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: 7655298
• 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/7655298
• 关键词: Biology; Birth; Breathing; Cells; Cicatrix; Cleaved cell; Cleft Lip; Clinic; 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; 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; overexpression; 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级联的事件，这些事件与包括胚胎上皮融合的形态发生过程具有潜在的重要关系。实际上，这两个过程可能会共享共同的因素以关闭孔并形成接缝。一个潜在因素是干扰素调节因子6（IRF6）。以前，IRF6被证明对于人类嘴唇和口感的发展至关重要。该提案的目的是评估皮肤伤口愈合中的IRF6。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的分化和增殖，这是皮肤和口感中的上皮细胞类型。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IRF6。我们对该提案的最初启发是，在IRF6中有突变的Van der Woude患者在手术修复裂缝后比患有唇lip或pape的人（并且有两个未突破的IRF6副本）更可能患有更差的结果。 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）缺乏IRF6小鼠的角质形成细胞在体外迁移受损。因此，我们的数据表明，IRF6处于已知与伤口愈合，TGFB信号传导和中间丝之间的两种途径之间的支点，并支持IRF6对于伤口愈合至关重要的假设。在特定目标1中，我们将在正常皮肤伤口愈合过程中确定IRF6的空间和时间表达，并测试该表达是否需要TGFB3。在特定的目标2中，我们将利用人类和鼠组织和细胞来确定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人体在受伤后和发育过程中闭合孔和形成接缝的机制之一的理解。这将为识别伤口愈合的治疗靶标提供机会，也许还可以干预和纠正源自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，这是与健康相关成本增加的主要原因。我们希望更好地了解身体在受伤和发育过程中如何关闭孔和形成接缝。