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

描述（由申请人提供）：皮肤愈合涉及一系列有序的事件，这些事件与胚胎上皮融合等形态发生过程有潜在的重要关系。事实上，这两个过程可能有共同的因素来关闭孔和形成接缝。一个潜在的因素是干扰素调节因子6 （IRF6）。此前，IRF6被证明对人类嘴唇和上颚的发育至关重要。本提案的目的是评估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（皮肤和腭中的上皮细胞类型）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伤口的正确愈合需要Irf6在空间和时间上的适当表达。我们提出这一建议的最初灵感是，具有IRF6突变的Van der Woude患者在唇裂或腭裂患者（并且具有两个非突变的IRF6拷贝）手术修复后的结果更可能更差。随后的初步数据显示，1)诱导Irf6在腭部表达需要Tgfb3，这是一个参与无疤痕伤口愈合的基因2)Irf6在表皮棘层表达，3)Irf6调节角质形成细胞的分化和增殖，4)Irf6调节Krt14和Krt17的表达，这是已知参与伤口愈合的角蛋白，5)缺乏Irf6的小鼠角质形成细胞在体外迁移受损。因此，我们的数据表明，Irf6处于已知参与伤口愈合的两条通路（Tgfb信号通路和中间丝）之间的支点，并支持Irf6对伤口愈合至关重要的假设。在Specific Aim 1中，我们将确定Irf6在正常皮肤伤口愈合过程中的时空表达，并测试这种表达是否需要Tgfb3。在Specific Aim 2中，我们将利用人类和小鼠的组织和细胞，确定Irf6在体外和体内伤口愈合中的作用。这些研究的成功完成将增加我们对身体在受伤和发育过程中关闭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，也可能干预和纠正源于胚胎融合失败的异常。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，这是与健康相关的成本上升的主要原因。我们希望更好地了解身体在受伤和发育过程中是如何闭合孔洞和形成接缝的。

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.