Circulating urinary microRNAs as systemic biomarkers of healing outcomes in diabetic foot ulcers

循环尿 microRNA 作为糖尿病足溃疡愈合结果的系统生物标志物

• 批准号: 10658981
• 负责人: Rivka C. Stone
• 金额: $ 39.88万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-04 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10658981
• 关键词: Affect; Amputation; Area; Biological Assay; Biological Markers; Chronic; Clinical; Clinical Management; Complications of Diabetes Mellitus; Custom; Data; Detection; Development; Diabetes Mellitus; Diabetic Foot; Diabetic Foot Ulcer; Enrollment; Funding; Funding Mechanisms; Infrastructure; Intervention; Laboratories; Measures; Methods; MicroRNAs; Modeling; Monitor; Morbidity - disease rate; National Institute of Diabetes and Digestive and Kidney Diseases; Outcome; Pain; Patients; Phase; Physicians; Predictive Value; Prognostic Marker; Prospective cohort; Protocols documentation; Qualifying; Quality of life; ROC Curve; Regression Analysis; Reproducibility; Risk; Risk Factors; Running; Sampling; Scientist; Small RNA; Specificity; Systemic disease; Testing; Training; Ulcer; Urine; Validation; biomarker panel; biomarker validation; candidate marker; chronic ulcer; circulating microRNA; clinical implementation; cohort; cost effective; data reduction; design; disability; foot; healing; improved; meetings; miRNA expression profiling; microRNA biomarkers; mortality; nano-string; open wound; participant enrollment; point of care; predictive modeling; prognostic; prognostic model; prospective; response; standard of care; treatment response; urinary; wound closure

Project summary Diabetic foot ulcers (DFUs) are a widespread, serious, and common complication of diabetes. Diabetes-related amputations are associated with disability, drastic reduction in quality of life, high morbidity and resulting alarming mortality rate of 35% over 5 years. Non-invasive detectable biomarkers that correlate with healing outcomes of DFU are critically needed for early targeting of hard-to-heal ulcers for advanced interventions beyond standard of care (SOC) therapy, as well as for timely monitoring of response to treatment. Preliminary evidence developed in our laboratory supports circulating urinary microRNAs (miRNAs) as detectable biomarkers for DFUs and other diabetes-associated complications; these miRNAs can be isolated and quantified from urine in a technically robust and reproducible manner. Utilizing an R61/R33 funding mechanism in response to RFA-DK-21-001, this project will capitalize upon patient enrollment in the existing protocols and infrastructure of the Diabetic Foot Consortium to develop a practical, quantitative, non-invasive, cost-effective prognostic biomarker comprised of a urinary microRNA subset that, when assessed in patients at baseline, accurately and reliably differentiates DFUs that have the capacity to heal with SOC from those that do not. Specifically, in R61/ Exploratory phase, a combined data reduction and prognostic modeling approach will be applied to narrow the determine miRNome of top 10-20 miRNA parameters that predict DFU clinical healing outcomes at Week 12. Sensitivity, specificity, and accuracy of predictions will be evaluated and with successful completion of R61 milestones the model will progress to the R33/Validation phase, in which the custom miRNA subset biomarker panel will be interrogated for its ability to predict healing outcomes in a prospectively enrolled cohort of 100 additional patients with open DFUs. Results of the Validation phase will yield a biomarker ready for submission for FDA biomarker qualification approval and subsequent direct clinical implementation as a point-of-care assessment to guide clinical management decisions and improve wound closure outcomes, thereby reducing associated DFU morbidity and mortality.

项目摘要 糖尿病足溃疡（DFU）是糖尿病的广泛，严重和常见的并发症。与糖尿病有关 截肢与残疾，生活质量的急剧降低，发病率高和结果有关 在5年内，令人震惊的死亡率为35％。与愈合相关的非侵入性可检测生物标志物 DFU的结果至关重要的是要早期针对高级干预措施的难以割溃疡 除了护理标准（SOC）疗法以及及时监测对治疗的反应。初步的 在我们的实验室中提出的证据支持循环尿道（miRNA）作为可检测的 DFU和其他糖尿病相关并发症的生物标志物；这些miRNA可以隔离，并且 以技术强大且可重复的方式从尿液中量化。利用R61/R33资金机制 为了响应RFA-DK-21-001，该项目将利用现有协议的患者入学和 糖尿病足财团的基础设施，发展实用，定量，无创，成本效益 预后生物标志物由尿中microRNA子集组成，当在基线时对患者进行评估时 准确，可靠地区分了有能力与SOC治愈的能力与没有能力的DFU。 具体而言，在R61/探索阶段中，合并的数据还原和预后建模方法将是 应用于缩小预测DFU临床愈合的前10-20个miRNA参数的miRNOME 在第12周的结果。将评估敏感性，特异性和预测的准确性，并随之评估 成功完成R61里程碑该模型将发展到R33/验证阶段，其中 自定义miRNA子集生物标志物面板将因其预测治愈结果的能力而受到质疑 前瞻性地招募了100名开放式DFU的患者。验证阶段的结果将 产生一个生物标志物，准备提交FDA生物标志物资格批准和随后的直接临床 实施作为指导临床管理决策并改善伤口的护理点评估 结束结果，从而降低了相关的DFU发病率和死亡率。