IRF6 and Wound Healing

项目摘要 每一次被切开，都会造成一个伤口。在美国进行了超过7000万例手术 2000年，超过50%的美国人需要术后伤口护理。此外，慢性伤口影响650万人 患者每年花费超过250亿美元用于治疗。伤口愈合对人类的经济和社会影响 我们的社会需要进一步的研究，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）的遗传变异可以识别 个体有不良愈合结果的风险，这表明IRF6是一种新的组织转录调节因子， 修复.我们有证据表明，在小鼠中，Irf6的下调和上调改变了不同的方面， 组织修复，这表明适当的稳态Irf6需要充分愈合。此外，委员会认为， Irf6缺陷型角质形成细胞关闭体外划痕伤口的能力受损。这些角质细胞 与野生型相比，它们更大，更圆，并表现出更多的应力纤维和增加的RhoA活性 细胞RhoA特异性激活蛋白Arhgap 29在伤口愈合过程中上调， 在缺乏Irf6的组织中，使其成为完美的下游效应器。虽然很明显，IRF6的表达是 对于正常的伤口愈合是重要的，基本上对其细胞或分子机制一无所知。 行动上这项研究的总体目标是利用我们独特的小鼠和患者细胞， 结合独特的鼠模型，以阐明IRF6如何有助于组织修复。我们假设 IRF6通过Arhgap 29抑制RhoA GT3来调节表皮迁移。我们提出两个目标 为了检验这一假设：1）鉴定IRF6依赖性角质形成细胞迁移的机制，和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，并提供一个新的研究方向。 确定伤口愈合中涉及的治疗靶点的基础。

Project Summary 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.