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，没有足够的治疗方法。临床观察和实验研究支持这样的观点，即粘膜愈合比皮肤更快，疤痕更少。这些观察有力地表明，1)成年人保持愈合的能力和最小的疤痕，2)成年人的皮肤愈合可以被操纵，以减少疤痕的形成。目前，促进成人粘膜修复的机制尚不清楚。可能是特权粘膜修复的关键因素包括固有的上皮反应、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。到目前为止，上皮-上皮下相互作用可能指导愈合和瘢痕形成的概念几乎没有得到实验的关注。这种应用的假设是，上皮-结缔组织的相互作用在决定瘢痕形成的过程中起着关键作用，而且这些相互作用在皮肤和粘膜中是不同的。这项研究的直接目标是确定在黏膜创面和皮肤创面的上皮和上皮下组织中唯一产生的元素。该研究计划将利用我们在小鼠(LAD)、人类(PtM)和兔子()身上开发的三种成对粘膜和皮肤修复系统。目标1将利用蛋白质组和基因组分析来确定在粘膜和皮肤伤口部位差异表达的因子。在上皮室和结缔组织室产生的因子将通过后续的定位分析来确定。这一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(位于伊利诺伊州大学)，以及其他地方的基因组分析设施，提供一种新颖的全面分析皮肤和粘膜对损伤的反应如何不同。AIM 2将使用体外试验来评估AIM 1中确定的目标分子调节与瘢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的形成。目的3将在体内增生性瘢痕形成的临床前模型中确定靶因素是否可以减少瘢痕形成。该项目的长期目标是开发一个创新的研究中心，专注于识别和了解调节疤痕形成的新因素，目标是开发有用的治疗策略，以减少成年人的疤痕形成。

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.