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