Role of Gardnerella vaginalis in the Urinary Tract

摘要 这项提议的总体目标是为我提供开始职业生涯所需的技能和专业知识 在泌尿系统疾病领域的转化医学研究，特别是尿路细菌感染 一条小路。为了实现这一目标，我将使用K01机制来实现以下培训目标：目标1： 产生创新数据，以便在备受推崇的同行评议期刊上发表。复发性尿路 感染(UTI)对妇女的影响不成比例，而且很常见，代价高昂，有时甚至危及生命。 大肠埃希氏菌是最常见的尿路感染病原体，已在小鼠模型中显示为 建立耐抗生素组织储存库，在膀胱腔急性感染后持续很长时间 解决了。长期以来，细菌从这样的水库中出现一直被认为是复发的可能来源之一。 对人类的感染。我们已经在一种新的小鼠模型中表明，阴道加德纳氏菌是一种常见的成员 导致大肠杆菌从膀胱储存库中涌出，并引发复发性尿路感染 这一集。这项研究计划中概述的实验验证了阴道毛滴虫引起尿路感染的假设。 通过损伤膀胱上皮复发(目标1)和调节宿主炎症反应(目标1 2)。这些研究将增加我们对尿路感染复发的机制的理解，并具有 有可能将阴道毛滴虫确定为易感女性风险的生物标记物。目标2：在以下方面获得专业知识 进行翻译研究。我会参加培训活动，包括研讨会和授课 课程由美国国立卫生研究院临床中心提供，并由 华盛顿大学医学院临床与转化科学研究所(ICTS)。这 指导将教会我临床研究设计和实施的语言和程序，这是必不可少的 对于我来说，要实现领导一个跨学科团队进行T1临床研究的目标。在我的指导下 共同导师和ICTS的研究设计和生物统计小组，我将通过以下方式磨练我在这方面的技能 进行嵌套病例对照研究，试图证实我们的小鼠模型在人类临床上的发现 标本。目标3：发展我的专业能力，扩大我的职业关系网。华盛顿 大学有丰富的职业发展机制，通过整合中心提供 研究、教学和学习、研究生和教务办公室以及CRTC。我会参加的 关于研究伦理、科学手稿和补助金撰写、学术工作面试、 实验室财务和管理。此外，我将在全国会议上参加具有启发性的研讨会 泌尿学和传染病，我将在那里展示我的研究成果和网络，并建立合作 与该领域的领先研究人员建立关系。我已经组建了一个指导委员会，其中包括 UTI研究领域的领导者，这将评估我的科学和职业生涯的完成情况 发展里程碑，并促进我向独立调查员的过渡。

ABSTRACT The overall goal of this proposal is to provide me with the skills and expertise necessary to launch my career in translational medical research in the field of urologic disease, particularly bacterial infections of the urinary tract. To achieve this goal, I will use the K01 mechanism to meet the following training objectives: Objective 1: Generate innovative data for publication in highly regarded peer-reviewed journals. Recurrent urinary tract infections (UTI) disproportionately affect women and are common, costly and sometimes life threatening. Escherichia coli is the most frequent causative agent of UTI, and has been shown in mouse models to establish antibiotic-resistant tissue reservoirs that persist long after acute infection of the bladder lumen is resolved. Bacterial emergence from such reservoirs has long been regarded as one likely origin of recurrent infections in humans. We have shown in a novel mouse model that Gardnerella vaginalis, a common member of the urogenital microbiota, causes E. coli to emerge from bladder reservoirs and initiate a recurrent UTI episode. The experiments outlined in this research plan test the hypothesis that G. vaginalis induces UTI recurrence by damaging the bladder epithelium (Aim 1) and modulating the host inflammatory response (Aim 2). These studies will increase our understanding of the mechanisms driving UTI recurrence and have the potential to identify G. vaginalis as a biomarker of risk in susceptible women. Objective 2: Gain expertise in performing translational research. I will engage in training activities, including seminars and didactic coursework offered by the NIH Clinical Center and through the Clinical Research Training Center (CRTC) of the Institute for Clinical and Translational Sciences (ICTS) at Washington University School of Medicine. This instruction will teach me the language and procedures of clinical study design and execution and is essential for me to meet my goal of leading a transdisciplinary team doing T1 clinical research. With guidance from my co-mentors and the Research Design and Biostatistics Group of the ICTS, I will hone my skills in this area by performing a nested case-control study that seeks to confirm the findings of our mouse model in human clinical specimens. Objective 3: Develop my professional abilities and grow my professional network. Washington University has a wealth of career development mechanisms offered through the Center for the Integration of Research, Teaching, and Learning, the Offices of Postgraduate and Faculty Affairs and the CRTC. I will attend seminars and courses on research ethics, scientific manuscript and grant writing, academic job interviewing, laboratory finances and management. Additionally, I will attend instructive seminars at national meetings on urology and infectious diseases, where I will present my research findings and network and build collaborative relationships with leading researchers in the field. I have assembled a mentoring committee that includes leaders in the field of UTI research, which will evaluate the completion of both my scientific and career development milestones and facilitate my transition to an independent investigator.