ORWH: SCOR--Sex /Gender Factors Affecting Women's Health

在全球范围内，尿路感染（uti）是美国最常见的传染病之一，每年发生1.5亿次，直接医疗费用超过60亿美元。尿路感染主要影响女性，因为女性解剖和疾病的提升性质。革兰氏阴性杆菌大肠杆菌是这些感染的最常见原因，其发病率很高。此外，对原发感染的主要临床问题之一是复发。接受单纯尿路感染治疗的女性有25-50%的机会复发感染。一般认为，尿路感染是由非侵入性细菌引起的，本质上是急性的，并且是自限性的。也有人认为，反复感染是由于肠道或阴道储存库中的大肠杆菌再次接种尿路所致。最近的证据表明，这种教条在某些情况下可能是不正确的和具有误导性的，并可能干扰对这些感染的适当评估和治疗。本提案旨在阐明急性和复发性尿路感染的分子和流行病学基础。将特别强调更好地定义尿路感染的流行病学，确定妇女急性症状性尿路感染后膀胱和阴道持久细菌储存库的存在，并阐明参与宿主-病原体相互作用的分子因素。在无症状和有症状的膀胱感染和阴道定植之间的时间关联将在临床设置进行评估。通过将强大的遗传系统与功能基因组学（在体外和小鼠模型中定义）、生物化学、细胞生物学和高分辨率电子显微镜相结合，阐明了特征明确的尿路致病菌株的毒力决定因素的分子特征。膀胱如何对感染作出反应的机制细节，以及具体的毒力。影响宿主反应的因素将通过芯片、定量RT-PCR和激光捕获显微切片来确定。该建议代表了三个项目之间复杂而综合的网络，并将导致对整个感染周期中发生的宿主-病原体相互作用的新理解，包括膀胱中的宿主防御反应和细菌病原体破坏这些防御的毒力机制。这项研究的结果可能会彻底改变尿路感染的评估方式，并导致新的和更好的方法来治疗和预防这种主要影响妇女的感染。

On a global basis, urinary tract infections (UTIs), which are among the most common infectious diseases in the United States, occur -150 million times annually and account for more than $6 billion in direct health care costs. UTIs primarily affect women because of the female- anatomy and the ascending nature of the disease. The Gram-negative bacterium Escherichia coli is the most common cause of these infections which account for significant morbidity. In addition, to the original infection one of the major clinical problems is recurrence. A woman treated for an uncomplicated UTI has a 25-50% chance of developing a recurrent infection. It has generally been assumed that UTIs are caused by non-invasive bacteria, that they are acute in nature, and are self-limited. It has also been assumed that recurrent infections are due to re-inoculation of the urinary tract with E.coli from an intestinal or vaginal reservoir. Recent evidence suggests that this dogma may in some cases be incorrect and misleading and could be interfering with the proper evaluation and treatment of these infections. This proposal seeks to elucidate the molecular and epidemiologic basis of acute and recurrent UTIs. Special emphasis will be placed on better defining the epidemiology of UTIs, determining the presence of persistent bacterial bladder and vaginal reservoirs following acute symptomatic UTI in women and elucidating the molecular factors involved in the host-pathogen interaction. The temporal, associations between asymptornatic and symptomatic bladder infection and vaginal colonization in the clinical setting will be assessed. Molecular characterization of the virulence determinants in well-characterized uropathogenic strains will be elucidated by blending a powerful genetic system with functional genomics, defined in vitro and murine models, biochemistry, cell biology, and high resolution electron microscopy. The mechanistic details of how the bladder responds to infection, and how specific virulence. factors affect this host response will be determined using microarray, quantitative RT-PCR and laser capture microdis section. This proposal represents an intricate and integrated network between three projects and will lead to a new understanding of the host-pathogen interactions that occur throughout the infectious cycle including the host defense response in the bladder and the virulence mechanisms by which bacterial pathogens subvert these defenses. Results of this research could revolutionize the way UTIs are evaluated and lead to new and better ways to treat and prevent this infection that primarily affects women.