Multiple targets for beta adrenergic antagonist mediate wound healing

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Diabetic foot ulceration (DFU) is a complication in 15-25% of patients with diabetes that puts them at risk for disseminated infection, osteomyelitis, leg amputations, and death. An effective therapy to enhance healing and limit the dire consequences of DFU remains an unmet need. Topically applied timolol, a beta adrenergic receptor antagonist, has been reported to improve healing of DFU and other chronic wounds. The mechanisms by which it does, are not well understood, and evidence suggests that the drug targets both the host and the wound microbiota. Our ongoing VA-funded randomized control trial to determine efficacy of topically applied timolol to improve DFU healing provides a unique opportunity to examine the molecular mechanisms of action in a fully annotated cohort of patients treated with the drug compared to controls. One of the goals of the proposed work is to discover pathways that mediate action of timolol in both improving healing of chronic wounds, and of limiting bacterial growth and biofilm formation. Specific Aim 1 will generate meta-transcriptomic signatures of treated and control patients’ wound tissue and wound microbiota, and use bioinformatic techniques to understand targets of the therapy. Given the cohorts of both healing and non-healing patients, Specific Aim 2 will use machine learning of the temporal transcriptomic data to develop a predictive algorithm for ulcers that have the potential to heal with standard of care and those that do not. Since all bacterial species do not respond to timolol with decrease growth and biofilm formation, Specific Aim 3 will examine clinical isolate cultures taken from non-healing wounds for their molecular response to timolol in vitro. These studies will elucidate the mechanism of action of timolol, an inexpensive and widely available drug, for improving healing of chronic wounds, and will provide a predictive algorithm for identifying patients whose wounds are unlikely to heal with standard of care, providing an opportunity for earlier intervention with advanced therapies.