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

描述（由申请方提供）：皮肤愈合涉及一系列有序事件，这些事件与形态发生过程（包括胚胎上皮融合）具有潜在的重要关系。事实上，这两种工艺可能具有共同的因素来闭合孔和形成接缝。干扰素调节因子6（Interferon Regulatory Factor 6，IRF6）以前，IRF6被证明是人类唇和腭发育所必需的。本提案的目的是评价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，适当的伤口愈合需要适当的空间和时间表达的Irf6。我们提出这一建议的最初灵感是，IRF 6突变的货车德沃德患者在唇腭裂手术修复后的结果比唇腭裂患者（并且有两个非突变的IRF 6拷贝）更可能更差。随后的初步数据显示，1）上腭中Irf 6表达的诱导需要Tgfb 3，一种参与无疤痕伤口愈合的基因2）Irf 6在表皮棘层中表达，3）Irf 6调节角质形成细胞分化和增殖，4）Irf 6调节Krt 14和Krt 17的表达，已知角蛋白参与伤口愈合，和5）来自Irf6缺陷小鼠的角质形成细胞在体外具有受损的迁移。因此，我们的数据表明，Irf6是在两个途径之间的支点已知参与伤口愈合，Tgfb信号和中间丝，并支持的假设，Irf6是必不可少的伤口愈合。在特定目标1中，我们将确定正常皮肤伤口愈合过程中Irf6的时空表达，并测试这种表达是否需要Tgfb3。在具体目标2中，我们将利用人类和小鼠组织和细胞，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后和发育过程中关闭漏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，也许还可以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，这是健康相关成本上升的主要原因。我们希望更好地了解身体如何在受伤后和发育过程中关闭漏洞并形成接缝。

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.