Role of skin injury-induced inflammation in wound healing

项目总结 像糖尿病足溃疡(DFU)这样的慢性皮肤创伤是退伍军人的一个严重的医疗问题。高达三分之一 的糖尿病患者发生DFU，这是导致小腿截肢以及皮肤和骨骼截肢的主要原因 感染和死亡的独立风险因素。由于目前的治疗方法有限，而且往往无效，因此 迫切需要更好地了解发病机制，以便确定新的和改进的治疗慢性疾病的方法 糖尿病和其他疾病状态下的伤口。反复皮肤损伤和皮肤炎症是相互独立的 与DFU的发病机制有关；然而，关于皮肤损伤和炎症的认识存在空白 在糖尿病(和健康)皮肤中相互作用，以及这种相互作用如何损害伤口愈合。我们最近 确定了一种由机械性皮肤损伤激活的炎症反应，并将其称为皮肤 损伤诱导的炎症反应。我们的初步数据表明，IL-1信号启动了这种反应 并参与了DFU的发病机制。该项目的目标是确定IL-1信号如何调节 皮肤损伤引发炎症反应，促进伤口正常愈合和受损 2型糖尿病小鼠模型的伤口愈合。我们的中心假设是IL-1信号激活皮肤 在正常和糖尿病伤口愈合过程中，损伤诱导的炎症反应和促进瘢痕形成 这种失调的IL-1信号会放大炎症，损害糖尿病伤口的愈合。目标1将 角质形成细胞来源的IL-1和IL-1受体信号在正常皮肤创面愈合中的作用 并确定干扰IL-1信号是否减少了瘢痕形成并促进了正常伤口愈合。目标2 将研究IL-1和IL-1受体信号在2型糖尿病小鼠模型中的作用 确定干扰IL-1信号是否促进糖尿病伤口愈合。目标3将使用体外培养的人 从健康和糖尿病患者的皮肤中确定IL-1和血糖控制对皮肤的贡献 损伤诱导的炎症反应转录组在整个皮肤组织和在单细胞水平。这 该项目将确定IL-1/IL-1R1轴激活在健康和健康人群皮肤损伤诱导的炎症中的作用 糖尿病人和小鼠皮肤以及伤口愈合过程中IL-1/IL-1R1信号的后果。这 再加上在这些研究中发现新的分子靶点，将有助于进一步的研究和 开发新的治疗方法，以促进糖尿病和其他疾病状态下的伤口愈合。

PROJECT SUMMARY Chronic skin wounds like diabetic foot ulcers (DFU) are a serious medical problem in Veterans. Up to one third of patients with diabetes develop DFU, a leading cause of lower leg amputations as well as skin and bone infections and an independent risk factor for death. As current therapies are limited and often ineffective, there is a critical need to better understand pathogenesis in order to identify new and improved therapies for chronic wounds in diabetes and other disease states. Repetitive skin injury and skin inflammation are independently implicated in DFU pathogenesis; however, gaps in knowledge exist regarding how skin injury and inflammation interact in diabetic (and healthy) skin and how this interaction could impair wound healing. We recently identified an inflammatory response that is activated by mechanical skin injury and refer to this as the skin injury-induced inflammatory response. Our preliminary data suggest the IL-1 signaling initiates this response and contributes to DFU pathogenesis. The objective of this project is to determine how IL-1 signaling regulates the skin injury-induced inflammatory response and contributes to normal wound healing as well as impaired wound healing in a mouse model of type 2 diabetes. Our central hypothesis is IL-1 signaling activates the skin injury-induced inflammatory response and promotes scarring during normal and diabetic wound healing and that dysregulated IL-1 signaling amplifies inflammation and impairs diabetic wound healing. Aim 1 will determine the role of keratinocyte-derived IL-1 and IL-1 receptor signaling during normal skin wound healing in mice and determine if disrupting IL-1 signaling reduces scarring and enhances normal wound healing. Aim 2 will examine the role of IL-1 and IL-1 receptor signaling in a mouse model of type 2 diabetes mellitus and determine if disrupting IL-1 signaling enhances diabetic wound healing. Aim 3 will use ex vivo-cultured human skin from healthy and diabetics subjects to define the contributions of IL-1 and blood sugar control to the skin injury-induced inflammatory response transcriptome in whole skin tissue and at the level of single cells. This project will define the role of IL-1/IL-1R1 axis activation on skin injury-induced inflammation in healthy and diabetic human and mouse skin and the consequences of IL-1/IL-1R1 signaling during wound healing. This coupled with identification of new molecular targets during these studies will facilitate further research and development of new therapies to promote wound healing in diabetes and other disease states.