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

有助于抑制糖尿病足和腿部静脉溃疡伤口愈合的核心机制

• 批准号: 10631934
• 负责人: Jamie Lee Burgess
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631934
• 关键词: Affect; Amputation; Animal Model; Apoptosis; Aryl Hydrocarbon Receptor; Bacterial Infections; Benign; Bioinformatics; Biological Assay; Cell Cycle Progression; Cells; Characteristics; Clinical; Complex; Complications of Diabetes Mellitus; Coupled; Data; Development; Diabetic Foot; Diabetic Foot Ulcer; Diagnostic; Disease; Economic Burden; Epidermis; Etiology; Fibroblast Growth Factor Receptor 2; Fibrosis; Flow Cytometry; Foundations; Genetic Transcription; Goals; Health Care Costs; Healthcare Systems; Histopathology; Human; Immune response; Impaired healing; Impairment; Infection; Inflammatory Response; Knowledge; Laboratories; Leg; Leg Ulcer; Maps; Mediating; MicroRNAs; Microbial Biofilms; Modeling; Molecular; Morbidity - disease rate; National Institute of Diabetes and Digestive and Kidney Diseases; Organ; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Persons; Phenotype; Population; Prevention; Proliferating; Quality of life; Receptor Signaling; Regulatory Pathway; Role; STAT1 protein; Sampling; Side; Signal Pathway; Signal Transduction; Skin; Staphylococcus aureus; Staphylococcus epidermidis; Stat3 protein; Testing; Tissue Sample; Tissues; Ulcer; Venous; Wound Infection; Wound models; angiogenesis; antimicrobial; cell motility; chronic wound; commensal bacteria; effective therapy; fighting; genetic signature; healing; host microbiome; human tissue; inhibitor; innovation; insight; methicillin resistant Staphylococcus aureus; microbiome; migration; mortality; new therapeutic target; novel; pathogen; receptor; recurrent infection; repaired; response; skin microbiome; targeted treatment; therapeutic target; therapy development; transcriptome; transcriptome sequencing; transcriptomics; treatment strategy; wound; wound closure; wound environment; wound healing; wound treatment

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.

项目摘要 糖尿病足溃疡（DFU）和下肢静脉溃疡（VLU）是常见的慢性伤口，具有使人衰弱的影响 患者的生活质量、发病率和死亡率，给医疗保健系统带来重大经济负担 国际吧慢性伤口的有效治疗方法很少。它们的效力进一步受到 和感染复发。虽然病因不同，但DFU和VLU具有共同的特征 例如过度增殖、非迁移性表皮、纤维化、血管生成减少和失调的表皮细胞， 炎症反应。此外，一个主要的共同特征是微生物组从良性转变为良性。 从细菌到病原体。不幸的是，缺乏动物模型， 概括了人类慢性伤口状况阻碍了对这种复杂宿主微生物组的理解 互动因此，我们的实验室专注于分析人体组织样本，以破译核心分子 导致DFU和VLU的非愈合表型的途径。我们使用了DFU的组织样本 和VLU（n=19），RNAseq和生物信息学分析，以确定核心慢性伤口转录组常见 这两种慢性伤口的治疗方法对这种新颖独特的核心慢性伤口基因特征的分析表明， 抑制可能由微生物组调节的两种宿主反应途径：芳烃 受体（AHR）信号通路和信号转导和转录激活因子3（STAT3）通路。 由于这些途径与宿主抗微生物反应以及细胞迁移有关， 增殖，我们假设AHR和STAT3信号通路的抑制是由 微生物组失调并损害慢性伤口愈合。因此，本提案的目的是了解 伤口微生物组调节AHR（Aim 1）和STAT3（Aim 2）通路的机制， DFU和VLU。我们将使用一种综合方法，包括患者的伤口样本， 细胞和人类皮肤离体伤口感染模型。通过使用与患者相关的伤口模型，我们将大大 进一步了解伤口微生物组调节宿主反应的机制， 慢性伤口，并有助于抑制愈合。反过来，理解 微生物组与AHR和STAT3通路的研究将进一步确定伤口感染的新治疗靶点。 预防和治疗伤口感染将对DFU和DFU的愈合结果产生重大影响。 VLU，降低小腿截肢率、发病率和死亡率。

项目成果

Chronic wound microenvironment mediates selection of biofilm-forming multi drug resistant Staphylococcus epidermidis with capability to impair healing.

慢性伤口微环境介导对形成生物膜的多重耐药性表皮葡萄球菌的选择，从而损害愈合。

• DOI: 10.21203/rs.3.rs-2562300/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Dinic,Miroslav;Verpile,Rebecca;Meng,Jingjing;Marjanovic,Jelena;Burgess,JamieL;Plano,Lisa;Hower,Suzanne;Thaller,SethR;Banerjee,Santanu;Lev-Tov,Hadar;Tomic-Canic,Marjana;Pastar,Irena
• 通讯作者: Pastar,Irena