Mapping the Glucuronidome

项目摘要 葡萄糖醛酸苷组图谱。最重要的哺乳动物解毒（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。率 葡萄糖醛酸化被膳食化合物改变，葡萄糖醛酸化化学物质的成功消除是 通过微生物去除葡萄糖醛酸部分来抑制，再生活性且通常有毒的化合物。 葡萄糖醛酸苷库的变化对预防、诊断和治疗 慢性病最近的研究工作集中在微生物组操纵对药物代谢的作用上。 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 用于NSAID和化学疗法并提高药物治疗功效。综合研究 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）中代谢物的光谱测定法 以及用于微生物组功能分析的高通量组学技术。本研究旨在 开发一个整合的多组学管道，包括新的代谢组学方法，宏基因组学， 测序和分子生物学技术，以确定宿主-葡糖苷酸-微生物组的生理效应 交互.该培训将提供一个合作的努力之间的异生物质代谢，质量 光谱分析和微生物组专家通过实验破坏葡萄糖醛酸化，绘制葡萄糖醛酸苷交换图 动力学，并量化所得的宿主代谢信号传导。这项研究将为发展一个 急需的，第一个同类的，全面的，公开的葡萄糖醛酸化数据库，促进 将强大的代谢组学方法结合到研究中， 新陈代谢.拟议的研究将为目前对宿主-微生物组相互作用效应的理解提供信息 对异生物质代谢和宿主健康的影响，对个体化 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.