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

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/文摘

项目成果

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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

Biology of Lymphangiogenesis in the Adult Lung
成人肺淋巴管生成的生物学
  • 批准号:
    10501003
  • 财政年份:
    2022
  • 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:
    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:
Microscopy-Image Analysis and FACS Core
显微镜图像分析和 FACS 核心
  • 批准号:
    8213818
  • 财政年份:
    2011
  • 资助金额:
    $ 59.59万
  • 项目类别:
Microscopy-Image Analysis and FACS Core
显微镜图像分析和 FACS 核心
  • 批准号:
    8147556
  • 财政年份:
    2010
  • 资助金额:
    $ 59.59万
  • 项目类别:
New Approaches for the Study of Lung Fibrocytes
肺纤维细胞研究的新方法
  • 批准号:
    8059488
  • 财政年份:
    2010
  • 资助金额:
    $ 59.59万
  • 项目类别:
New Approaches for the Study of Lung Fibrocytes
肺纤维细胞研究的新方法
  • 批准号:
    8204402
  • 财政年份:
    2010
  • 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:
    7677294
  • 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:

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