Microbial Chemical Sensing and Host Responses

微生物化学传感和宿主反应

• 批准号: 10595034
• 负责人: Jason Michael Crawford
• 金额: $ 154.58万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595034
• 关键词: Animals; Area; Bacteria; Bacterial Transformation; Biological; Biological Process; Biology; Cells; Chemicals; Collection; Communication; Data; Data Set; Disease; Drug Receptors; Drug Targeting; FDA approved; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Health; Human; Human Microbiome; Immune response; Intestines; Lead; Ligands; Measurement; Mediating; Medical; Metabolic Biotransformation; Metabolic Pathway; Metabolism; Microbe; Modernization; Molecular; Natural Products; Organism; Orphan; Pathway interactions; Pharmaceutical Preparations; Phylogenetic Analysis; Physiology; Production; Reporting; Research; Sampling; Serum; Signal Transduction; Signaling Molecule; Source; Structure; Structure-Activity Relationship; System; Technology; Therapeutic; bacterial metabolism; candidate identification; dark matter; drug discovery; drug metabolism; guided inquiry; gut bacteria; gut microbes; gut microbiota; high throughput screening; host microbiota; human disease; human model; human tissue; member; metabolome; metabolomics; microbial; microbiome; microbiota; novel; programs; receptor-mediated signaling; response; screening; secondary metabolite; small molecule; stressor; targeted treatment

Summary. The tens of thousands of microbial metabolites produced by the trillions of bacterial cells that colonize our intestines (our microbiota) are poorly understood, and current estimates suggest that we only know the biological functions of 0.1% of all small molecules derived from the microbiota. Some of the metabolites in this so called “dark matter” of the metabolome will undoubtedly have profound impacts on human physiology. Here, we will establish how the human microbiome “communicates” with the host via dark-matter-derived molecular modulation of host G protein-coupled receptors (GPCRs), including GPCR signaling effects mediated by novel small molecules encoded by the microbiota (Aim 1a), GPCR signaling effects derived from endogenous host chemicals (Aim 1b), and gut bacterial transformations of GPCR-targeted medical drugs that rewire chemical signaling programs at the host-microbiota interface (Aim 2). A major focus will be the structural, functional, and biosynthetic characterization of novel metabolites associated with “orphan” GPCR signaling where only limited chemical and biological information is currently available. Our proposal takes advantage of the results from two high-throughput screens and one targeted screen, which each focused on different aspects of how microbial or host metabolism impacts host GPCR signaling at a detailed molecular level. In preliminary high-throughput studies: 1) We have analyzed ~150 diverse human gut bacteria for secretion of metabolites that activate conventional GPCRs (314 GPCRs) using a high-throughput GPCR screening system (Aim 1a). We have characterized bacterial metabolites identified by this screen that activate three orphan GPCRs to date and have thus established a pipeline for “GPCR deorphanization.” 2) We have screened human tissues for small molecules that activate “orphan” GPCRs with no reported ligand information available (Aim 1b), providing a basis to elucidate the structure and distribution of endogenous orphan GPCR signals. 3) We have evaluated the processing of 271 FDA-approved drugs (including 62 GPCR-targeted drugs) by a panel of dozens of gut microbiota-derived bacteria. This preliminary data includes 585,000 drug-by-microbiota measurements. Many drug metabolism products and bacterial responses to drugs can be observed in the metabolomics data, guiding the discovery of novel GPCR drug transformations and “specialized” metabolites from the gut microbiota whose production is induced in response to GPCR drugs (Aim 2). The proposed studies will represent a heretofore unprecedented structure-function-based exploration of the “dark matter” of the microbiota metabolome and how it is “sensed” by the host. Such studies may illuminate novel GPCR- and microbiota-targeted therapeutic strategies for a diversity of human diseases.

摘要 由数万亿细菌细胞产生的数万种微生物代谢产物， 肠道（我们的微生物群）知之甚少，目前的估计表明，我们只知道生物学 来自微生物群的所有小分子的0.1%的功能。这种所谓的 “暗物质”的代谢组无疑将对人体生理产生深远的影响。在这里，我们将 确定人类微生物组如何通过暗物质衍生的分子与宿主“交流” 调节宿主G蛋白偶联受体（GPCR），包括由 由微生物群编码的新型小分子（Aim 1a），源自内源性的GPCR信号传导效应 宿主化学物质（目标1b），以及GPCR靶向药物的肠道细菌转化， 宿主-微生物群界面的信号程序（Aim 2）。一个主要的重点将是结构，功能， 与“孤儿”GPCR信号传导相关的新代谢物的生物合成表征， 目前已有化学和生物信息。我们的建议利用了两个结果 高通量筛选和一个有针对性的筛选，每一个都集中在微生物如何在不同的方面， 或宿主代谢在详细的分子水平上影响宿主GPCR信号传导。在初步的高通量 研究：1）我们分析了~150种不同的人类肠道细菌分泌的代谢物， 使用高通量GPCR筛选系统（Aim 1a）的常规GPCR（314 GPCR）。我们有 迄今为止，通过该筛选鉴定的特征性细菌代谢物激活了三种孤儿GPCR， 从而建立了“气相化学还原去磷”的管道。2)我们筛选了人体组织中的小分子 激活“孤儿”GPCR，没有报道的配体信息（目标1b），为 阐明内源性孤儿GPCR信号的结构和分布。3)我们已经评估了 271种FDA批准的药物（包括62种GPCR靶向药物）由一个由数十个肠道 微生物群衍生的细菌。这些初步数据包括585，000个药物微生物群测量。许多 药物代谢产物和细菌对药物的反应可以在代谢组学数据中观察到， 新的GPCR药物转化和来自肠道微生物群的“专门”代谢物的发现， 响应于GPCR药物诱导产生（目的2）。拟议中的研究将代表迄今为止 对微生物代谢组的“暗物质”进行了前所未有的基于结构-功能的探索， 它被宿主“感知”。这些研究可以阐明新的GPCR和微生物靶向治疗 应对多种人类疾病的策略。