Multiple targets for beta adrenergic antagonist mediate wound healing

糖尿病足溃疡(DFU)是一种并发症，在15%-25%的糖尿病患者中 他们面临播散性感染、骨髓炎、腿部截肢和死亡的风险。卓有成效的 促进愈合和限制DFU的可怕后果的治疗仍然是一个未得到满足的需求。 据报道，局部应用β-肾上腺素能受体拮抗剂噻吗洛尔可改善病情。 DFU和其他慢性伤口的愈合。它所用的机制不是很好 明白，有证据表明这种药物既针对宿主也针对伤口 微生物区系。我们正在进行的由退伍军人事务部资助的随机对照试验，以确定局部应用 应用噻吗洛尔促进DFU愈合提供了一个独特的检查分子的机会 在接受药物治疗的完全注释的患者队列中的作用机制 控制。拟议工作的目标之一是发现调解行动的途径 噻吗洛尔既能促进慢性创面的愈合，又能限制细菌生长和生物被膜 队形。特定目标1将生成治疗和对照的元转录签名 患者的伤口组织和伤口微生物区系，并使用生物信息学技术来了解 治疗的靶点。考虑到治愈和未痊愈患者的队列，具体目标是 2将使用时间转录数据的机器学习来开发预测算法 对于有可能在标准护理下愈合的溃疡和那些不能治愈的溃疡。因为所有的 细菌对噻吗洛尔无反应，生长和生物被膜形成减少，特异性 AIM 3将检查从未愈合的伤口中提取的临床分离培养物的分子 体外对噻吗洛尔的反应。这些研究将阐明噻吗洛尔的作用机制，以及 廉价且可广泛获得的药物，用于改善慢性伤口的愈合，并将提供 一种预测算法用于识别伤口不太可能愈合的患者 护理，为采用先进疗法进行早期干预提供了机会。

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.