The Role of the Microbiome in Diabetic Foot Ulcers

项目摘要/摘要 糖尿病足溃疡(DFU)仍然是糖尿病最常见的并发症之一， 导致截肢的主要原因是每六个人中就有一个人因此而过早死亡。 糖尿病的多种复杂因素参与并干扰了正常的生理愈合过程。五年制 发生DFU后的死亡率为40%，是非糖尿病队列的10倍。尽管有重大科学研究 伤口愈合生理学的研究进展：只有一半的DFU在标准护理下愈合 都被满足了。这一不幸的事实突显了确定可修改的治愈风险因素的必要性，这些因素可能是 DFU治疗中未愈合事件的原因。 DFU微生物群可能代表了这些重要的可修改的危险因素，在获得伤口愈合。这个 DFU微生物组由与DFU共生的所有微生物区系的遗传物质组成。过去时 观察性研究表明，这些微生物中的一个或多个是导致无法愈合的因素，但这些 研究受到显著的设计限制，缺乏一致的评估。大多数研究都是 仅横断面设计，主要集中在非感染的DFU上。此外，这些研究并没有 在所有研究中一致地收集生物标本。在这个职业发展中，我们建议了解一下 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中的运动轨迹 伤口的进展有三个目标。目标1将对DFU患者进行横断面队列比较 应用元基因组学下一代测序方法研究DFI患者对非感染DFU的微生物组 (MNGS)。目标2将利用这一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 应用mNGS预测儿童DFU感染病原体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微生物组中可修改的风险因素 将导致用于预防和/或治疗DFU的干预性临床试验。 这项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 糖尿病足并发症方面的专业知识。临床试验执行和生物统计学方面的正式培训将提供 实践经验，并将为成功完成这一项目以及今后的工作奠定基础 调查。我职业发展中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，将为患者带来新的治疗方法 从DFU来的。Rodica Pop-Busui博士和Keith Kaye博士是这个项目的理想导师，他们的 在糖尿病、神经病变、传染病和临床试验经验方面的互补专业知识。浩瀚无边 密歇根大学的资源，包括密歇根临床与健康研究所和 公共卫生学院将为成功完成这项提议作出重大贡献。

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.