Mapping the Glucuronidome

项目摘要 绘制葡萄糖醛酸体的图谱。哺乳动物最重要的解毒(灭活)方法之一是 葡萄糖醛酸与生物活性化合物的化学加成，即葡萄糖醛酸化反应。这一速度 葡萄糖醛酸化作用被饮食化合物改变，成功地消除了葡萄糖醛酸化化学物质 被微生物去除的葡萄糖糖醛酸部分抑制，再生活性的，通常是有毒的化合物。 葡萄糖醛酸池的变化对糖尿病的预防、诊断和治疗具有重要意义 慢性病。最近的研究工作集中在微生物组操纵对药物的作用上。 代谢，特别是抑制微生物β-葡萄糖醛酸苷酶以减少药物不良反应 使用非类固醇抗炎药和化疗，并提高药物治疗效果。对…的综合研究 由于质量的最新进展，宿主-代谢物-微生物相互作用的生理学意义是可能的 用于鉴定和定量复杂混合物(血液、尿液和粪便)中代谢物的光谱方法 以及用于微生物组功能分析的高通量组学技术。这项拟议的研究旨在 开发集成了新的代谢组学方法、元基因组学的综合多组学流水线 用测序和分子生物学技术确定宿主-葡萄糖醛酸苷-微生物组的生理效应 互动。培训将提供异种新陈代谢、质量 光谱学和微生物组专家实验性地扰乱葡萄糖醛酸化作用，绘制葡萄糖醛酸苷交换图 动力学，并量化由此产生的宿主代谢信号。这项研究将为开发一种 亟需的、首创的、全面的和公开可用的葡萄糖醛酸化数据库，促进 结合强大的代谢组学方法进行研究，促进对异源生物的理解 新陈代谢。这项拟议的研究将有助于目前对宿主-微生物群相互作用效应的理解 关于异种代谢和宿主健康，对个性化发展的重要启示 药物和微生物靶向治疗。

Project Summary Mapping the Glucuronidome. One of the most important mammalian detoxification (inactivation) methods is the chemical addition of glucuronic acid to biologically active compounds, glucuronidation. The rate of glucuronidation is altered by dietary compounds and the successful elimination of glucuronidated chemicals is inhibited by microbial removal of the glucuronic acid moiety, regenerating the active, and often toxic, compound. Changes in the pool of glucuronides have important implications for the prevention, diagnosis, and treatment of chronic diseases. Recent research efforts have focused on the role of microbiome manipulation on drug metabolism, specifically the inhibition of microbial β-glucuronidase enzymes for reducing adverse drug reactions to NSAIDs and chemotherapies and improving pharmaceutical treatment efficacy. Comprehensive research of the physiologic implications of host-metabolite-microbe interactions is possible due to recent advances in mass spectrometry methods for identifying and quantifying metabolites in complex mixtures (blood, urine, and feces) and high-throughput -omics techniques for functional analysis of the microbiome. This proposed research aims to develop an integrative multi-omics pipeline incorporating novel metabolomic methods, metagenomic sequencing, and molecular biology techniques to define the physiologic effects of host-glucuronide-microbiome interactions. The training will provide for a collaborative effort between xenobiotic metabolism, mass spectrometry, and microbiome experts to experimentally disrupt glucuronidation, map glucuronide exchange dynamics, and quantify resultant host metabolic signaling. The research will provide for the development of a much needed, first-of-its-kind, comprehensive, and publicly available database of glucuronidation, facilitating the incorporation of powerful metabolomics methods to research advancing the understanding of xenobiotic metabolism. The proposed research will inform the current understanding of host-microbiome interaction effects on xenobiotic metabolism and host health, with important implications for the development of individualized medicine and microbe-targeted therapies.