Multimodal mass spectrometry imaging of mouse and human liver

小鼠和人类肝脏的多模态质谱成像

• 批准号: 10817566
• 负责人: Brent R Stockwell
• 金额: $ 15万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10817566
• 关键词: 3-Dimensional; Administrative Supplement; Antibodies; Architecture; Atlases; Cells; Cellular Structures; Chicago; Cirrhosis; Data Set; Databases; Disease; Extracellular Matrix; Fibrosis; Future; Human; Human BioMolecular Atlas Program; Illinois; Liver; Maps; Metabolic; Modality; Molecular; Multimodal Imaging; Mus; Nature; Organ; Preparation; Primary carcinoma of the liver cells; Proteome; Proteomics; Resolution; Sampling; Signal Transduction; Spatial Distribution; Structure; Time; Tissues; Universities; Variant; Vision; Visualization; cell type; data integration; extracellular; lipidome; lipidomics; mass spectrometric imaging; metabolome; metabolomics; meter; multimodality; multiple omics; programs; technology development

Project summary We request an administrative supplement to build the first spatially-resolved 3D map of the human liver integrating both cellular components and metabolites and the extracellular matrix for the first time. This collaborative effort between the HuBMAP Transformative Technology Development team led by Dr. Tian (University of Pittsburgh, Pitt) and Dr. Stockwell (Columbia University, CU) and the Demonstration Program team led by Dr. Naba (University of Illinois Chicago, UIC) is in line with HuBMAP’s vision for comprehensive organ mapping, providing an unprecedented view into liver architecture with a depth never achieved before. An extensive effort has been made to profile the extracellular matrix (ECM) composition – or matrisomes – of various organs; however, there is still lack of study on the spatial distribution of ECM components surrounding cells and contributing to functional multicellular structures, their variation in normal vs. disease, and molecular signaling/crosstalk with cells. The challenges lie in (1) the lack of panels of validated anti-ECM antibodies, (2) the difficulty in performing multiplexed mapping of multi-level biomolecules at single-cell resolution, and (3) the difficulty to integrate datasets generated using multiple “-omic” modalities in a single sample. The team led by Dr. Tian developed a mass spectrometry imaging (H2O)n>25k-GCIB-SIMS dual-SIMS workflow, integrating untargeted metabolomics, lipidomics, and targeted proteomics (up to 40 targets) on the same tissue section at subcellular spatial resolution (1 µm). Together with the team led by Dr. Stockwell, a robust multimodal imaging workflow has been established to generate a spatially-resolved atlas of liver tissue, visualizing major tissue structures, cell types, and metabolic states of cell types. Leveraging the draft of the human liver matrisome obtained by Dr. Naba and the content of MatrisomeDB, the database of ECM proteomics datasets her team created, we propose to create a spatially-resolved map of essential human liver matrisome components, along with our current multiplexed liver map at the single-cell level. This project will present a new opportunity to delineate the spatial organization of cellular and extracellular biomolecules, the definition of functional tissue units, including information on microenvironmental niches. This will allow, in the future, to define the nature of the interactions and signals established between cells and their surrounding ECM, and to begin to understand disease-associated dysregulations (e.g., fibrosis, cirrhosis, hepatocellular carcinoma).

项目摘要 我们请求一种行政补品来构建人类的第一个空间分辨的3D地图 肝脏都整合细胞成分和代谢产物以及第一个细胞外基质 时间。 Hubmap变革技术开发之间的这种协作努力 由蒂安博士（匹兹堡大学，皮特大学）和斯托克韦尔博士（CU哥伦比亚大学）领导的团队 由Naba博士（伊利诺伊大学芝加哥大学）领导的示威计划团队正在 与Hubmap对全面器官映射的愿景一致，提供了前所未有的视图 进入以前从未达到深度的肝脏建筑。 已经做出了广泛的努力，以介绍细胞外基质（ECM）组成或 伴有各种器官；但是，仍然缺乏对空间分布的研究 ECM围绕细胞的ECM成分，并有助于功能性多细胞结构，它们 正常疾病与疾病的变化以及分子信号传导/与细胞串扰。挑战在于 （1）缺乏经过验证的抗ECM抗体的面板，（2）执行多路复用的困难 单细胞分辨率的多级生物分子的映射，（3）难以集成 在单个样本中使用多个“ -omic”模态生成的数据集。由天博士领导的团队 开发了质谱成像（H2O）N> 25k-GCIB-SIMS双SIMS工作流程，集成 在同一 亚细胞空间分辨率（1 µm）处的组织截面。与斯托克韦尔博士领导的团队一起 建立了强大的多模式成像工作流程，以生成空间分辨的地图集 肝组织，可视化细胞类型的主要组织结构，细胞类型和代谢状态。 利用Naba博士获得的人类肝母系草稿和内容 MatrisomedB，她的团队创建的ECM蛋白质组学数据集的数据库，我们建议创建 一张空间分辨的人类肝脏组成分的空间分辨图，以及我们的当前 单细胞级别的多路复用肝图。 该项目将提供一个新的机会，以描绘蜂窝的空间组织和 细胞外生物分子，功能组织单元的定义，包括有关 微环境利基。这将来将允许定义互动的性质 以及在细胞及其周围的ECM之间建立的信号，并开始理解 与疾病相关的失调（例如纤维化，肝硬化，肝细胞癌）。