Dissecting the contributions of Langerhans cell to cutaneous wound healing

项目摘要 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 愈合伤口给美国医疗保健系统造成了370亿美元的负担。随着该国人口的持续增长 随着年龄的增长和糖尿病的日益严重，这些数字预计将持续上升。的发展 减轻不愈合伤口的治疗策略依赖于对机制的基本理解 调节皮肤修复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，朗格汉斯细胞（LC），皮肤驻留免疫细胞的子集，是必不可少的， 成功的伤口愈合，特别是新血管的形成。然而，人们对 LCs在皮肤修复过程中的特殊功能。使用基因工程小鼠模型， 可以特异性地靶向细胞死亡或特定基因的缺失，我们建议调查时间和 LC介导伤口愈合的分子机制。我们假设在对皮肤的反应中 损伤时，LC分泌血管内皮生长因子A（VEGFa）进入皮肤宏观环境， 促进血管生成和皮肤修复。这一假设基于：1）我们的数据表明，在没有LC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， LC在伤口愈合过程中的多个时间点表达VEGFa基因。在本项目中，我们将定义 LC在伤口愈合的增殖阶段指导的特定细胞过程，以及 分子需要执行这些功能之一：血管重建。

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.