Dissecting the contributions of Langerhans cell to cutaneous wound healing

项目总结 伤口愈合是医疗保健的一个至关重要的领域，但目前的医疗技术未能解决 仅在美国就有650万慢性损伤患者的需求。每年，非 愈合的伤口给美国医疗体系带来了370亿美元的负担。随着这个国家的人口继续增长 随着年龄的增长和糖尿病的加剧，这些数字预计将持续上升。的发展。 减少未愈合伤口死亡的治疗策略依赖于对其机制的基本了解。 调节皮肤修复的物质。这项工作的目标是通过识别信号事件来提高这种理解 驱动成功的皮肤再生，以及负责传播这些信号的特定细胞类型。我们 最近发现，郎格汉斯细胞(LCS)是皮肤常驻免疫细胞的一个子集，对 伤口成功愈合，特别是新血管的形成。然而，人们对此知之甚少。 LCS在皮肤修复中的特殊功能。使用基因工程小鼠模型，在其中LCS 可以特异性地针对细胞死亡或特定基因的缺失，我们建议调查时间和 LCS介导伤口愈合的分子机制。我们假设对皮肤的反应 损伤，LCS分泌血管内皮生长因子A(VEGFA)进入皮肤大环境，以 促进血管生成和真皮修复。这一假设是基于：1)我们的数据表明，在没有LCS的情况下， 修复过程--如血运重建--被完全废除，2)我们的初步发现 在伤口愈合过程中，LC在多个时间点表达VEGFA基因。在本项目中，我们将定义 LCS在创面愈合的增殖期指导的特定细胞过程以及信号转导 执行这些功能之一所需的分子：血运重建。

PROJECT SUMMARY Wound healing is a critically important field of healthcare, yet current medical technologies fail to address the needs of 6.5 million patients who suffer from chronic injuries in the United States alone. Each year, non- healing wounds inflict a $37 billion burden on the U.S. healthcare system. As the country’s population continues to age and become increasingly diabetic, these numbers are projected to consistently rise. The development of therapeutic strategies to mitigate the toll of non-healing wounds relies on basic understanding of the mechanisms that regulate skin repair. The goal of this work is to improve this understanding by identifying signaling events that drive successful skin regeneration, and specific cell types responsible for propagating those signals. We recently revealed that Langerhans cells (LCs), a subset of skin-resident immune cells, are imperative to successful wound healing, particularly for the formation of new blood vessels. Little is known, however, about the specific function of LCs during cutaneous repair. Using genetically engineered mouse models in which LCs can be specifically targeted for cell death or deletion of specific genes, we propose to investigate the timing and molecular mechanisms through which LCs mediate wound healing. We hypothesize that in response to skin injury, LCs secrete Vascular Endothelial Growth Factor A (VEGFa) into the cutaneous macroenvironment to promote angiogenesis and dermal repair. This hypothesis is based on: 1) our data that in the absence of LCs, reparative processes—such as revascularization—are completely abrogated, and 2) our preliminary findings that LCs express the gene for VEGFa at multiple time points during wound healing. In this project, we will define the specific cellular processes that LCs direct during the proliferative phase of wound healing, as well as the signaling molecule required to perform one of these functions: revascularization.