Epithelial-connective tissue interactions: Influence on scar formation

描述（由申请人提供）：疤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，瘢痕较少的观点。这些观察结果有力地表明：1)成年人保持最小疤痕的愈合能力；2)成人皮肤愈合可以通过控制来减少疤痕的形成。目前，成人粘膜修复改善的机制尚不明确。可能是特权粘膜修复的关键因素包括先天上皮反应，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疤痕结果的概念很少得到实验关注。这种应用的假设是上皮-结缔组织相互作用在决定疤痕形成中起关键作用，并且这些相互作用在皮肤和粘膜中是不同的。本研究的直接目标是确定粘膜和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）中开发的三种配对粘膜和皮肤修复模型系统。目的1将利用蛋白质组学和基因组分析来确定在粘膜和皮肤伤口部位表达不同的因素。在上皮和结缔组织区室中产生的因子将通过后续定位分析确定。该Aim将利用新开发的芝加哥生物医学联盟蛋白质组学/生物信息学项目（位于伊利诺伊大学），以及其他地方的基因组分析设施，提供对皮肤和粘膜损伤反应差异的新颖综合分析。Aim 2将采用体外实验来评估Aim 1中鉴定的靶分子调节与疤痕形成和愈合相关的细胞功能的能力，包括胶原合成和肌成纤维细胞形成。目的3将确定目标因子是否可以减少体内增生性疤痕形成的临床前模型中的疤痕形成。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.