IRF6 and Wound Healing

 描述（由申请人提供）：每次切开，都会造成伤口。2000年在美国进行了超过7000万例手术，其中超过50%需要术后伤口护理。此外，慢性伤口影响650万患者，每年治疗费用超过250亿美元。伤口愈合对我们社会的经济和社会影响需要进一步研究，以更好地了解调节组织修复的机制。在以前的研究中，我们已经表明，干扰素调节因子6（IRF6）的遗传变异识别个体的风险为不良愈合结果，这表明IRF6是一种新的组织修复的转录调节因子。我们有证据表明，下调和上调的Irf6在小鼠中改变组织修复的不同方面，这表明，适当的稳态的Irf6是需要充分愈合。此外，Irf6缺陷型角质形成细胞在其闭合体外划痕伤口的能力方面受损。这些角质细胞 更大，更圆，并表现出更多的应力纤维和增加的RhoA活性相比，野生型细胞。Arhgap29是一种RhoA特异性激活蛋白，在伤口愈合过程中上调，在Irf6缺陷组织中下调，使其成为完美的下游效应子。虽然IRF6的表达对于正常的伤口愈合是重要的，但基本上对其细胞或分子作用机制一无所知。本研究的总体目标是利用我们独特的小鼠和患者细胞，结合独特的小鼠模型，阐明IRF6如何有助于组织修复。我们假设IRF6通过抑制RhoA GT3通过Arhgap29调节表皮迁移。我们提出了两个目的来验证这一假设：1）确定IRF6依赖性角质形成细胞迁移的机制，2）确定ARHGAP 29如何介导IRF6的功能。该项目的成功完成将确立IRF6在组织修复中的贡献，并为确定参与伤口愈合的治疗靶点提供基础。

 DESCRIPTION (provided by applicant): 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.