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 我们要求行政补充，以建立第一个空间分辨率的三维地图的人类 肝脏整合细胞成分和代谢物以及细胞外基质， 时间HuBMAP转型技术开发部门与 由田博士（匹兹堡大学，皮特）和斯托克韦尔博士（哥伦比亚大学，CU）领导的团队 由Naba博士（伊利诺伊大学芝加哥分校，UIC）领导的演示计划团队在 符合HuBMAP的全面器官映射愿景，提供前所未有的视图 以前所未有的深度进入肝脏结构。 已经进行了广泛的努力来分析细胞外基质（ECM）组成-或 matrisomes -各种器官;然而，仍然缺乏对空间分布的研究， 细胞周围的ECM成分，并有助于功能性多细胞结构，其 正常与疾病的变化，以及与细胞的分子信号传导/串扰。困难在于 (1)缺乏经过验证的抗ECM抗体组，（2）进行多重检测的困难 以单细胞分辨率绘制多级生物分子，以及（3）难以整合 在单个样本中使用多个“组学”模态生成的数据集。田博士带领的团队 开发了质谱成像（H2O）n> 25 k-GCIB-西姆斯双SIMS工作流程，集成 非靶向代谢组学、脂质组学和靶向蛋白质组学（多达40个靶点） 亚细胞空间分辨率（1 µm）的组织切片。与斯托克韦尔博士领导的团队一起， 已经建立了一个强大的多模态成像工作流程，以生成空间分辨图谱 肝脏组织，可视化主要组织结构，细胞类型和细胞类型的代谢状态。 利用Naba博士获得的人类肝脏基质体草案和 MatrisomeDB是她的团队创建的ECM蛋白质组学数据集数据库，我们建议创建 一个基本的人类肝脏基质体成分的空间分辨图，沿着我们目前的 单细胞水平的多重肝脏图。 该项目将提供一个新的机会，描绘细胞的空间组织， 细胞外生物分子，功能组织单位的定义，包括信息 微环境生态位这将允许在未来定义相互作用的性质 以及细胞与其周围ECM之间建立的信号，并开始了解 疾病相关失调（例如，纤维化、肝硬化、肝细胞癌）。