Transcriptional Regulation of Wound Healing in Human Gingiva and Skin

人类牙龈和皮肤伤口愈合的转录调控

• 批准号: 9890781
• 负责人: Trevor Leonardo
• 金额: $ 5.13万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890781
• 关键词: Adult; Affect; Binding Proteins; Bioinformatics; Biological; Burn injury; Cicatrix; Clinical Treatment; Collagen; Complex; Custom; Cutaneous; Data; Data Set; Development; Epithelial; Epithelium; Event; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Gingiva; Goals; Human; Hypertrophic Cicatrix; Impairment; In Vitro; Inflammatory; Investigation; Keloid; Kidney Diseases; Laboratories; Lead; Learning; Light; Location; Methods; Mus; Myocardial Infarction; Network-based; Nucleic Acid Regulatory Sequences; Oral; Oral cavity; Oral mucous membrane structure; Organ; Pathology; Pathway interactions; Pattern; Phase; Phenotype; Proteins; Pulmonary Fibrosis; Regulator Genes; Repression; Research; Research Personnel; Research Training; Resources; Role; Sampling; Skin; Skin wound healing; Small Interfering RNA; Systems Biology; Time; Tissues; Training; Transcriptional Regulation; Vertebrates; Wound models; base; body system; burn wound; career development; cell type; chronic wound; craniofacial tissue; design; functional improvement; healing; improved; in vivo; knock-down; mouse model; novel; regenerative; response; response to injury; skin regeneration; skin wound; tissue regeneration; tissue repair; transcription factor; wound; wound closure; wound healing

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.

项目摘要 本申请提出了一个定制的研究培训计划，旨在促进发展的 申请人成为独立调查员。该计划包括生物信息学和 实验室实验，沿着量身定制的专业和职业发展机会。培训 该计划得到了UIC出色的地方和机构资源的支持。拟议 研究将检查控制疤痕形成的机制，这是愈合反应的常见结果。 瘢痕是由胶原蛋白、细胞外基质和成纤维细胞组成的纤维团。疤痕形成可以 导致受影响的器官系统的显著的长期损伤。过度的疤痕形成也是一种 再生策略的障碍，包括那些针对颅面区域复杂组织的策略。 一种表现出快速且几乎无瘢痕愈合的组织是口腔粘膜。口腔粘膜的创伤愈合 与皮肤愈合不同的是，它具有更快的上皮再生、更短的炎症期、短暂的 血管生成反应和最小的瘢痕形成。该项目的目标是获得全面的 理解口腔粘膜和皮肤中伤口愈合随时间的转录调节。的 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。我们假设 口腔和皮肤伤口的转录调节网络本质上是不同的， 关键转录因子的基因调控是导致不同愈合表型的原因， 在这两个组织之间。利用来自实验室的>95个样品的独特的人类微阵列数据集， 皮肤和牙龈伤口，我们的研究将集中在转录因子（TF），蛋白质，可以激活或 以协调的方式抑制大量基因的转录。目标1将利用一个网络- 的方法来鉴定在创伤愈合中协调动态基因表达变化的TF， 人类牙龈和皮肤。具体而言，目标1将a）鉴定独特地靶向口腔或皮肤中的基因的TF 愈合，B）发现调节两种组织中伤口愈合的共有TF，以及c）预测候选瘢痕- 促进TF。将辨别这些TF靶向的下游生物途径。目标2将在 体内和体外伤口模型，以确定候选瘢痕促进TF的作用。我们将使用体内 基于siRNA的方法敲低小鼠皮肤伤口中的候选瘢痕促进TF。TF，其 体内抑制导致减少的瘢痕形成和/或加速的伤口闭合将在 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 关键TF总之，这些目标将提供有关转录因子在转录调控中作用的新信息。 瘢痕形成的调节。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、皮肤再生和其它纤维化病理。