IRF6 and Wound Healing

IRF6 和伤口愈合

• 批准号: 9921641
• 负责人: MARTINE DUNNWALD
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921641
• 关键词: Actins; Adhesions; Adult; Affect; Behavior; Biochemical; Biological Assay; Caring; Cell Adhesion; Cell Culture Techniques; Cell Line; Cell Proliferation; Cells; Cicatrix; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Collection; Cutaneous; Data; Defect; Down-Regulation; E-Cadherin; Embryo; Enhancers; 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; Social Impacts; Societies; Stress Fibers; Surgical incisions; Syndrome; Testing; Therapeutic; Time; Tissues; Transcriptional Regulation; United States; Up-Regulation; Van der Woude syndrome; Variant; Wound Healing; 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; repaired; therapeutic target; tissue repair; transcription factor; wound; wound closure

Project Summary 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.

项目摘要 每次切开切口，都会创建伤口。联合国进行了超过7000万次手术 2000年，多50％以上需要外科伤口护理。此外，慢性伤口影响650万 每年花费超过250亿美元的患者接受治疗。伤口愈合对 我们的社会需要进一步的研究，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）的遗传变异鉴定 康复结果不良的人，表明IRF6是组织的新转录调节剂 维修。我们有证据表明，小鼠中IRF6的下调和上调改变了不同的方面 组织修复，这表明IRF6的适当稳态需要适当的愈合。此外， IRF6缺乏的角质形成细胞闭合体外刮伤伤口的能力受损。这些角质形成细胞 与野生型相比 细胞。 ARHGAP29是一种RhoA特异性激活蛋白，在伤口愈合过程中被上调，并下调 在IRF6缺陷的组织中，使其成为完美的下游效应器。尽管很明显IRF6表达是 对于正常伤口愈合很重要，基本上对其细胞或分子机制一无所知 行动。这项研究的总体目标是利用我们独特的鼠和患者细胞， 结合独特的鼠模型，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。我们提出了两个目标 要检验该假设：1）确定IRF6依赖性角质形成细胞的机制，2）确定 ARHGAP29如何介导IRF6的功能。 该项目的成功完成将确定IRF6在组织维修中的贡献，并提供 确定与伤口愈合有关的治疗靶标的基础。

项目成果

Investigating the Effects of IRF6 on Focal Adhesions in Keratinocytes.

研究 IRF6 对角质形成细胞局部粘附的影响。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Lowenberg,Sarah;Antiguas,Angelo;Dunnwald,Martine
• 通讯作者: Dunnwald,Martine

Murine Excisional Wound Healing Model and Histological Morphometric Wound Analysis.

• DOI: 10.3791/61616
• 发表时间: 2020-08-21
• 期刊: JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
• 影响因子: 1.2
• 作者: Rhea, Lindsey;Dunnwald, Martine
• 通讯作者: Dunnwald, Martine

Arhgap29 is Required for Proper Palatogenesis and its Loss in Ectodermal-Derived Cells Results in a Kinked Tail Phenotype.

Arhgap29 是正常腭发育所必需的，外胚层衍生细胞中 Arhgap29 的缺失会导致尾部打结表型。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Adelizzi,EmilyC;Doolittle,Bethany;Dunnwald,Martine
• 通讯作者: Dunnwald,Martine

ARHGAP29 Regulates Keratinocyte Migration through the RhoA/ROCK Pathway.

ARHGAP29 通过 RhoA/ROCK 途径调节角质形成细胞迁移。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Rhea,Lindsey;Garnica,Bailey;Reeb,Tanner;Dunnwald,Elliot;Dunnwald,Martine
• 通讯作者: Dunnwald,Martine