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:10453066
- 负责人:
- 金额:$ 24.3万
- 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 2024-01-31
- 项目状态:已结题
- 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 MouseLeadLigandsLungMediator of activation proteinModelingMolecularMonitorMusPatientsPersonsPharmacologic SubstancePharmacologyPlayReagentRecoveryRoleSARS-CoV-2 infectionSentinelSeverity of illnessSignal TransductionSourceStructure of parenchyma of lungSurvival RateTamoxifenTestingTherapeuticTracheaVirusVirus Diseasescytokineimprovedinfluenza infectioninsightlung preservationlung regenerationmacrophagemortalitymouse modelneutralizing antibodynotch proteinnovelnovel strategiespulmonary 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
在感染流感或SARS的患者中,高炎症反应是疾病严重程度和死亡的主要原因-
CoV-2。在严重病例中,巨噬细胞反应失调导致急性呼吸窘迫的进展
综合征(ARDS)。然而,巨噬细胞是如何被激活的在很大程度上仍不清楚,特别是在新冠肺炎的肺中。
有趣的是,我们和其他人发现免疫感应簇状细胞异位存在于肺泡区。
(实质)被功能不明的H1N1(PR8)病毒感染后。我们的初步数据显示,这些
丛生细胞来源于薄壁组织中异位的基细胞(也称为豆荚细胞)。更重要的是,簇状细胞
减少和消融巨噬细胞堆积,提高存活率和更好的恢复,
伴随着IL-25水平的下降。药物抑制Notch信号可减少异位数目
PR8感染肺中的簇状细胞。这些发现导致了一种假设,即簇状细胞促进巨噬细胞聚集
通过IL-25和通过抑制Notch减少绒毛细胞来源来减弱过度的巨噬细胞
回应并改善肺功能。我们制定了两个具体的目标来进一步检验这一假设。目标1:确定
在感染流感或SARS-CoV-2时,簇状细胞是否通过IL-25调节巨噬细胞的反应。我们会
还利用一种新的R26hACE2小鼠系构建了第一个靶向SARS-CoV-2感染模型。目标2:检验假设
Notch抑制减少了豆荚细胞的丛生细胞,并减弱了病毒感染的巨噬细胞反应
肺部。为此,我们将删除豆荚细胞中的Rbpjk,并使用一种新的Notch诱饵来抑制Notch信号。把这个放在一起
该项目将首次对丛生细胞在驱动调节失调的巨噬细胞中所起的作用提供机械性的见解
病毒感染的肺部的反应。它还将提供新的方法来减少丛生细胞的分化和衰减
过度炎症。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Jianwen Que其他文献
Jianwen Que的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Jianwen Que', 18)}}的其他基金
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:
$ 24.3万 - 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:
$ 24.3万 - 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:
$ 24.3万 - 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:
$ 24.3万 - 项目类别:
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:
10555330 - 财政年份:2022
- 资助金额:
$ 24.3万 - 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:
$ 24.3万 - 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:
$ 24.3万 - 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:
$ 24.3万 - 项目类别:
相似海外基金
Targeted ablation of cerebral atherosclerosis using supramolecular self-assembly
利用超分子自组装靶向消融脑动脉粥样硬化
- 批准号:
24K21101 - 财政年份:2024
- 资助金额:
$ 24.3万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
心房細動に対するPulsed Field Ablationの組織創傷治癒過程を明らかにする網羅的研究
阐明房颤脉冲场消融组织伤口愈合过程的综合研究
- 批准号:
24K11201 - 财政年份:2024
- 资助金额:
$ 24.3万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
遅延造影心臓MRIによる心房細動Ablation冷却効果の比較:28 vs. 31 mm Cryoballoon
使用延迟对比增强心脏 MRI 比较房颤消融冷却效果:28 毫米与 31 毫米 Cryoballoon
- 批准号:
24K11281 - 财政年份:2024
- 资助金额:
$ 24.3万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
CAREER: Heat Penetration Depth and Direction Control with Closed-Loop Device for Precision Ablation
职业:利用闭环装置控制热穿透深度和方向,实现精确烧蚀
- 批准号:
2338890 - 财政年份:2024
- 资助金额:
$ 24.3万 - 项目类别:
Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
- 批准号:
2334777 - 财政年份:2024
- 资助金额:
$ 24.3万 - 项目类别:
Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
- 批准号:
2334775 - 财政年份:2024
- 资助金额:
$ 24.3万 - 项目类别:
Continuing Grant
InSPACE-VT_Development and Validation of Virtual Pace Mapping to Guide Catheter Ablation of Ventricular Tachycardia
InSPACE-VT_虚拟起搏测绘的开发和验证以指导室性心动过速导管消融
- 批准号:
EP/Z001145/1 - 财政年份:2024
- 资助金额:
$ 24.3万 - 项目类别:
Fellowship
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
- 批准号:
2334776 - 财政年份:2024
- 资助金额:
$ 24.3万 - 项目类别:
Continuing Grant
Cryo laser-ablation system (157+193nm) with 'triple-quad' plasma mass spectrometer, Cryo-LA-ICPMS/MS
带有“三重四极杆”等离子体质谱仪、Cryo-LA-ICPMS/MS 的冷冻激光烧蚀系统 (157 193nm)
- 批准号:
515081333 - 财政年份:2023
- 资助金额:
$ 24.3万 - 项目类别:
Major Research Instrumentation
MRI: Acquisition of a Laser Ablation - Inductively Coupled Plasma - Triple Quadrupole - Mass Spectrometer (LA-ICP-QQQ-MS) System For Research and Education
MRI:获取用于研究和教育的激光烧蚀 - 电感耦合等离子体 - 三重四极杆 - 质谱仪 (LA-ICP-MS/MS) 系统
- 批准号:
2320040 - 财政年份:2023
- 资助金额:
$ 24.3万 - 项目类别:
Standard Grant