Biology of Lymphangiogenesis in the Adult Lung
成人肺淋巴管生成的生物学
基本信息
- 批准号:10636911
- 负责人:
- 金额:$ 59.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAdultAllelesAnatomyAttenuatedBiologyBlood VesselsCell CountCell LineCell NucleusCell ProliferationCellsCellular biologyContralateralCre lox recombination systemDataDeoxyuridineDerivation procedureDiseaseDistalFluid BalanceGasesGenetic EngineeringGenetic TranscriptionGoalsGrantHealthHeartHeterogeneityHomeoboxHomeostasisImmuneImmune responseInfectionInflammationInfluenzaKnowledgeLabelLeftLifeLiverLobeLocationLungLymphangiogenesisLymphaticLymphatic Endothelial CellsLymphatic SystemMessenger RNAMicroanatomyModelingMolecular AnalysisMusMyelogenousNuclearNuclear ProteinNuclear RNAPathway interactionsPhasePhenotypePhysiologicalPlayPopulationProcessProliferatingPropertyRNAReactionRegulationRoleSignal PathwaySignal TransductionSiteSourceSystemSystems BiologyTimeTissuesVenousViralViral Load resultViral Respiratory Tract InfectionVirusbiological systemseffective therapyexperimental studyfetalflugenetic informationimmune functioninfluenza infectioninsightlung healthlung lobemechanical signalpostnatalprotein expressionpulmonary functionresponsetissue injurytraffickingtranscription factortranscriptome sequencingtreatment strategy
项目摘要
PROJECT SUMMARY/ABSTRACT
The lung’s lymphatic system plays a critical role in lung health by maintaining fluid homeostasis and by serving
as a conduit for immune cell trafficking. Despite the importance of this network however, there are significant
knowledge gaps in the basic biology of this system and its key cellular constituent, the lymphatic endothelial cell
(LEC). For one, very little is known regarding the origin and replacement of lung LECs in adult life and how
different origins and micro-anatomical locations of LECs might be associated with different roles, specifically in
immune responses. Indeed, whether lung LECs comprise a heterogeneously and functionally distinct set of cell
subtypes or a largely homogenous population is unknown. After instillation of flu into the mouse left lung lobe,
we observed a local and vigorous lymphangiogenic reaction manifested by early vessel dilation followed by
expansion of the lymphatic network itself. This is associated with a significant 1.5-2-fold increase of LECs at 7
days post-infection (dpi) and a significant 2-3-fold increase at 21 dpi, a time when the virus is cleared. Edu
labeling demonstrated that 20% of LECs are proliferating at 7 dpi vs. <1% in control mice. These data along
with observations suggesting 2 distinct sources of adult LECS, one fetal and from a venous origin, and one post-
natal and from a myeloid origin, underscore the potential for LEC heterogeneity both functionally and micro-
anatomically. This will be addressed in Aim 1 by evaluating the role and localization of these 2 sources of LECs
during adult lung homeostasis and viral-induced lymphangiogenesis by lineage tracing. These studies will be
supplemented by single nuclear RNA sequencing in Aim 2 to generate LEC specific genetic information that will
be key to understanding LEC heterogeneity and immune response to infection, along with derivation of LEC
subset tissue localization markers. We also found that the flu-infected lung is characterized by decreased LEC
nuclear localization of YAP and TAZ, which are the primary transcriptional effectors in the Hippo signaling
pathway. This highly conserved pathway is a central regulator of cell phenotype in many biological systems with
decreased nuclear YAP/TAZ signifying signal inhibition. Taken together, these findings suggest that the status
of Hippo signaling may be a key factor regulating LEC proliferation and phenotype. Lastly, we observed vigorous
LEC proliferation in the contralateral uninfected lung, suggesting the interesting possibility that LEC proliferation
is a systemic response to flu. These issues will be further studied in Aim 3 by the selective deletion of hippo
signaling in LECs and by examining lymphangiogenesis in liver and heart in our flu model. In sum, we posit that
the state-of-the art shows a pronounced need for basic information that can resolve fundamental questions in
the field of lung lymphatic biology. With strong background data and robust models, we believe that the studies
in this grant will help to resolve these basic questions, and as result will expand and deepen our understanding
of LEC origin, mechanism of expansion, heterogeneity, function, and phenotype regulation.
项目总结/摘要
肺的淋巴系统在肺健康中起着至关重要的作用,它通过维持体液平衡,
作为免疫细胞运输的管道。尽管这个网络的重要性,但是,
在该系统的基础生物学及其关键细胞成分淋巴管内皮细胞方面的知识空白
(LEC)。首先,关于成年后肺LEC的起源和替代以及如何发生的知之甚少。
LEC的不同起源和显微解剖位置可能与不同的作用有关,特别是在
免疫反应。事实上,肺LEC是否包含一组异质的和功能不同的细胞,
亚型或很大程度上同质的群体是未知的。将流感病毒滴入小鼠左肺叶后,
我们观察到局部和强烈的淋巴管生成反应,表现为早期血管扩张,
淋巴网络本身的扩张。这与7 ℃时LEC显著增加1.5-2倍有关
感染后10天(dpi),病毒被清除的21 dpi时显著增加2-3倍。Edu
标记证实20%的LEC在7 dpi增殖,而对照小鼠中<1%。这些数据沿着
观察结果表明成人LECS有2个不同来源,一个是胎儿来源,来自静脉,另一个是术后来源。
纳塔尔和骨髓来源,强调LEC异质性的可能性,无论是功能上还是微观上,
从解剖学上讲这将在目标1中通过评估这两个LEC来源的作用和本地化来解决
在成人肺稳态和病毒诱导的淋巴管生成过程中,通过谱系追踪。这些研究报告将
在Aim 2中补充单核RNA测序,以产生LEC特异性遗传信息,
是理解LEC异质性和感染免疫应答的关键,沿着LEC的衍生
亚组组织定位标记物。我们还发现,流感感染肺的特征是LEC减少,
雅普和TAZ的核定位,它们是Hippo信号传导中的主要转录效应子
通路这种高度保守的途径是许多生物系统中细胞表型的中心调节因子,
细胞核雅普/TAZ比值降低,信号抑制。综上所述,这些发现表明,
Hippo信号转导通路可能是调节LEC增殖和表型的关键因素。最后,我们观察到,
LEC增殖在对侧未感染的肺,提示有趣的可能性,LEC增殖
是对流感的系统性反应这些问题将在目标3中通过选择性删除hippo来进一步研究
通过在LEC中的信号传导以及在我们的流感模型中检查肝脏和心脏中的淋巴管生成。总之,我们认为,
最先进的技术表明,对能够解决以下基本问题的基本信息的需求是明显的:
肺淋巴生物学领域。有了强大的背景数据和强大的模型,我们相信这些研究
在这个赠款将有助于解决这些基本问题,并因此将扩大和加深我们的理解
LEC的起源,扩展机制,异质性,功能和表型调节。
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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Alan Fine Fine其他文献
Alan Fine Fine的其他文献
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{{ truncateString('Alan Fine Fine', 18)}}的其他基金
MEDICAL STUDENT SUMMER RESEARCH PROGRAM IN HEART, LUNG AND BLOOD DISEASES (RPHLB)
医学生心脏、肺和血液疾病夏季研究计划 (RPHLB)
- 批准号:
10597664 - 财政年份:2019
- 资助金额:
$ 59.59万 - 项目类别:
MEDICAL STUDENT SUMMER RESEARCH PROGRAM IN HEART, LUNG AND BLOOD DISEASES (RPHLB)
医学生心脏、肺和血液疾病夏季研究计划 (RPHLB)
- 批准号:
10400064 - 财政年份:2019
- 资助金额:
$ 59.59万 - 项目类别:
Hematopoeitic cell fates in the developing lung
发育中的肺中的造血细胞命运
- 批准号:
7791324 - 财政年份:2008
- 资助金额:
$ 59.59万 - 项目类别:
Hematopoeitic cell fates in the developing lung
发育中的肺中的造血细胞命运
- 批准号:
7525953 - 财政年份:2008
- 资助金额:
$ 59.59万 - 项目类别:
Hematopoeitic cell fates in the developing lung
发育中的肺中的造血细胞命运
- 批准号:
7677294 - 财政年份:2008
- 资助金额:
$ 59.59万 - 项目类别:
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