Metabolomic Mechanisms of Nutritional Immunity in the Urinary Tract

项目摘要 尿路感染（UTI）是常见的，驱动广泛的抗生素使用，并且正变得越来越多。 抵抗治疗。人们普遍认为，尿液的化学成分起着影响 在UTI发病机制中的作用，但这一直难以转化为临床实践。最近，我们发现 尿支持先天免疫蛋白抗菌铁螯合能力的个体差异 铁角蛋白（SCN;也称为脂质运载蛋白-2或NGAL）。使用基于质谱的代谢组学，我们 将这些差异与人类尿液代谢物的特定化学类别联系起来。这项工作和其他工作 支持尿代谢物在先天性抗菌免疫中的功能作用。临床泌尿系病原体 许多表型和遗传适应泌尿环境，表明多种选择性 压力与尿成分有关。在这里，我们将确定人类尿液代谢组学对UTI的影响 发病机制由于人类尿液是一种化学成分复杂的生物流体，我们将结合联合收割机最近的生物分析， 当代数据科学方法的进步，以确定影响代谢组学网络 细菌生长和行为。通过识别这些网络，探索它们精确的生化功能， 了解它们的生理起源，我们将为转化为病人护理提供基础。拟议的分析 实验表明，我们的假设是，尿液成分在 在抗感染中的作用，并且应该在治疗上靶向以预防或治疗感染。

PROJECT SUMMARY Urinary tract infections (UTIs) are commonplace, drive extensive antibiotic use, and are becoming increasingly resistant to treatment. There is general agreement that the chemical composition of urine plays an influential role in UTI pathogenesis but this has been difficult to translate to clinical practice. Recently, we found wide individual differences in urine's ability to support antibacterial iron chelation by the innate immune protein siderocalin (SCN; also known as Lipocalin-2 or NGAL). Using mass spectrometry-based metabolomics, we linked these differences to a specific chemical class of human urinary metabolites. This and other work supports a functional role for urinary metabolites in innate antibacterial immunity. Clinical urinary pathogens posses numerous phenotypic and genetic adaptations to the urinary environment, suggesting multiple selective pressures related to urinary composition. Here we will identify human urinary metabolomic influences on UTI pathogenesis. Because human urine is a chemically complex biofluid, we will combine recent bioanalytical advances with contemporary data science approaches to identify metabolomic networks that influence bacterial growth and behavior. By identifying these networks, exploring their precise biochemical functions, and learning their physiologic origins we will provide a basis for translation to patient care. The proposed analyses and experiments represent a rigorous evaluation of our hypothesis that urinary composition plays an important role in infection resistance and should be targeted therapeutically to prevent or treat infections.