Diverse Homeostatic Roles for Distinct Macrophages in the Developing Lung Vasculature

不同巨噬细胞在发育中的肺血管系统中的多种稳态作用

基本信息

  • 批准号:
    10583456
  • 负责人:
  • 金额:
    $ 62.08万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-03-05 至 2025-02-28
  • 项目状态:
    未结题

项目摘要

Alveolarization, the final stage of lung development occurring primarily postnatally, markedly increases gas exchange surface area. Rapid growth of the pulmonary vasculature by angiogenesis during early alveolarization drives distal lung growth, and disrupted angiogenesis impairs alveolarization. In other organs, specialized macrophages support angiogenesis by promoting blood vessel formation, providing survival and migratory cues to EC, and facilitating vascular anastomoses. However, the role of macrophages in the developing pulmonary vasculature remains entirely unknown. We recently embarked on a project employing single cell RNA-sequencing to define macrophage diversity during late embryonic and early postnatal lung development. Macrophages are extremely heterogenous with diverse phenotypes that are lineage- and tissue- specific, and highly influenced by the microenvironment. Preliminary data in this proposal demonstrate a tremendous increase in macrophage diversity after birth. Specialized, highly proliferative macrophages present before birth are replaced after birth by a complex and dynamic mixture of diverse macrophage subtypes exhibiting unique gene signatures, developmental gradients in gene expression, and specific locations within the lung suggesting distinct functions in tissue remodeling, angiogenesis, and immunity. Interestingly, a subset of embryonic macrophages was found to completely encircle small arterioles and express numerous genes that regulate lung branching, angiogenesis, and EC phenotype. After birth, these cells transitioned to an intermediate subset present only during the first few weeks of postnatal life that expressed additional tissue remodeling genes. Taken together, our data suggest the hypothesis that distinct macrophage populations support alveolarization by regulating pulmonary vascular development through the expression of factors that influence vascular growth and remodeling, which will be tested through three specific aims. Aim 1 will combine multiplexed in situ hybridization, lineage tracing, studies in primary EC and macrophages, and advanced imaging in transgenic and knock-out mice to define the role of specific macrophage subsets in modulating EC phenotype and regulating lung parenchymal and vascular growth. Aim 2 will utilize multiplexed in situ hybridization, conditional knock out mouse models, and ligand-receptor profiling of single cell datasets from pulmonary EC and macrophages to probe pathways mediating macrophage-EC communication. Finally, Aim 3 will determine if chronic hyperoxia alters diversity and phenotype of the lung macrophages during acute injury and after recovery, and specifically impairs developmental and homeostatic functions of lung macrophages. The successful completion of these studies will provide a multifaceted view of the diverse functions of lung macrophages during embryonic and early postnatal development at single cell resolution, and identify new pathways that could be directly translated into novel strategies to modulate vascular growth and regeneration in diseases marked by impaired pulmonary angiogenesis.
肺泡化,肺发育的最后阶段,主要发生在出生后,显著增加

项目成果

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Cristina Maria Alvira其他文献

Cristina Maria Alvira的其他文献

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{{ truncateString('Cristina Maria Alvira', 18)}}的其他基金

Pericytes and postnatal alveolarization: Role of hypoxia inducible factors
周细胞和出生后肺泡化:缺氧诱导因素的作用
  • 批准号:
    10467727
  • 财政年份:
    2022
  • 资助金额:
    $ 62.08万
  • 项目类别:
Pericytes and postnatal alveolarization: Role of hypoxia inducible factors
周细胞和出生后肺泡化:缺氧诱导因素的作用
  • 批准号:
    10615235
  • 财政年份:
    2022
  • 资助金额:
    $ 62.08万
  • 项目类别:
Developmental Heterogeneity of Pulmonary Endothelial Phenotype at Single Cell Resolution
单细胞分辨率肺内皮表型的发育异质性
  • 批准号:
    10678976
  • 财政年份:
    2021
  • 资助金额:
    $ 62.08万
  • 项目类别:
Developmental Heterogeneity of Pulmonary Endothelial Phenotype at Single Cell Resolution
单细胞分辨率肺内皮表型的发育异质性
  • 批准号:
    10211048
  • 财政年份:
    2021
  • 资助金额:
    $ 62.08万
  • 项目类别:
Diverse Homeostatic Roles for Distinct Macrophages in the Developing Lung Vasculature
不同巨噬细胞在发育中的肺血管系统中的多种稳态作用
  • 批准号:
    10362528
  • 财政年份:
    2021
  • 资助金额:
    $ 62.08万
  • 项目类别:
Novel pathways regulating calcium mediated contractility in the pregnant uterus
调节妊娠子宫钙介导的收缩性的新途径
  • 批准号:
    10373975
  • 财政年份:
    2018
  • 资助金额:
    $ 62.08万
  • 项目类别:
Novel pathways regulating calcium mediated contractility in the pregnant uterus
调节妊娠子宫钙介导的收缩性的新途径
  • 批准号:
    9893885
  • 财政年份:
    2018
  • 资助金额:
    $ 62.08万
  • 项目类别:
Novel Molecular Mechanisms Regulating Postnatal Pulmonary Angiogenesis
调节产后肺血管生成的新分子机制
  • 批准号:
    8686276
  • 财政年份:
    2014
  • 资助金额:
    $ 62.08万
  • 项目类别:
Novel Molecular Mechanisms Regulating Postnatal Pulmonary Angiogenesis
调节产后肺血管生成的新分子机制
  • 批准号:
    9265926
  • 财政年份:
    2014
  • 资助金额:
    $ 62.08万
  • 项目类别:
Novel Molecular Mechanisms Regulating Postnatal Pulmonary Angiogenesis
调节产后肺血管生成的新分子机制
  • 批准号:
    9059764
  • 财政年份:
    2014
  • 资助金额:
    $ 62.08万
  • 项目类别:

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