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: 10015205
• 负责人: ROB KNIGHT
• 金额: $ 110.28万
• 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/10015205
• 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; 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.

项目摘要 抗生素耐药性是一个日益严重的问题，目前的药物管道没有跟上增长的步伐 抗生素耐药性的证据另一种策略是增强宿主免疫力。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， 传染病负担。最近的研究表明，进一步的收益是可能的，特别是在增加 植物化学物质回到高度加工的饮食通常在美国消费。然而，我们缺乏一个 基本了解这些成分是如何被微生物处理的，以及饮食来源的 分子、微生物组和宿主免疫系统共同抵抗感染性疾病。 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、饮食化合物）是昂贵的且高度多变量的。三个关键的见解， 使目前的项目是微型化的DNA和RNA测序分析先进的纳升- 大规模液体处理机器人，大大降低了成本，无目标和有目标的质量相结合 以高通量对相同样品进行光谱分析，以能够发现更大的化学空间， 以及在多个尺度上使用明确的空间图来整合整个身体的数据集的能力， 支持基于空间数据的可视化分析和深度学习方法。这些突破将 为膳食代谢物如何促进抗病性提供了一个全新的认识，并将 使我们能够开发一种新的基础设施，以整合来自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，这些结果将使我们能够选择生物材料， 在人类受试者中的生物标志物，提供关于内部营养和免疫状态的最大信息。 结果将针对NHANES和美国肠道队列进行测试。 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;创建和共享这些图谱的基础设施;以及 初步测试结果是否适用于大型人群。