IRF6 and Wound Healing

IRF6 和伤口愈合

• 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
• 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

 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.