成人保持愈合能力，瘢痕最小，2）成人皮肤愈合可以被操纵，以减少瘢痕形成。 目前，负责成人粘膜修复改善的机制还不清楚。 可能是特权粘膜修复的关键因素包括先天性上皮反应、成纤维细胞/结缔组织反应以及上皮和上皮下室之间的相互动态相互作用。 迄今为止，上皮-上皮下相互作用可能指导愈合和瘢痕形成结果的概念很少受到实验关注。 本申请的假设是上皮-结缔组织相互作用在决定瘢痕形成中起关键作用，并且这些相互作用在皮肤和粘膜中不同。 本研究的直接目标是确定粘膜与皮肤伤口的上皮和上皮下组织中独特产生的元素。 该研究计划将利用我们在小鼠（LAD），人类（PTM）和兔子（TAM）中开发的配对粘膜和皮肤修复的三种模型系统。 目的1将利用蛋白质组学和基因组学分析来鉴定在粘膜和皮肤伤口部位不同表达的因子。 将通过后续定位分析确定上皮和结缔组织隔室中产生的因子。 这个目标将利用新开发的芝加哥生物医学联盟的蛋白质组学/生物信息学项目（位于美国。伊利诺斯州），以及其他地方的基因组分析设施，以提供一个新的全面分析如何对皮肤和粘膜损伤的反应不同。 目标2将采用体外测定来评估目标1中鉴定的靶分子调节与瘢痕形成和愈合相关的细胞功能（包括胶原蛋白合成和肌成纤维细胞形成）的能力。 目的3将确定在增生性瘢痕形成的体内临床前模型中靶因子是否可以减少瘢痕形成。 该项目的长期目标是建立一个创新的研究中心，专注于识别和理解调节瘢痕形成的新因素，目标是开发有用的治疗策略，以减少成人瘢痕形成。

DESCRIPTION (provided by applicant): Scar formation remains an important clinical problem for which inadequate treatment is available. Clinical observation and experimental studies support the idea that mucosa heals more rapidly and with less scarring than skin. These observations strongly suggest that 1) adults maintain the capacity to heal with minimal scar, and 2) adult skin healing can be manipulated to reduce scar formation. At present, the mechanisms responsible for the improved repair of adult mucosa are poorly defined. Elements that might be the key to privileged mucosal repair include the innate epithelial response, the fibroblast/connective tissue response, and reciprocal dynamic interactions between the epithelial and subepithelial compartments. To date, the concept that epithelial-subepithelial interactions might guide healing and scarring outcomes has received little experimental attention. The hypothesis of this application is that epithelial-connective tissue interactions play a critical role in dictating scar formation, and that these interactions differ in skin and mucosa. The immediate goal of this research is to identify elements that are uniquely produced in epithelium and subepithelial tissue of mucosal versus skin wounds. The research plan will take advantage of three models systems of paired mucosal and skin repair that we have developed in mice (LAD), humans (PTM) and rabbits (TAM). Aim 1 will utilize proteomic and genomic analyses to identify factors that are differently expressed in mucosal and skin wound sites. Factors produced in epithelial and connective tissue compartments will be identified by follow-up localization analysis. This Aim will utilize the newly developed Chicago Biomedical Consortium for the Proteomics/Bioinformatics Project (located at U. Illinois), as well as genomic analysis facilities elsewhere to provide a novel comprehensive analysis of how the response to injury differs in skin and mucosa. Aim 2 will employ in vitro assays to assess the ability of target molecules identified in Aim 1 to modulate cellular functions related to scar formation and healing, including collagen synthesis and myofibroblast formation. Aim 3 will determine if target factors can reduce scar formation in an in vivo preclinical model of hypertrophic scar formation. The long-term goal of the project is to develop an innovative Research Center that will focus on identifying and understanding novel factors that modulate scarring, with a goal of developing useful therapeutic strategies to reduce scar formation in adults.