Role of Interferon Regulatory Factor 6 (Irf6) in cutaneous wound healing

干扰素调节因子 6 (Irf6) 在皮肤伤口愈合中的作用

• 批准号: 7448426
• 负责人: MARTINE DUNNWALD
• 金额: $ 7.5万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-07 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7448426
• 关键词: Biology; Birth; Breathing; Cells; Cicatrix; Cleaved cell; Cleft Lip; Clinic; Closure; Craniofacial Abnormalities; Cutaneous; Data; Dermal; Development; Disease; Embryo; Embryonic Development; Epidermis; Epithelial; Epithelial Cells; Event; Exhibits; Failure; Family; Functional disorder; Genes; Goals; Healed; Human; Impaired wound healing; In Vitro; Individual; Information Resources; Injury; Interferons; Intermediate Filaments; Keratin; Knockout Mice; Lip structure; Medial; Molecular; Morphogenesis; Mus; Mutate; Mutation; Operative Surgical Procedures; Outcome; Palate; Pathway interactions; Patients; Positioning Attribute; Process; Protein Overexpression; Role; Signal Transduction; Skin; Staging; Testing; Time; Tissues; Tongue; Transforming Growth Factor beta; Ursidae Family; Van der Woude syndrome; Wound Healing; adhesion process; cell motility; cell type; cleft lip and palate; cost; disease-causing mutation; healing; in vivo; innovation; interest; keratinocyte; keratinocyte differentiation; member; migration; palatal shelves; popliteal pterygium syndrome; receptor; repaired; therapeutic target; transforming growth factor beta3; wound

DESCRIPTION (provided by applicant): The healing of skin involves an ordered cascade of events that bears a potentially significant relationship to morphogenetic processes including embryological epithelial fusion. In fact, these two processes may share common factors to close holes and form seams. One potential factor is Interferon Regulatory Factor 6 (IRF6). Previously, IRF6 was shown to be essential for the development of the lip and palate in humans. The objective of this proposal is to evaluate Irf6 in cutaneous wound healing. In support of this hypothesis, Irf6 was shown to be necessary for skin development, and regulate differentiation and proliferation of keratinocytes, the epithelial cell type in skin and palate. Our long term goal is to understand the role of IRF6 in morphogenesis and tissue repair. The central hypothesis for our project is that proper wound healing requires appropriate spatial and temporal expression of Irf6. Our initial inspiration for this proposal is that Van der Woude patients, who have a mutation in IRF6, are more likely to have a worse outcome following surgical repair of cleft than individuals with cleft lip or palate (and have two non-mutated copies of IRF6). Subsequently preliminary data showed that 1) induction of Irf6 expression in the palate requires Tgfb3, a gene involved in scar-free wound healing 2) Irf6 is expressed in the spinous layer of the epidermis, 3) Irf6 regulates keratinocyte differentiation and proliferation, 4) Irf6 regulates expression of Krt14 and Krt17, keratins known to be involved in wound healing, and 5) keratinocytes from mice deficient for Irf6 have impaired migration in vitro. Thus, our data suggests that Irf6 is at the fulcrum between two pathways known to be involved in wound healing, Tgfb signaling and intermediate filaments, and supports the hypothesis that Irf6 is essential for wound healing. In Specific Aim 1, we will determine the spatial and temporal expression of Irf6 during normal cutaneous wound healing, and test whether this expression requires Tgfb3. In Specific Aim 2, we will determine the role of Irf6 in wound healing in vitro and in vivo, taking advantage of human and murine tissues and cells. Successful completion of these studies will increase our understanding of one of the mechanisms by which the body closes holes and forms seams following injury and during development. This will provide opportunities to identify therapeutic targets for wound healing, and perhaps also to intervene and correct abnormalities that originate from a failure in embryonic fusions. This proposal will evaluate the role of Interferon Regulatory Factor 6 in cutaneous wound healing, a major cause of rising health-related costs. We hope to better understand how body closes holes and forms seams following injury and during development.

描述（由申请人提供）：皮肤的愈合涉及一系列有序的事件，这些事件与包括胚胎上皮融合在内的形态发生过程具有潜在的重要关系。事实上，这两种工艺可能有共同的因素来封闭孔洞和形成接缝。干扰素调节因子 6 (IRF6) 是一种潜在因素。此前，IRF6 已被证明对于人类嘴唇和上颚的发育至关重要。该提案的目的是评估 Irf6 在皮肤伤口愈合中的作用。为了支持这一假设，Irf6被证明是皮肤发育所必需的，并调节角质形成细胞（皮肤和上颚的上皮细胞类型）的分化和增殖。我们的长期目标是了解 IRF6 在形态发生和组织修复中的作用。我们项目的中心假设是正确的伤口愈合需要 Irf6 的适当的空间和时间表达。我们对此提议的最初灵感是，IRF6 突变的 Van der Woude 患者在进行唇裂或腭裂手术修复后的结果更有可能比唇裂或腭裂患者（且具有两个非突变 IRF6 副本）更差。随后的初步数据显示，1) Irf6 在上颚表达的诱导需要 Tgfb3，这是一种参与无疤痕伤口愈合的基因 2) Irf6 在表皮棘层中表达，3) Irf6 调节角质细胞分化和增殖，4) Irf6 调节 Krt14 和 Krt17（已知参与伤口愈合的角蛋白）的表达，以及 5) Irf6 缺陷小鼠的角质形成细胞在体外迁移能力受损。因此，我们的数据表明，Irf6 位于已知参与伤口愈合的两条途径（Tgfb 信号传导和中间丝）之间的支点，并支持 Irf6 对于伤口愈合至关重要的假设。在具体目标1中，我们将确定正常皮肤伤口愈合过程中Irf6的空间和时间表达，并测试该表达是否需要Tgfb3。在具体目标 2 中，我们将利用人类和小鼠组织和细胞来确定 Irf6 在体外和体内伤口愈合中的作用。成功完成这些研究将增加我们对身体在受伤后和发育过程中闭合孔洞和形成接缝的机制之一的理解。这将为确定伤口愈合的治疗靶点提供机会，或许还可以干预和纠正胚胎融合失败引起的异常。该提案将评估干扰素调节因子 6 在皮肤伤口愈合中的作用，皮肤伤口愈合是健康相关成本上升的主要原因。我们希望更好地了解身体在受伤后和发育过程中如何闭合孔洞并形成接缝。