The Role of the Microbiome in Diabetic Foot Ulcers

项目总结/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， 这是导致下肢截肢的主要原因，每六个人中就有一个因此而早逝。 糖尿病的许多并发因素促进和中断正常的生理愈合过程。五年 DFU发生后的死亡率为40%，比非糖尿病队列高10倍。尽管科学家们 随着对伤口愈合生理学的理解的进步，当标准护理时，只有一半的DFU愈合 得到满足。这一不幸的事实强调了需要确定治疗的可改变的风险因素， DFU治疗中不愈合事件的原因。 DFU微生物组可能代表这些重要的可改变的风险因素，以获得伤口愈合。的 DFU微生物组由共存DFU的所有微生物群的遗传物质组成。过去 观察性研究表明，这些微生物群中的一种或多种是不愈合的贡献者，但这些微生物群 研究受到设计上的重大限制，缺乏共识评估。大多数研究是 仅采用横断面设计，主要关注未感染的DFU。此外，这些研究没有 在研究中一致地收集生物标本。在这一职业发展中，我们建议了解 微生物组在DFU发病机制中的作用，并了解DFU中微生物组的轨迹 三个目标中的伤口进展。目标1将对DFU患者进行横断面队列研究，以比较 使用宏基因组学下一代测序， （mNGS）。目标2将利用这一初始队列来纵向确定时间关系， 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预测抗生素治疗对感染DFU中已鉴定病原体的临床可行性， 初步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， 将导致干预性临床试验，以预防和/或治疗DFU。 这份工作对我的职业发展至关重要。我将成为一名独立的临床研究人员， 糖尿病足并发症的专业知识。临床试验执行和生物统计学方面的正式培训将提供 实践经验，并将为成功完成不仅是这个项目，而且是未来的阶段 调查事务所我的职业发展的临床试验部分将允许我从这个结果 研究并无缝过渡到干预性研究，这将为患者带来新的治疗方法。 从DFU。Rodica Pop-Busui博士和基思凯博士非常适合作为这个项目的导师，他们的 在糖尿病、神经病、传染病和临床试验经验方面的互补专业知识。绝 密歇根大学的资源，包括密歇根临床和健康研究所， 公共卫生学院，将大大有助于成功完成这一建议。

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.