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
- 来源:
- 关键词:2019-nCoVAblationAcute Lung InjuryAcute Respiratory Distress SyndromeAddressAlveolarAttenuatedAutomobile DrivingBasal CellCOVID-19COVID-19 pandemic effectsCell Differentiation processCellsCessation of lifeCoronavirus InfectionsDataDerivation procedureGeneticImmuneInfectionInfiltrationInflammationInflammatory ResponseInfluenzaInfluenza A Virus, H1N1 SubtypeIntestinesKnock-in MouseLeadLigandsLungMacrophageMediatorModelingMolecularMonitorMusPatientsPersonsPharmacologic SubstancePlayPod cellsReagentRecoveryRoleSARS-CoV-2 infectionSensorySentinelSeverity of illnessSignal TransductionSourceStructure of parenchyma of lungSurvival RateTamoxifenTestingTherapeuticTracheaVirusVirus Diseasescytokineimprovedinfluenza infectioninsightlung preservationlung regenerationmortalitymouse modelneutralizing antibodynotch proteinnovelnovel strategiespharmacologicpulmonary functionresponseside effectsingle cell analysistherapeutic target
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
期刊论文数量(0)
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科研奖励数量(0)
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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:
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:
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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