Multiple targets for beta adrenergic antagonist mediate wound healing

β 肾上腺素能拮抗剂的多个靶点介导伤口愈合

• 批准号: 10482306
• 负责人: Roslyn Rivkah ISSEROFF
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10482306
• 关键词: Adrenergic Antagonists; Adrenergic beta-Antagonists; Affect; Algorithms; Amputation; Bacteria; Bioinformatics; Biological Markers; Caring; Case Report Form; Catecholamines; Cessation of life; Clinical; Clinical Data; Clinical Trials; Complication; Culture Techniques; Data; Databases; Debridement; Diabetes Mellitus; Diabetic Foot Ulcer; Drug Targeting; Early Intervention; Expenditure; Funding; Gene Expression; Genes; Genetic Transcription; Goals; Growth; Healthcare Systems; Human; Immune response; In Vitro; Infection; Inflammatory; Inflammatory Response; Intervention; Leg; Machine Learning; Mediating; Microbial Biofilms; Molecular; Molecular Analysis; Molecular Mechanisms of Action; Osteomyelitis; Pathway interactions; Patients; Pharmaceutical Preparations; Proliferating; RNA; Randomized, Controlled Trials; Reporting; Risk; Surface; Swab; Systems Biology; Techniques; Technology; Testing; Time; Timolol; Tissues; Topical application; Transcript; Ulcer; Virulence Factors; Visit; Work; bacterial metabolism; beta-adrenergic receptor; blind; chronic ulcer; chronic wound; classification algorithm; cohort; comparison control; druggable target; effective therapy; efficacy evaluation; healing; improved; large datasets; metatranscriptomics; microbial; microbiome; microbiota; non-healing wounds; prediction algorithm; predictive modeling; response; standard care; standard of care; targeted treatment; transcriptome; transcriptome sequencing; transcriptomics; wound; wound healing

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.

糖尿病足溃疡（DFU）是15-25%的糖尿病患者的并发症， 他们有传播感染、骨髓炎、截肢和死亡的危险。有效 增强愈合和限制DFU的可怕后果的治疗仍然是未满足的需求。 据报道，局部应用噻吗洛尔（一种β肾上腺素能受体拮抗剂）可改善 DFU和其他慢性伤口的愈合。它的机制并不好 了解，有证据表明，药物的目标都主机和伤口 微生物群我们正在进行的VA资助的随机对照试验，以确定局部 应用噻吗洛尔改善DFU愈合提供了一个独特的机会，以检查分子 在一个完全注释的接受药物治疗的患者队列中， 对照拟议工作的目标之一是发现介导 噻吗洛尔在改善慢性伤口愈合和限制细菌生长和生物膜方面的作用 阵特异性目标1将生成处理组和对照组的元转录组特征 患者的伤口组织和伤口微生物群，并使用生物信息学技术来了解 治疗的目标。考虑到愈合和非愈合患者的队列， 2将使用时间转录组数据的机器学习来开发预测算法 对于那些有可能通过标准护理治愈的溃疡和那些没有治愈的溃疡。由于所有 细菌菌种对噻吗洛尔无反应，生长和生物膜形成减少，特异性 目的3将检测从不愈合伤口中提取的临床分离培养物的分子水平， 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， 廉价和广泛可用的药物，用于改善慢性伤口的愈合，并将提供 一种预测算法，用于识别其伤口不太可能以标准愈合的患者， 护理，提供了一个机会，早期干预与先进的治疗。