IRF6 and Wound Healing

IRF6 和伤口愈合

基本信息

批准号：
9889035
负责人：
MARTINE DUNNWALD
金额：
$ 39.97万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889035
关键词：
Actins Adhesions Adult Affect Behavior Biochemical Biological Assay Cell Adhesion Cell Culture Techniques Cell Line Cell Proliferation Cells Cicatrix Clustered Regularly Interspaced Short Palindromic Repeats Code Collection Data Defect Down-Regulation E-Cadherin Embryo Enhancers Epithelial Epithelium Exhibits Financial Hardship Funding Genes Genetic Genetic Transcription Genetic Variation Goals Guanosine Triphosphate Phosphohydrolases Health Homeostasis Impairment In Vitro Individual Infection prevention Inflammatory Response Injury Interferons Large Keratinocyte Mediating Modality Modeling Molecular Molecular Mechanisms of Action Mus Mutant Strains Mice Mutation Null Lymphocytes Operative Surgical Procedures Outcome Pathway interactions Patients Phase Phenotype Play Process Proteins Public Health Publishing Regulation Research Risk Role Shapes Single Nucleotide Polymorphism Skin Skin injury Skin repair Skin wound healing Social Impacts Societies Stress Fibers Surgical incisions Syndrome Testing Therapeutic Time Tissues Transcriptional Regulation United States Up-Regulation Van der Woude syndrome Variant cell behavior cell motility cell type chronic wound cost craniofacial development economic impact experimental study healing human tissue in vivo inhibitor/antagonist innovation insight interest keratinocyte migration mouse model novel orofacial cleft public health relevance repaired therapeutic target tissue repair transcription factor wound wound care wound closure wound healing

项目摘要

DESCRIPTION (provided by applicant): Every time an incision is made, a wound is created. Over 70 million surgeries were performed in the United States in 2000 with over 50% requiring postsurgical wound care. In addition, chronic wounds affect 6.5 million patients with over $25 billion spent annually on treatment. The economic and social impact of wound healing to our society requires further research to better understand the mechanisms regulating tissue repair. In previous studies, we have shown that genetic variations in Interferon Regulatory Factor 6 (IRF6) identify individuals at risk for poor healing outcome, suggesting that IRF6 is a novel transcriptional regulator of tissue repair. We have evidence that both downregulation and upregulation of Irf6 in the mouse alter different aspects of tissue repair, suggesting that the proper homeostasis of Irf6 is required for adequate healing. Furthermore, Irf6-deficient keratinocytes are impaired in their ability to close an in vitro scratch wound. These keratinocytes are larger, more round, and exhibit more stress fibers and increased RhoA activity compared with wild-type cells. Arhgap29, a RhoA-specific activating protein, is upregulated during wound healing and is downregulated in Irf6-deficient tissues, making it a perfect downstream effector. Although it is clear that IRF6 expression is important for normal wound healing, essentially nothing is known about its cellular or molecular mechanism of action. The overall goal of this study is to take advantage of our unique murine and patient cells, in combination with unique murine models, to elucidate how IRF6 contributes to tissue repair. We hypothesize that IRF6 regulates epidermal migration by inhibiting RhoA GTPase through Arhgap29. We propose two aims to test this hypothesis: 1) Identify the mechanism of IRF6-dependent keratinocyte migration, and 2) Determine how ARHGAP29 mediates the function of IRF6. The successful completion of this project will establish the contribution of IRF6 in tissue repair and provide a basis for identifying therapeutic targets involved in wound healing.

描述（由适用提供）：每次进行切口，都会赢得胜利。 2000年在美国进行了超过7000万次手术，需要超过50％的手术。此外，慢性伤口每年在治疗上花费超过250亿美元的650万患者。伤口康复对我们社会的经济和社会影响需要进一步的研究，以更好地了解调节组织修复的机制。在先前的研究中，我们已经表明，干扰素调节因子6（IRF6）的遗传变异确定了康复结果不良风险的个体，这表明IRF6是一种新型的组织修复转录调节剂。我们有证据表明，在小鼠中，IRF6的下调和上调都改变了组织修复的不同方面，这表明IRF6的适当稳态是适当的愈合所必需的。此外，IRF6缺陷的角质形成细胞因其闭合体外刮伤伤口的能力受损。这些角质形成细胞尽管很明显，IRF6表达对于正常伤口愈合很重要，但基本上对其细胞或分子作用机理一无所知。这项研究的总体目标是利用我们独特的鼠和患者细胞以及独特的鼠模型，以阐明IRF6如何促进组织修复。我们假设IRF6通过通过ARHGAP29抑制RhoA GTPase来调节表皮迁移。我们提出了两个旨在检验这一假设的目的：1）确定IRF6依赖性角质形成细胞迁移的机制，2）确定ARHGAP29如何介导IRF6的功能。该项目的成功完成将确定IRF6在组织修复中的贡献，并为识别与伤口愈合有关的治疗靶标提供了基础。