The Role of the Microbiome in Diabetic Foot Ulcers

微生物组在糖尿病足溃疡中的作用

• 批准号: 10523375
• 负责人: Brian M Schmidt
• 金额: $ 19.49万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523375
• 关键词: Address; Adult; Affect; American; Amputation; Antibiotic Therapy; Award; Bacteria; Biological Markers; Biometry; Caring; Clinical; Clinical Research; Clinical Trials; Communicable Diseases; Complications of Diabetes Mellitus; Consensus; Controlled Study; Cross-Sectional Studies; Data Coordinating Center; Debridement; Dependence; Development; Development Plans; Diabetes Mellitus; Diabetic Foot; Diabetic Foot Ulcer; Ecology; Event; Foundations; Functional disorder; Future; Genetic Materials; Goals; Health; Individual; Infection; Infrastructure; Institutes; Interruption; Intervention; Intervention Studies; Investigation; Laboratories; Lead; Leadership; Longitudinal Studies; Lower Extremity; Mentors; Metagenomics; Michigan; National Institute of Diabetes and Digestive and Kidney Diseases; Neuropathy; Observational Study; Pathogenesis; Patients; Performance; Physicians; Physiological; Physiology; Podiatry; Positioning Attribute; Practice Guidelines; Process; Public Health Schools; Research; Research Methodology; Research Personnel; Risk; Risk Factors; Role; Scientific Advances and Accomplishments; Scientist; Standardization; Sterile coverings; Techniques; Technology; Testing; Therapeutic; Training; United States; Universities; University resources; Variant; Vulnerable Populations; base; biobank; biomarker validation; career development; chronic ulcer; clinical care; clinical research site; clinical trial implementation; cohort; design; evidence base; experience; healing; host microbiome; improved; improved outcome; ineffective therapies; microbial; microbiome; microbiota; modifiable risk; mortality; new technology; next generation sequencing; non-diabetic; novel; pathogen; patient oriented; prevent; programs; public health relevance; risk stratification; skills; skin ulcer; standard of care; targeted treatment; tool; validation studies; wound; wound healing

PROJECT SUMMARY / ABSTRACT Diabetic foot ulcers (DFUs) remain one of the most common complications of diabetes mellitus (DM) and are the leading cause of lower extremity amputation with every sixth individual suffering an early demise as a result. Many complicating factors of DM contribute and interrupt normal physiologic healing processes. Five-year mortality after DFU occurrence is 40% and is 10-fold higher than non-diabetic cohorts. Despite major scientific advances in the understanding of wound healing physiology, only one-half of DFUs heal when standard of care is met. This unfortunate truth highlights the need to identify modifiable risk factors for healing that may be the cause of non-healing events in the treatment of DFUs. The DFU microbiome may represent these important modifiable risk factors in obtaining wound healing. The DFU microbiome is comprised of the genetic material of all the microbiota that cohabitate the DFU. Past observational studies have implicated one or more of these microbiotas as contributors to non-healing, but these studies have suffered from significant design limitations and lack consensus assessment. Most studies were only cross-sectional in design and focused primarily on non-infected DFUs. Furthermore, these studies did not collect biospecimens consistently across studies. In this career development, we propose to understand the role of the microbiome in the pathogenesis of DFU and understand the trajectories of the microbiome across DFU wound progression in three aims. Aim 1 will perform a cross-sectional cohort of patients with DFU to compare the microbiome of those with DFI to infection-free DFUs using metagenomics next generation sequencing (mNGS). Aim 2 will leverage this initial cohort to longitudinally determine the temporal relationships and interactions between pathogen presence, wound healing, and development of infection. Aim 3 will assess the clinical feasibility of using mNGS to predict antibiotic therapy against identified pathogens in infected DFU in a pilot clinical trial. The overall goal of this project is to identify modifiable risk factors in the DFU microbiome that will lead to interventional clinical trials to prevent and/or treat DFUs. This proposal is essential to my career development. I will become an independent clinical researcher with expertise in diabetic foot complications. The formal training in clinical trial execution and biostatistics will provide practical experiences and will set the stage for successful completion of not only this project, but also of future investigations. The clinical trial component of my career development will allow me to take the results from this study and seamlessly transition into interventional studies that will lead to new treatments for patients suffering from DFUs. Drs. Rodica Pop-Busui and Keith Kaye are ideally suited as mentors for this project with their complementary expertise in diabetes, neuropathy, infectious disease, and clinical trial experience. The vast resources of the University of Michigan, including the Michigan Institute for Clinical and Health Research and the School of Public Health, will significantly contribute to the successful completion of this proposal.

项目概要/摘要 糖尿病足溃疡（DFU）仍然是糖尿病（DM）最常见的并发症之一， 这是下肢截肢的主要原因，六分之一的人因此过早死亡。 糖尿病的许多复杂因素会促进或中断正常的生理愈合过程。五年 DFU 发生后的死亡率为 40%，比非糖尿病人群高 10 倍。尽管重大科学 对伤口愈合生理学理解的进步，在标准护理下只有一半的 DFU 能够愈合 已满足。这个不幸的事实凸显了需要识别可改变的治疗风险因素，这些因素可能是 DFU 治疗中不愈合事件的原因。 DFU 微生物组可能代表了伤口愈合过程中这些重要的可改变的风险因素。这 DFU 微生物组由与 DFU 共存的所有微生物群的遗传物质组成。过去的 观察性研究表明这些微生物群中的一种或多种是导致不愈合的原因，但这些 研究受到重大设计限制且缺乏共识评估。大多数研究是 仅采用横截面设计，主要关注未受感染的 DFU。此外，这些研究并没有 在各个研究中一致地收集生物样本。在这个职业发展中，我们建议了解角色 了解微生物组在 DFU 发病机制中的作用，并了解微生物组在 DFU 中的轨迹 三个目标的伤口进展。目标 1 对 DFU 患者进行横断面队列研究以进行比较 使用宏基因组学下一代测序将 DFI 患者的微生物组转变为无感染 DFU （mNGS）。目标 2 将利用这个初始队列来纵向确定时间关系和 病原体存在、伤口愈合和感染发展之间的相互作用。目标 3 将评估 使用 mNGS 预测针对感染 DFU 中已识别病原体的抗生素治疗的临床可行性 试点临床试验。该项目的总体目标是确定 DFU 微生物组中可改变的风险因素， 将导致预防和/或治疗 DFU 的介入临床试验。 这个建议对我的职业发展至关重要。我将成为一名独立的临床研究员 糖尿病足并发症的专业知识。临床试验执行和生物统计学的正式培训将提供 实践经验，不仅为本项目的成功完成奠定了基础，也为未来的项目奠定了基础 调查。我职业发展的临床试验部分将使我能够从中获得结果 研究并无缝过渡到介入研究，这将为患者带来新的治疗方法 来自 DFU。博士。 Rodica Pop-Busui 和 Keith Kaye 非常适合担任该项目的导师，他们的 糖尿病、神经病、传染病和临床试验经验方面的互补专业知识。广阔的 密歇根大学的资源，包括密歇根临床与健康研究所和 公共卫生学院将为该提案的成功完成做出重大贡献。