The Lung Endothelium as an Instructive Niche for the Innate Immune System during Vascular Injury

肺内皮细胞作为血管损伤期间先天免疫系统的指导性生态位

基本信息

  • 批准号:
    10706498
  • 负责人:
  • 金额:
    $ 233.93万
  • 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:
    2022-09-20 至 2027-08-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT OF PROGRAM The loss of lung vascular barrier integrity in settings as diverse as trauma and bacterial or viral infections is a hallmark of acute lung injury (ALI) and its serious variant ARDS. ALI is characterized by protein-rich edema and ultimately respiratory failure. Targeted therapies remain an urgent unmet need. It is now becoming increasingly clear that the lung endothelium is a complex monolayer, almost an organ itself, consisting of not only alveolar endothelial cells (EC) but also specific EC populations found in pulmonary microvessels, arteries and veins. Recently, we have shown using RNA-sequencing that the lung EC demonstrate significant upregulation of genes involved in processes related to immune function such as leukocyte cell adhesion, leukocyte migration, and regulation of immune system. This finding was consistent with lung EC being continuously exposed to the external environment, unlike EC in other organs such as the brain or heart. Studying this immune regulatory function of the lung endothelium is crucial for understanding how the EC controls immunity and the host defense function of lungs, and also how its dysregulation or impairment of the immune response leads to pathogenesis of ALI. This Program builds on the extraordinary success of a previous 20-year entity, evident by our accomplishments. We have helped establish the lung endothelium as a node for understanding the lung’s response to infection and injury and our work has led to better understanding of ways of treating endothelial barrier breakdown in lungs. This revised application, focusing on the enigmatic innate immune function of the lung endothelium, is built on foundations of synergy and collaborations. Our Supporting data show the central role of the lung endothelium in driving inflammatory lung injury, and at the same time provides clues that will lead to new lung injury targeting therapies. Project 1 will test the hypothesis that the post-translationally modified endoplasmic reticulum-localized spinghosine-1-phosphate receptor S1PR1 in an unexpected manner reprograms lung endothelium to activate a signaling cascade that induces inflammatory lung injury. Project 2 will test the hypothesis that a novel lung endothelial cell expressed ubiquitin E3 ligase CHFR (checkpoint with fork-head and ring finger domain) identified by us regulates VE-cadherin-mediated endothelial barrier integrity and lung’s innate immune function. Targeting CHFR thus holds promise for preventing inflammatory lung injury. Project 3 will test the hypothesis that lung endothelial mitochondrial dysfunction and induction of mitophagy regulate endothelial regeneration and serve as a key check point for restoring homeostasis and preventing inflammatory injury. These Projects are supported by innovative scientific Cores (Epigenetics and Transcriptomics (Core B), Cellular Imaging (Core C), and Intravital Imaging and Physiology (Core D) that will make it possible to rigorously address the innate immune function of the lung endothelium and its role in orchestrating restoration of homeostasis. We hope to unravel the innate immune function of the lung endothelium, thus providing strategies to develop new targeted therapies against ALI and ARDS.
程序摘要

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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DOLLY MEHTA其他文献

DOLLY MEHTA的其他文献

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{{ truncateString('DOLLY MEHTA', 18)}}的其他基金

Targeting mechanisms activating ion-channel for preventing acute lung injury
激活离子通道的靶向机制预防急性肺损伤
  • 批准号:
    10659781
  • 财政年份:
    2023
  • 资助金额:
    $ 233.93万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10706500
  • 财政年份:
    2022
  • 资助金额:
    $ 233.93万
  • 项目类别:
The Lung Endothelium as an Instructive Niche for the Innate Immune System during Vascular Injury
肺内皮细胞作为血管损伤期间先天免疫系统的指导性生态位
  • 批准号:
    10494611
  • 财政年份:
    2022
  • 资助金额:
    $ 233.93万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10494612
  • 财政年份:
    2022
  • 资助金额:
    $ 233.93万
  • 项目类别:
S1PR1 Mislocalization in Lung Endothelium Regulates Innate Immune Function and Mediates Inflammatory Lung Injury
S1PR1 在肺内皮细胞中的错误定位调节先天免疫功能并介导炎症性肺损伤
  • 批准号:
    10706510
  • 财政年份:
    2022
  • 资助金额:
    $ 233.93万
  • 项目类别:
S1PR1 Mislocalization in Lung Endothelium Regulates Innate Immune Function and Mediates Inflammatory Lung Injury
S1PR1 在肺内皮细胞中的错误定位调节先天免疫功能并介导炎症性肺损伤
  • 批准号:
    10494616
  • 财政年份:
    2022
  • 资助金额:
    $ 233.93万
  • 项目类别:
CREB Instruction of Macrophage Fate and Lung fluid homeostasis
CREB对巨噬细胞命运和肺液稳态的指导
  • 批准号:
    10305990
  • 财政年份:
    2021
  • 资助金额:
    $ 233.93万
  • 项目类别:
CREB Programming of Alveolar Macrophage Population and Inflammatory Lung Injury
肺泡巨噬细胞群和炎症性肺损伤的 CREB ​​编程
  • 批准号:
    10491070
  • 财政年份:
    2021
  • 资助金额:
    $ 233.93万
  • 项目类别:
CREB Programming of Alveolar Macrophage Population and Inflammatory Lung Injury
肺泡巨噬细胞群和炎症性肺损伤的 CREB ​​编程
  • 批准号:
    10701930
  • 财政年份:
    2021
  • 资助金额:
    $ 233.93万
  • 项目类别:
CREB Instruction of Macrophage Fate and Lung fluid homeostasis
CREB对巨噬细胞命运和肺液稳态的指导
  • 批准号:
    10625859
  • 财政年份:
    2021
  • 资助金额:
    $ 233.93万
  • 项目类别:

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Treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome
急性肺损伤和急性呼吸窘迫综合征的治疗
  • 批准号:
    8429041
  • 财政年份:
    2011
  • 资助金额:
    $ 233.93万
  • 项目类别:
Analysis of extravascular lung water dynamics and exhaustive evaluation of pulmonary epithelial metabolites to establish a novel therapeutic approach for acute lung injury/ acute respiratory distress syndrome
分析血管外肺水动力学和详尽评估肺上皮代谢物,以建立急性肺损伤/急性呼吸窘迫综合征的新治疗方法
  • 批准号:
    22592023
  • 财政年份:
    2010
  • 资助金额:
    $ 233.93万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
OBSERVATIONAL STUDY OF ACUTE LUNG INJURY & ACUTE RESPIRATORY DISTRESS SYNDROME
急性肺损伤的观察性研究
  • 批准号:
    7603766
  • 财政年份:
    2007
  • 资助金额:
    $ 233.93万
  • 项目类别:
Treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome
急性肺损伤和急性呼吸窘迫综合征的治疗
  • 批准号:
    8328484
  • 财政年份:
    2005
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    $ 233.93万
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Treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome
急性肺损伤和急性呼吸窘迫综合征的治疗
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  • 财政年份:
    2005
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    $ 233.93万
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Treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome
急性肺损伤和急性呼吸窘迫综合征的治疗
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    8602427
  • 财政年份:
    2005
  • 资助金额:
    $ 233.93万
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Treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome
急性肺损伤和急性呼吸窘迫综合征的治疗
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  • 财政年份:
    2005
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    $ 233.93万
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急性肺损伤和急性呼吸窘迫综合征的治疗
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急性肺损伤和急性呼吸窘迫综合征的治疗
  • 批准号:
    8654999
  • 财政年份:
    2005
  • 资助金额:
    $ 233.93万
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急性肺损伤和急性呼吸窘迫综合征的治疗
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    8020428
  • 财政年份:
    2005
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