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，占直接医疗费用的60多亿美元。尿路感染主要影响女性，因为女性的解剖结构和疾病的上升性质。革兰氏阴性杆菌大肠埃希菌是这些感染的最常见原因，这些感染占很大的发病率。此外，原发感染的一大临床问题是复发。接受简单尿路感染治疗的女性有25%-50%的机会发展为复发感染。通常认为尿路感染是由非侵袭性细菌引起的，本质上是急性的，是自我限制的。也有人认为，反复感染是由于从肠道或阴道储蓄器重新接种尿路中的大肠杆菌造成的。最近的证据表明，这种教条在某些情况下可能是不正确和误导性的，并可能干扰对这些感染的适当评估和治疗。这项建议旨在阐明急性和复发性尿路感染的分子和流行病学基础。将特别强调更好地界定尿路感染的流行病学，确定女性急性症状性尿路感染后持续细菌膀胱和阴道储存库的存在，并阐明宿主-病原体相互作用所涉及的分子因素。无症状性和症状性膀胱感染与阴道定植之间的时间相关性将在临床环境中进行评估。通过将强大的遗传系统与在体外和小鼠模型、生物化学、细胞生物学和高分辨率电子显微镜下定义的功能基因组学相结合，将阐明具有良好特征的致病菌株的毒力决定因素的分子特征。膀胱对感染的反应机制细节，以及特定的毒力如何。影响宿主反应的因素将通过基因芯片、定量RT-PCR和激光捕获微区切片来确定。这一建议代表了三个项目之间复杂而完整的网络，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颠覆这些防御的毒力机制。这项研究的结果可能会彻底改变对尿路感染的评估方式，并导致治疗和预防这种主要影响女性的感染的新的、更好的方法。

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.