Mapping host-microbe-metabolite interactions in 3D to find diet-derived enhancers of immunity

绘制 3D 宿主-微生物-代谢物相互作用图，寻找饮食来源的免疫增强剂

• 批准号: 10226176
• 负责人: ROB KNIGHT
• 金额: $ 110.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226176
• 关键词: 3-Dimensional; American; Antimicrobial Resistance; Back; Biocompatible Materials; Biological Assay; Biological Markers; Chemicals; Communicable Diseases; Consumption; DNA sequencing; Data; Data Set; Diet; Dietary Component; Disease Resistance; Enhancers; Gene Expression; Human; Immune system; Immunity; Individual; Infrastructure; Laboratory Study; Liquid substance; Maps; Mass Spectrum Analysis; Metabolite Interaction; Microbe; Minerals; Miniaturization; National Health and Nutrition Examination Survey; Nutritional status; Pharmaceutical Preparations; Phytochemical; Population; Process; Research Personnel; Resistance; Robot; Sampling; Supplementation; System; Testing; United States; Visual; Vitamins; Work; base; burden of illness; cohort; cost; deep learning; dietary; human subject; immunological status; improved; insight; metabolome; microbiome; mouse model; nanolitre scale; prevent; public health relevance; side effect; transcriptome sequencing

Project Summary Antimicrobial resistance is an increasing problem, and current drug pipelines are not keeping pace with the rise of antimicrobial resistance. An alternative strategy is to boost host immunity. An often overlooked side-effect of the vitamin and mineral supplementation projects of the 1940s is that these supplements greatly reduced infectious disease burden. Recent work has shown that further gains may be possible, especially in adding phytochemicals back to highly processed diets typically consumed in the United States. However, we lack a fundamental understanding of how these components are processed by the microbiome, and how diet-derived molecules, microbiome and host immune system work together to resist infectious disease. A key barrier preventing us from making these discoveries is that each individual assay (microbiome, host gene expression metabolome, dietary compounds) is expensive and highly multivariate. Three key insights that enable the current project are the miniaturization of DNA and RNA sequencing assays on advanced nanoliter- scale liquid handling robots, greatly reducing the cost, the combination of untargeted and targeted mass spectrometry on the same samples in high throughput to enable discovery of a much greater chemical space, and the ability to use explicitly spatial maps on multiple scales to integrate the dataset throughout the body and enable both visual analytics and deep learning approaches based on spatial data. These breakthroughs will provide a fundamentally new understanding of how dietary metabolites promote disease resistance, and will allow us to develop a new infrastructure to integrate results from many investigators in different laboratories studying various aspects of these systems. Additionally, the results will allow us to choose biomaterials and biomarkers in human subjects that provide maximum information about internal nutritional and immune status. Results will be tested against the NHANES and American Gut cohorts. The results of this project will therefore be: 3D maps of mouse models showing how the microbiome, diet, and host gene expression produce immunity; an infrastructure for creating and sharing these maps; and a preliminary test of whether the results extend to large human populations.

项目概要 抗生素耐药性是一个日益严重的问题，目前的药物管道未能跟上这一问题的增长 的抗菌素耐药性。另一种策略是增强宿主免疫力。一个经常被忽视的副作用 20世纪40年代的维生素和矿物质补充项目是这些补充品大大减少 传染病负担。最近的工作表明，进一步的收获是可能的，特别是在增加 植物化学物质又回到了美国通常消费的高度加工的饮食中。然而，我们缺乏一个 对微生物组如何处理这些成分以及饮食如何产生的基本了解 分子、微生物组和宿主免疫系统共同抵抗传染病。 阻止我们做出这些发现的一个关键障碍是每个单独的检测（微生物组、宿主 基因表达代谢组、膳食化合物）价格昂贵且高度多元。三个关键见解 使当前项目能够在先进的纳升上实现 DNA 和 RNA 测序测定的小型化 规模液体搬运机器人，大大降低成本，非目标质量和目标质量的结合 高通量对相同样品进行光谱分析，以发现更大的化学空间， 以及在多个尺度上明确使用空间地图来整合整个身体的数据集的能力 支持基于空间数据的视觉分析和深度学习方法。这些突破将 提供对饮食代谢如何促进疾病抵抗力的全新认识，并将 允许我们开发新的基础设施来整合不同实验室的许多研究人员的结果 研究这些系统的各个方面。此外，结果将使我们能够选择生物材料和 人类受试者的生物标志物可提供有关内部营养和免疫状态的最大信息。 结果将针对 NHANES 和 American Gut 队列进行测试。 因此，该项目的结果将是：小鼠模型的 3D 地图，显示微生物组、饮食和 宿主基因表达产生免疫力；用于创建和共享这些地图的基础设施；和一个 初步测试结果是否适用于大量人群。