Tuft Cells Modulate Macrophage Response Following Lung Viral Infection

簇细胞调节肺部病毒感染后的巨噬细胞反应

基本信息

  • 批准号:
    10555330
  • 负责人:
  • 金额:
    $ 20.25万
  • 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:
    2022-02-01 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT The hyperinflammatory response is a major cause of disease severity and death in patients infected by influenza or SARS- CoV-2. In severe cases dysregulated macrophage responses contribute to the progression of acute respiratory distress syndrome (ARDS). Nevertheless, how macrophages are activated remains largely unknown, especially in COVID-19 lungs. Intriguingly, we and others found that the immune sensing tuft cells are ectopically present in the alveolar region (parenchyma) following infection by H1N1 (PR8) virus with unclarified functions. Our preliminary data show that these tuft cells are derived from ectopic basal cells (also known as pod cells) in the parenchyma. More importantly, tuft cell reduction and ablation result in reduced macrophage accumulation, improved survival rate and better recovery, accompanied by the decreased level of Il-25. Pharmacological inhibition of Notch signaling reduces the numbers of ectopic tuft cells in PR8-infected lungs. These findings lead to the hypothesis that tuft cells enhance macrophage accumulation through Il-25 and that reducing tuft cell derivation through Notch inhibition attenuates excessive macrophage responses and improves lung function. We formulate two specific aims to further test the hypothesis. Aim1: To determine whether tuft cells modulate macrophage responses through Il-25 upon infection with influenza or SARS-CoV-2. We will also use a novel R26hACE2 mouse line to build the first targeted SARS-CoV-2 infection model. Aim 2: To test the hypothesis that Notch inhibition reduces tuft cell derivation from pod cells and attenuates macrophage responses in virus-infected lungs. In this aim, we will delete Rbpjk in pod cells and use a novel Notch decoy to inhibit Notch signaling. Together this project will provide the first mechanistic insights into the role played by tuft cells in driving dysregulated macrophage responses in virus-infected lungs. It will also offer new approaches to reduce tuft cell differentiation and attenuate hyperinflammation.
摘要

项目成果

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Jianwen Que其他文献

Jianwen Que的其他文献

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{{ truncateString('Jianwen Que', 18)}}的其他基金

Tuft Cells Modulate Macrophage Response Following Lung Viral Infection
簇细胞调节肺部病毒感染后的巨噬细胞反应
  • 批准号:
    10453066
  • 财政年份:
    2022
  • 资助金额:
    $ 20.25万
  • 项目类别:
The Enrichment Program
强化计划
  • 批准号:
    10612981
  • 财政年份:
    2022
  • 资助金额:
    $ 20.25万
  • 项目类别:
Gastroesophageal junction stem cells as the origin of Barretts esophagus and cancer
胃食管连接处干细胞是巴雷特食管和癌症的起源
  • 批准号:
    10506097
  • 财政年份:
    2022
  • 资助金额:
    $ 20.25万
  • 项目类别:
SOX4-Mediated Transcription Program in Esophageal Adenocarcinoma
SOX4 介导的食管腺癌转录程序
  • 批准号:
    10662315
  • 财政年份:
    2022
  • 资助金额:
    $ 20.25万
  • 项目类别:
Depletion of Barrett's and Esophageal Adenocarcinoma Cells with CRISPR/Cas13d
使用 CRISPR/Cas13d 消除 Barrett 细胞和食管腺癌细胞
  • 批准号:
    10831233
  • 财政年份:
    2022
  • 资助金额:
    $ 20.25万
  • 项目类别:
The Enrichment Program
强化计划
  • 批准号:
    10443140
  • 财政年份:
    2022
  • 资助金额:
    $ 20.25万
  • 项目类别:
SOX4-Mediated Transcription Program in Esophageal Adenocarcinoma
SOX4 介导的食管腺癌转录程序
  • 批准号:
    10407747
  • 财政年份:
    2022
  • 资助金额:
    $ 20.25万
  • 项目类别:
Improve Lung Regeneration Through Targeting Tuft Cells Following Viral Infection
通过靶向病毒感染后的簇细胞改善肺再生
  • 批准号:
    10679030
  • 财政年份:
    2021
  • 资助金额:
    $ 20.25万
  • 项目类别:
Improve Lung Regeneration Through Targeting Tuft Cells Following Viral Infection
通过靶向病毒感染后的簇细胞改善肺再生
  • 批准号:
    10471373
  • 财政年份:
    2021
  • 资助金额:
    $ 20.25万
  • 项目类别:
Improve Lung Regeneration Through Targeting Tuft Cells Following Viral Infection
通过靶向病毒感染后的簇细胞改善肺再生
  • 批准号:
    10298186
  • 财政年份:
    2021
  • 资助金额:
    $ 20.25万
  • 项目类别:

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