PATHOGENIC MECHANISMS IN UTI

据估计，全球每年发生1.5亿次尿路感染，直接医疗费用超过60亿美元，使尿路感染成为非常严重的公共卫生负担。该计划项目提出的研究将提高我们对尿路感染的流行病学、微生物生态学、分子发病机制和预防的了解。该项目的目标将通过建立一个多学科研究小组来实现，该小组将合作执行四个相互关联的项目。项目1将进行一项双盲安慰剂对照试验，以确定脆性乳杆菌阴道益生菌是否会减少女性尿路感染复发的发生率。这项试验还将研究益生菌菌株与受试者阴道上皮细胞的粘附性，从而提供对宿主和相关微生物机制的洞察。项目2将解决这样的假设，即膀胱和阴道上皮中的细胞表面糖鞘糖脂在结构上被组织成称为小凹的多营养性质膜组件，并且小凹参与了上皮细胞对附着和摄取泌尿系致病性埃希氏菌的初始反应。项目3将采用在上一个资助期开发的两项新技术，即高密度微阵列和全基因组突变扫描，以在基因组水平上表征致尿性埃希氏菌菌株在反复尿路感染过程中以及从无症状向有症状感染转变过程中的分子适应。该项目还将确定这种适应性进化如何影响尿路病原体结合和入侵上皮细胞、引发炎症的能力。 并抵抗吞噬作用。在项目4中，宿主易感性与复发性膀胱炎或 在特定选择的候选宿主基因中有已知或新的突变的肾盂肾炎将被检查。待研究的候选基因有Toll样受体(TLR2、TLR4和TLR6)、趋化因子受体(CXCRI和CXCR2)和干扰素受体(干扰素-yR1和干扰素-yR2)。实验室核心将为项目提供微生物学研究、原代膀胱和阴道上皮细胞、尿毒力基因特征、细菌黏附分析和其他资源。行政/生物统计核心将协调整个项目，并向所有调查人员提供生物统计专业知识。拟议的研究将有助于更好地了解尿路感染的致病机制，并将产生预防尿路感染的新方法。

An estimated 150 million UTIs occur annually on a global basis, accounting for direct health care costs exceeding 6 billion dollars and making UTIs a very significant public health burden. This program project proposes studies that will improve our understanding of the epidemiology, microbial ecology, molecular pathogenesis and prevention of UTIs. The objectives of the project will be met through the development of a multidisciplinary research team that will collaborate to carry out four interrelated projects. Project 1 will undertake a double-blind placebo-controlled trial to determine whether a Lactobacillus crispatis vaginal probiotic will reduce the incidence of recurrent UTIs in women. The trial will also study adherence of the probiotic strain to vaginal epithelial cells from the subjects and will thus provide insight into the host and microbial mechanisms involved. Project 2 will address the hypothesis that cell surface glycosphingolipids in the bladder and vaginal epithelium are structurally organized into pleotrophic plasma membrane assemblies called caveolae and that caveolae participate in the initial epithelial response to attachment and uptake of uropathogenic e. coil Project 3 will employ two novel technologies that were developed during the previous funding period, namely high density microarrays and whole genome mutation scanning to characterize on a genomic level the molecular adaptation that uropathogenic E. coil strains undergo in the course of recurrent UTIs and in shifting from an asymptomatic to symptomatic infection. The project will also define how such adaptive evolution affects the ability of uropathogens to bind and invade epithelial cells, induce inflammation and resist phagocytosis. In Project 4, the association of host susceptibility to recurrent cystitis or pyelonephritis with known or novel mutations in specifically selected candidate host genes will be examined. The candidate genes to be studied are toll-like receptors (TLR2, TLR4, and TLR6), chemokine receptors (CXCRI and CXCR2), and interferon y receptors (IFN-yR1 and IFN-yR2). A laboratory core will provide microbiological studies, primary bladder and vaginal epithelial cells, characterization of urovirulence genes, bacterial adherence assays and other resources to the projects. An Administrative/Biostatistical Core will coordinate the overall project and provide biostatistical expertise to all investigators. The proposed studies will result in an improved understanding of pathogenetic mechanisms in UTIs and will result in new approaches to prevention of UTIs.