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.