Mapping the Glucuronidome

绘制葡萄糖醛酸糖苷酸组图

基本信息

批准号：
10605902
负责人：
Nina Boyle
金额：
$ 3.57万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10605902
关键词：
Affect Antibiotic Therapy Antibiotics Aryl Hydrocarbon Receptor Beta-glucuronidase Bile Acids Biological Biological Assay Blood Blood specimen C57BL/6N Mouse Carcinogens Chemicals Chronic Disease Chronology Colon Colon Carcinoma Complex Mixtures Cytochrome P450 Data Databases Development Diagnosis Diet Digestion Disease Drug Metabolic Detoxication Drug Prescriptions Enterohepatic Circulation Enzymes Epithelium Excision Fatty Acids Feces Frequencies Gene Expression Genes Genomics Germ-Free Glucuronic Acids Glucuronides Glucuronosyltransferase Goals Health Hormones Inflammation Inflammatory Inflammatory Bowel Diseases Influentials Intestinal permeability Intestines Knowledge Ligands Liver Long-Term Effects Malignant Neoplasms Maps Mass Spectrum Analysis Measures Metabolic Metabolism Metagenomics Methods Microbe Molecular Molecular Biology Techniques Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Non-Steroidal Anti-Inflammatory Agents Nutrient Obesity Outcome Pathway interactions Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Pharmacologic Substance Phase Physiological Prevention Process Qualifying Regulator Genes Research Research Proposals Risk Factors Role Sampling Signal Transduction Stress Structure Taxonomy Techniques Toxic effect Training Treatment Efficacy Ulcer United States Urine Vitamins Xenobiotic Metabolism Xenobiotics absorption adverse drug reaction chemical addition chemotherapy constitutive androstane receptor dietary drug metabolism experimental study gut microbiome host microbiome improved in vivo individualized medicine insight metabolomics metagenomic sequencing microbial microbial community microbiome microbiome analysis multiple omics novel pregnane X receptor public database receptor reconstitution sample collection side effect skills stool sample targeted treatment toxicant transcription factor urinary water solubility

项目摘要

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.

项目概要绘制葡萄糖醛酸组图是最重要的哺乳动物解毒（灭活）方法之一。葡萄糖醛酸与生物活性化合物的化学加成，葡萄糖醛酸化的速率。膳食化合物会改变葡萄糖醛酸化，成功消除葡萄糖醛酸化化学物质是通过微生物去除葡萄糖醛酸部分来抑制，从而再生活性且通常有毒的化合物。葡萄糖醛酸苷库的变化对于以下疾病的预防、诊断和治疗具有重要意义：最近的研究工作集中在微生物组操纵对药物的作用。代谢，特别是抑制微生物 β-葡萄糖醛酸酶，以减少药物不良反应对NSAIDs和化疗以及提高药物治疗疗效的综合研究。由于质量的最新进展，宿主-代谢物-微生物相互作用的生理影响是可能的用于识别和量化复杂混合物（血液、尿液和粪便）中代谢物的光谱测定方法和用于微生物组功能分析的高通量组学技术本提议的研究目标。开发综合多组学管道，结合新颖的代谢组学方法、宏基因组学测序和分子生物学技术来定义宿主-葡萄糖苷酸-微生物组的生理效应该培训将提供外源代谢、质量之间的协作。光谱测定法和微生物组专家通过实验破坏葡萄糖醛酸化，绘制葡萄糖醛酸交换图动力学，并量化由此产生的宿主代谢信号。该研究将为开发一种新的方法提供依据。急需的、首创的、全面的、公开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，增进对异生素的理解拟议的研究将为当前对宿主-微生物组相互作用影响的理解提供信息。外源代谢和宿主健康，对个体化的发展具有重要意义医学和微生物靶向治疗。