Human and mouse transcriptome profiling identifies cross-species homology of mononuclear phagocytes

人类和小鼠转录组分析鉴定单核吞噬细胞的跨物种同源性

基本信息

  • 批准号:
    10523110
  • 负责人:
  • 金额:
    $ 98.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-12-15 至 2027-11-30
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract The mononuclear phagocyte (MP) system plays a fundamental role in both innate and adaptive immunity. It includes three broad classes of MPs extensively characterized in the mouse: (1) macrophages, including alveolar macrophages, Langerhans cells, and three distinct subtypes of interstitial macrophages; (2) tissue-trafficking monocytes; and (3) dendritic cells (DCs), which fall into two main types (DC1 and DC2), though DC2 can be further subdivided. All these MPs, except AMs and LCs, which are unique to lung and skin, reside in multiple organs, including the heart, skin, liver, and gut. MP subtypes demonstrate a clear division of labor during innate and adaptive immunity with little to virtually no functional redundancy, which means that specific interactions among them are crucial for optimal immune responses against viral, bacterial, and fungal infections. Currently, however, multiple fundamental gaps for the identification and understanding of how these MPs function in human organs limit our ability to develop prevention and treatment strategies across diseases. This project will investigate cross-species and cross-tissue homologies at the cellular, gene expression and functional levels. We will obtain fresh human and mouse tissue from multiple organs (lung, skin, and their draining lymph nodes), and employ three broad approaches. First, we will use both bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) to identify cross-species and cross-tissue homology. RNA-seq provides sequencing depth (i.e., whole-transcriptome coverage), and scRNA-seq provides the ability to confirm bulk homologous MP subtypes and examine the heterogeneity within previously defined MP subtypes. Thus, bioinformatics analyses will identify clusters of homologous MP cell types and align them across species. Second, for each cluster identified, we will identify genes conserved across species and tissues, and those that are unique to a given homologous MP subtype, termed marker genes. The results of these analyses will provide specific genetic markers for human MP subtypes and genetic treatment targets. Broadly speaking, there are two categories of key marker genes we will functionally investigate: those conserved in human-mouse MP counterparts that (1) have been well-defined in mice, but not previously investigated in their human counterparts; and (2) not well-defined or extensively studied in either species. Third, we will undertake a rigorous functional validation of the key genes identified in human-mouse MP counterparts. This includes (a) in-vivo murine models with selective depletion of specific genes using transgenic and conditional knockout (KO) mice; (b) in vitro model systems for human MPs, including assays for antigen acquisition and processing, cellular interactions, and induction of adaptive immune responses; and (c) create time-lapse videos with cellular-level microscopy for functional and morphological characterization.
项目总结/文摘

项目成果

期刊论文数量(0)
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科研奖励数量(0)
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Claudia V Jakubzick其他文献

Claudia V Jakubzick的其他文献

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{{ truncateString('Claudia V Jakubzick', 18)}}的其他基金

Human and mouse transcriptome profiling identifies cross-species homology of mononuclear phagocytes
人类和小鼠转录组分析鉴定单核吞噬细胞的跨物种同源性
  • 批准号:
    10318670
  • 财政年份:
    2020
  • 资助金额:
    $ 98.4万
  • 项目类别:
Functional roles of human pulmonary DC's in the lung draining lymph nodes
人肺 DC 在肺引流淋巴结中的功能作用
  • 批准号:
    9900854
  • 财政年份:
    2017
  • 资助金额:
    $ 98.4万
  • 项目类别:
Induction of cytotoxic T cells by pulmonary dendritic cells
肺树突状细胞诱导细胞毒性 T 细胞
  • 批准号:
    8787774
  • 财政年份:
    2013
  • 资助金额:
    $ 98.4万
  • 项目类别:
Induction of cytotoxic T cells by pulmonary dendritic cells
肺树突状细胞诱导细胞毒性 T 细胞
  • 批准号:
    8602857
  • 财政年份:
    2013
  • 资助金额:
    $ 98.4万
  • 项目类别:
Induction of cytotoxic T cells by pulmonary dendritic cells
肺树突状细胞诱导细胞毒性 T 细胞
  • 批准号:
    8458307
  • 财政年份:
    2013
  • 资助金额:
    $ 98.4万
  • 项目类别:

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