Core mechanisms that contribute to inhibition of wound healing in diabetic foot and venous leg ulcers

项目摘要 糖尿病足溃疡(DFU)和静脉性腿部溃疡(VLU)是常见的慢性创面，其影响是虚弱的。 对患者的生活质量、发病率和死亡率的影响，给医疗系统带来了重大的经济负担 全世界。对于慢性伤口的有效治疗方法很少。它们的有效性进一步受到存在的限制 和感染的复发。虽然起因不同，但DFU和VLU具有共同的特征 如过度增殖、非迁移性表皮、纤维化、血管生成减少和去调节 炎症反应。此外，微生物群的一个主要共同特征是从良性的 细菌与丰富的病原体共生。不幸的是，缺乏密切相关的动物模型 概述了人类慢性创伤的状况，阻碍了对这个复杂的宿主-微生物群的理解 互动。因此，我们实验室的重点是对人体组织样本进行分析，以破译核心分子。 导致DFU和VLU不可愈合表型的途径。我们用了DFU的组织样本 和VLU(n=19)、RNAseq和生物信息学分析来确定核心慢性伤口转录组的共同 对这两种慢性伤口都适用。对这种新颖而独特的核心慢性伤口基因特征的分析表明 抑制可能受微生物群调节的两条寄主反应通路：芳烃 受体(AHR)信号通路和信号转导与转录激活因子3(STAT3)通路。 由于这些途径与宿主的抗微生物反应以及细胞迁移有关，并且 ，我们假设AHR和STAT3信号通路的抑制是由一种 微生物群失调，损害慢性伤口愈合。因此，这项提议的目标是理解 创伤微生物群调控AHR(Aim 1)和STAT3(Aim 2)途径的机制 DFU和VLU。我们将使用一种综合的方法，包括患者的伤口样本，主要是人类 细胞与人皮肤体外伤口感染模型。通过使用与患者相关的创伤模型，我们将大大 进一步了解创伤微生物群调节寄主反应的机制 慢性创伤，并有助于抑制愈合。反过来，理解 具有AHR和STAT3通路的微生物组将进一步确定伤口感染的新治疗靶点。 伤口感染的预防和治疗将对DFU和DFU的愈合结果产生重大影响 VLU，减少小腿截肢、发病率和死亡率。

Project Summary Diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs) are prevalent chronic wounds with a debilitating impact on patient quality of life, morbidity, and mortality, imposing a major economic burden to healthcare systems worldwide. Effective treatments for chronic wounds are scarce. Their efficacy is further limited by the presence and recurrence of infection. While arising from different etiologies, both DFUs and VLUs share common features such as a hyperproliferative, non-migratory epidermis, fibrosis, decreased angiogenesis, and a de-regulated inflammatory response. In addition, a major common characteristic is a shift in the microbiome from benign commensal bacteria to an abundance of pathogens. Unfortunately, a lack of animal models that closely recapitulates the human chronic wound condition impedes the understanding of this complex host-microbiome interaction. Thus, our laboratory focuses on the analyses of human tissue samples to decipher core molecular pathways that contribute to the non-healing phenotype of DFUs and VLUs. We used tissue samples from DFUs and VLUs (n=19), RNAseq and bioinformatic analysis to determine a core chronic wound transcriptome common for both types of chronic wounds. Analyses of this novel and unique core chronic wound gene signature indicates suppression of two host response pathways that may be modulated by the microbiome: the aryl hydrocarbon receptor (AHR) signaling pathway and the signal transducer and activator of transcription 3 (STAT3) pathway. As these pathways have been implicated in host antimicrobial response, as well as cell migration, and proliferation, we postulate that suppression of the AHR and STAT3 signaling pathways is mediated by a dysregulated microbiome and impairs chronic wound healing. Thus, the goal of this proposal is to understand the mechanisms by which the wound microbiome modulates the AHR (Aim 1) and STAT3 (Aim 2) pathways in DFUs and VLUs. We will use an integrative approach that includes patients’ wound samples, primary human cells and human skin ex vivo wound infection models. By using patient-relevant wound models, we will greatly advance understanding of the mechanisms by which the wound microbiome modulates the host response in chronic wounds and contribute to the inhibition of healing. In turn, understanding the interaction of the microbiome with the AHR and STAT3 pathways will further identify novel therapeutic targets for wound infections. Prevention and treatment of wound infections will have a major impact on healing outcomes of both DFUs and VLUs, decreasing lower leg amputations, morbidity and mortality.