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
基本信息
- 批准号:10211048
- 负责人:
- 金额:$ 70.82万
- 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:2021-09-15 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:APLN geneATAC-seqAdultAffectAirAir SacsAlveolarAlveolar Cell Type IAppearanceAreaAutomobile DrivingBirthBlood VesselsBronchopulmonary DysplasiaCell ProliferationCellsChronicComplicationCuesDataData SetDevelopmentDiseaseDistalEndothelial CellsEndotheliumExperimental ModelsGasesGene ExpressionGene Expression ProfileGenesGenetic TranscriptionGrowthHeterogeneityHyperoxiaImageImpairmentIn VitroInfantKITLG geneKnockout MiceKnowledgeLifeLigandsLungMediatingMicrocirculationMolecularMusNatural regenerationNeonatal Hyperoxic InjuryOrganPathway interactionsPerinatalPhasePhenotypePopulationPremature BirthProcessResolutionRoleSignal TransductionStimulusSurfaceTestingTimeTransgenic OrganismsTranslatingWorkangiogenesisblood vessel developmentin vivoloss of functionlung developmentlung injurymigrationmouse modelnovelnovel strategiesnovel therapeutic interventionpaternal imprintpostnatalpostnatal developmentprematureprogenitorrapid growthreceptorreceptor expressionresponseself-renewalsingle-cell RNA sequencingstemstem cellstargeted treatmenttranscription factortranscriptomicsvirtual
项目摘要
Postnatal lung growth during alveolarization markedly increases gas exchange surface area. Rapid
growth of the pulmonary vasculature during early alveolarization drives distal lung growth. As alveolarization
slows, the vasculature transitions from a phase of angiogenic growth to quiescence, however the molecular
mechanisms regulating this transition remain poorly defined. This gap in knowledge confounds efforts to develop
targeted therapies to treat diseases of dysregulated angiogenesis and impaired alveolarization, including
bronchopulmonary dysplasia, the most common complication of preterm birth. We recently employed single cell
transcriptomics to define endothelial cell (EC) diversity during postnatal lung development and to identify novel
mechanisms regulating pulmonary angiogenesis and quiescence. Our preliminary data identified a tremendous
increase in EC diversity after birth, marked by the appearance of numerous transcriptionally distinct clusters. A
highly proliferative EC cluster is abundant before birth, virtually disappears just after birth, but peaks again at
early alveolarization, a time of exponential pulmonary angiogenesis. The microvascular EC (MEC) broadly
separated into Car4 expressing (Car4+) and Car4- MEC. In contrast with gradual changes in gene expression
in the Car4+ MEC over time, gene expression changed dramatically in the Car4- MEC, with separation of this
population into two transcriptionally distinct clusters of “early” (P1-P7) and “late” (P21) Car4- MEC. High
expression of the paternally imprinted gene-3 (Peg3), a gene expressed by self-renewing progenitor cells,
distinguished the “early” from the “late” Car4- MEC. Peg3 also enhances NFkB signaling, a pathway we
previously identified as essential for pulmonary angiogenesis during early alveolarization. Of note, the expression
of receptor-ligand pairs suggested that cross-talk stemming from the Car4+ MEC may promote pro-proliferative
and pro-angiogenic signaling in the Car4- MEC. Taken together, our data suggest the overall hypothesis that the
early Car4- MEC represent a specialized, highly proliferative and angiogenic EC population required for the rapid
growth of the pulmonary vasculature during early alveolarization, which will be tested through three specific aims.
Aim 1 will utilize transgenic and cell-specific knock out mice, advanced imaging, and loss of function studies in primary
EC to probe the role of Peg3 in promoting proliferation, angiogenesis and NFkB activation in Car4- MEC. Aim 2 will
use FACS sorted Car4+ and Car4- MEC and a novel mouse model permitting targeting of Car4+ MEC to test if
interaction between these two distinct MEC promotes postnatal angiogenesis. Finally, Aim 3 will employ
computational ligand-receptor analysis, ATAC-Seq, and EC-specific knock out mice to determine if chronic
hyperoxia impairs angiogenesis by impairing Car4- MEC proliferation, Peg3-mediated self-renewal and Car4+
and Car4- MEC cross-talk. The successful completion of these studies will provide a deep view of pulmonary
vascular development at single cell resolution, and identify new pathways that may be translated into novel
strategies to enhance lung growth and regeneration in diseases marked by impaired pulmonary angiogenesis.
出生后肺泡化期间的肺生长显著增加了气体交换表面积。快速
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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:
$ 70.82万 - 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:
$ 70.82万 - 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:
$ 70.82万 - 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:
10583456 - 财政年份:2021
- 资助金额:
$ 70.82万 - 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:
$ 70.82万 - 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:
$ 70.82万 - 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:
$ 70.82万 - 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:
$ 70.82万 - 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:
$ 70.82万 - 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:
$ 70.82万 - 项目类别:
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