Microbial Chemical Sensing and Host Responses

微生物化学传感和宿主反应

• 批准号: 10380093
• 负责人: Jason Michael Crawford
• 金额: $ 154.54万
• 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/10380093
• 关键词: Animals; Area; Bacteria; Bacterial Transformation; Biological; Biological Process; Biology; Cells; Chemicals; Collection; Data; Data Set; Disease; Drug Receptors; Drug Targeting; FDA approved; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; 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; base; 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; 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.

概括。 数万亿个细菌细胞产生的成千上万的微生物代谢产物，使我们的定植 肠道（我们的菌群）知之甚少，目前的估计表明我们只知道生物学 源自微生物群的所有小分子的0.1％的功能。所谓的一些代谢产物 代谢组的“暗物质”无疑会对人类生理产生深远的影响。在这里，我们会的 确定人类微生物组如何通过深色 - 衍生的分子与宿主“通信” 宿主G蛋白偶联受体（GPCR）的调节，包括由GPCR信号传导效应介导的 由微生物群编码的新型小分子（AIM 1A），GPCR信号传导效应源自内源性 宿主化学药品（AIM 1B）和以GPCR为靶向的医疗药物的肠道细菌转化 主机菌接口的信号程序（AIM 2）。重点将是结构，功能和 与“孤儿” GPCR信号相关的新代谢产物的生物合成表征，仅限 目前可用化学和生物学信息。我们的建议利用了两个的结果 高通量屏幕和一个目标屏幕，每个屏幕都集中在微生物的不同方面 或宿主代谢在详细的分子水平上影响宿主GPCR信号传导。在初步高通量中 研究：1）我们已经分析了约150种潜水员人类肠道细菌，用于分泌激活的代谢物 使用高通量GPCR筛选系统（AIM 1A）的常规GPCR（314 GPCR）。我们有 该屏幕鉴定出的细菌代谢物的特征是激活三个孤儿GPCR，并具有 因此，建立了“ GPCR去畸变”的管道。 2）我们已经筛选了小分子的人体组织 激活“孤儿” GPCR，没有可用的配体信息（AIM 1B），为 阐明内源性孤儿GPCR信号的结构和分布。 3）我们评估了 由数十个肠道处理271种FDA批准的药物（包括62个GPCR药物） 微生物群衍生的细菌。该初步数据包括585,000个逐粒药物测量。许多 在代谢组数据中可以观察到药物代谢产物和细菌对药物的反应，并指导 从肠道菌群中发现新型GPCR药物转化和“专业”代谢产物的发现 响应GPCR药物诱导生产（AIM 2）。拟议的研究将代表迄今 基于结构功能的前所未有的基于对微生物群代谢组的“暗物质”的探索以及如何 主机“感知”了。此类研究可能会阐明新型的GPCR和微生物群靶向疗法 各种各样的人类疾病的策略。