Transcriptional Regulation of Wound Healing in Human Gingiva and Skin

项目总结 这项申请提出了一个定制的研究培训计划，旨在促进 申请人成为一名独立的调查员。该计划包括生物信息学和 实验室实验，以及量身定做的专业和职业发展机会。培训 该计划得到了UIC现有的当地和机构资源的支持。建议数 研究将检查控制疤痕形成的机制，疤痕形成是愈合反应的常见结果。 疤痕是由无序的胶原蛋白、细胞外基质和成纤维细胞组成的纤维性肿块。疤痕形成可以 导致受影响器官系统的长期严重损害。过度的疤痕形成也是一种 阻碍再生的策略，包括那些针对头面部复杂组织的策略。 口腔粘膜是一种愈合迅速且几乎无疤痕的组织。口腔黏膜创面愈合是 与皮肤愈合的区别在于更快的再上皮化，缩短的炎症期，短暂的 血管生成反应，以及最小的疤痕形成。这个项目的目标是获得一个全面的 了解口腔粘膜和皮肤中伤口愈合随时间的转录调节。这个 研究计划利用系统生物学方法来了解口腔如何实现无疤痕 对损伤的转录反应，以及皮肤愈合反应如何导致疤痕形成。我们假设 口腔和皮肤创伤的转录调控网络本质上是不同的，并且 关键转录因子的基因调控是导致不同愈合表型的原因 在这两张纸巾之间。利用独特的人类微阵列数据集-gt；95来自实验样本 对于皮肤和牙龈创伤，我们的研究将集中在转录因子(TF)，即可以激活或 协同抑制大量基因转录。AIM 1将利用一个网络- 基于基因的方法识别在创伤愈合中协调动态基因表达变化的因子 人的牙龈和皮肤。具体地说，目标1将a)确定口腔或皮肤中唯一靶向基因的因子 愈合，b)发现在两个组织中调节伤口愈合的共享TF，以及c)预测候选疤痕- 推广TF。这些转录因子所针对的下游生物途径将被识别出来。AIM 2将利用 体内和体外创面模型，以确定候选的促瘢痕因子的作用。我们将使用体内的 基于siRNA的方法在小鼠皮肤伤口中敲除候选的促进瘢痕的因子。其传入的TFS 体内抑制导致减少疤痕形成和/或加速伤口闭合将在 更广泛的体内机制研究。体外研究将提供有关这些机制的信息。 危急TFS。总之，AIMS将提供有关转录因子在转录中的作用的新信息 对瘢痕形成的调控。这些发现将适用于各种各样的情况，包括烧伤， 慢性伤口、增生性瘢痕、瘢痕疙瘩形成、皮肤再生和其他纤维化病理。

PROJECT SUMMARY This application proposes a customized research training plan designed to promote the development of the applicant into an independent investigator. The plan includes advanced training in both bioinformatics and laboratory experimentation, along with tailored professional and career development opportunities. The training plan is supported by the outstanding availability of local and institutional resources at UIC. The proposed research will examine the mechanisms that control scar formation, a common result of the healing response. Scars are a fibrous mass of disorganized collagen, extracellular matrix, and fibroblasts. Scar formation can lead to significant long term impairments of the organ system affected. Excessive scar formation is also a barrier to regenerative strategies, including those that target the complex tissues of the craniofacial region. One tissue that exhibits rapid and nearly scarless healing is the oral mucosa. Wound healing of oral mucosa is differentiated from cutaneous healing by a faster re-epithelialization, a shortened inflammatory phase, a brief angiogenic response, and minimal scar formation. The goal of this project is to gain a comprehensive understanding of the transcriptional regulation of wound healing over time in the oral mucosa and skin. The research plan utilizes a systems biology approach to learn how the oral cavity implements a scarless transcriptional response to injury, and how the skin healing response leads to scarring. We hypothesize that the transcriptional regulatory networks of oral and cutaneous wounds are intrinsically different, and that gene regulation by key transcription factors is responsible for the differential healing phenotypes between these two tissues. Utilizing a unique human microarray dataset of >95 samples from experimental skin and gingival wounds, our studies will focus on transcription factors (TFs), proteins that can activate or repress the transcription of a large number of genes in a coordinated fashion. Aim 1 will utilize a network- based approach to identify TFs that orchestrate the dynamic gene expression changes in wound healing of human gingiva and skin. Specifically, Aim 1 will a) identify TFs that uniquely target genes in oral or skin healing, b) discover shared TFs that regulate wound healing in both tissues, and c) predict candidate scar- promoting TFs. Downstream biological pathways targeted by these TFs will be discerned. Aim 2 will utilize in vivo and in vitro wound models to determine the role of candidate scar-promoting TFs. We will use an in vivo siRNA-based approach to knock down candidate scar-promoting TFs in murine skin wounds. TFs whose in vivo repression leads to decreased scar formation and/or accelerated wound closure will be further studied in more extensive in vivo mechanistic studies. In vitro studies will provide mechanistic information about these critical TFs. Together, the Aims will provide new information about the role of TFs in the transcriptional regulation of scar formation. The findings will be applicable to a wide variety of conditions, including burns, chronic wounds, hypertrophic scars, keloid formation, skin regeneration, and other fibrotic pathologies.