The Role of Macrophage Metabolic Crosstalk in CF Chronic Lung Inflammation
巨噬细胞代谢串扰在 CF 慢性肺部炎症中的作用
基本信息
- 批准号:10930185
- 负责人:
- 金额:$ 63.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-23 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:BindingBronchiectasisCellsChronicClinical MedicineCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorDataFailureGlycolysisGoalsImmuneImpairmentInflammationInflammatoryInflammatory ResponseInvestigationIon ChannelKnowledgeLipidsLongevityLungLung infectionsMacrophageMediatingMetabolicMetabolismMicroRNAsMissionMorbidity - disease rateMutationPathogenesisPathway interactionsPersonsPhenotypePopulationPublic HealthPulmonary Cystic FibrosisPulmonary InflammationQuality of lifeRegulator GenesResearchResolutionRespiratory FailureRoleSamplingStimulusSurfaceTestingTransfectionUnited States National Institutes of Healthcell typechronic infectioncohortcystic fibrosis patientsdifferential expressionextracellular vesicleshuman diseasehuman subjectimprovedinnovationneutrophilnew therapeutic targetnovel therapeutic interventionpreventrecruitresponsetranscription factortranslational studyvesicular release
项目摘要
Project Summary
Patients with cystic fibrosis (CF) suffer from chronic infections and lung inflammation leading to bronchiectasis
and, ultimately, respiratory failure. Although recent advances, including the approval of highly effective CFTR
modulator therapy (HEMT), have improved the overall quality of life of people with CF (PwCF), chronic
infection and inflammation are the primary cause of morbidity. Although the magnitude of the inflammatory
response is known to be increased in the CF lung, the mechanisms underlying persistent inflammation are
unknown. We have shown that lung macrophages are critical to the local inflammatory response in CF. Lung
macrophages include resident lung macrophages, as well as lung macrophages that are recruited to the lung
in response to inflammatory stimuli. Our preliminary data demonstrate that CF recruited lung macrophages
have decreased expression of Nrf2, a transcription factor known to regulate cellular metabolism, compared to
non-CF bronchiectasis and control subjects, and this did not improve with HEMT. We also found that CF
recruited lung macrophages are persistently glycolytic and inflammatory, even in the setting of HEMT, while
non-CF bronchiectasis and healthy recruited lung macrophages can transition to an inflammation resolving
phenotype. As immune cell crosstalk can be mediated by extracellular vesicles (EVs), we investigated the
impact of resident lung macrophage EVs on the inflammatory response of recruited lung macrophages and
found that CF resident lung macrophage EVs induce persistent inflammation in recruited lung macrophages.
Lastly, we have preliminary data showing increased miRNAs predicted to inhibit Nrf2 and reduced levels of
inflammation resolving lipids in EVs from CF resident lung macrophages. Thus, we hypothesize that specific
miRNAs and lipids within CF resident LM EVs reduce Nrf2 levels in recruited LMs, causing persistent
glycolysis and failure to transition to an inflammation resolving phenotype. In Aim 1, we will test the hypothesis
that there are functionally important immunometabolic differences in CF lung macrophages that are specific to
CF and persist after HEMT. In this Aim, we will fully characterize subpopulations of lung macrophages in the
CF lung and will quantify differences in cellular metabolism and inflammation resolution between resident and
recruited lung macrophages in PwCF, non-CF bronchiectasis subjects, and healthy subjects. In Aim 2, we will
test the hypothesis that specific miRNAs within EVs released by CF resident lung macrophages impact the
inflammatory response of recruited lung macrophages. In Aim 3, we will test the hypothesis that the lipid
content of EVs released by CF resident lung macrophages prevents the shift to an inflammation resolution
phenotype in recruited lung macrophages. The proposed studies are unique because they involve human
subjects before and after HEMT and thus, our data will be directly relevant to PwCF. In addition, our studies
will provide new and essential information on the mechanisms of persistent lung inflammation in CF and will
allow us to identify targets for novel therapies to reduce harmful CF lung inflammation and improve the lives
and longevity of people living with CF.
项目摘要
囊性纤维化(CF)患者患有慢性感染和肺部炎症,导致支气管扩张
最终导致呼吸衰竭尽管最近的进展,包括批准高效的CFTR
调节剂治疗(HEMT),改善了CF(PwCF)患者的整体生活质量,慢性
感染和炎症是发病的主要原因。尽管这场炎症的严重程度
已知CF肺中的反应增加,持续性炎症的潜在机制是
未知我们已经表明,肺巨噬细胞是至关重要的CF的局部炎症反应。肺
巨噬细胞包括驻留的肺巨噬细胞,以及被募集到肺的肺巨噬细胞
对炎症刺激的反应。我们的初步数据表明,CF招募肺巨噬细胞,
Nrf2的表达降低,Nrf2是一种已知调节细胞代谢的转录因子,
非CF支气管扩张和对照受试者,这并没有改善与HEMT。我们还发现,CF
招募的肺巨噬细胞持续糖酵解和炎症,即使在HEMT的设置,而
非CF支气管扩张和健康的肺巨噬细胞可以转变为炎症消退
表型由于免疫细胞串扰可以由细胞外囊泡(EV)介导,我们研究了免疫细胞串扰。
常驻肺巨噬细胞EV对招募的肺巨噬细胞的炎症反应的影响,
发现CF驻留肺巨噬细胞EV在募集的肺巨噬细胞中诱导持续性炎症。
最后,我们有初步的数据显示,增加的miRNAs预测抑制Nrf2和减少的水平,
CF驻留肺巨噬细胞EV中的炎症溶解脂质。因此,我们假设,
CF驻留LM EV内的miRNA和脂质降低了招募LM中的Nrf2水平,导致持续的Nrf2水平升高。
糖酵解和未能转变为炎症消退表型。在目标1中,我们将检验假设
CF肺巨噬细胞中存在功能上重要的免疫代谢差异,
CF和HEMT后持续存在。在这个目标中,我们将充分表征肺巨噬细胞的亚群,
CF肺,并将量化居民和非居民之间细胞代谢和炎症消退的差异。
在PwCF、非CF支气管扩张受试者和健康受试者中招募肺巨噬细胞。在目标2中,我们将
测试CF驻留肺巨噬细胞释放的EV内的特异性miRNA影响
募集的肺巨噬细胞的炎症反应。在目标3中,我们将检验脂质
CF驻留肺巨噬细胞释放的EV含量阻止向炎症消退的转变
在募集的肺巨噬细胞中的表型。这些研究是独一无二的,因为它们涉及人类
因此,我们的数据将直接与PwCF相关。此外,我们的研究
将为CF中持续性肺部炎症的机制提供新的和重要的信息,
使我们能够确定新疗法的目标,以减少有害的CF肺部炎症并改善生活
和CF患者的寿命。
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)
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{{ truncateString('ALIX ASHARE', 18)}}的其他基金
Macrophage Pathogen Interactions in Regional Cystic Fibrosis Lung Inflammation
巨噬细胞病原体在局部囊性纤维化肺部炎症中的相互作用
- 批准号:
10630960 - 财政年份:2020
- 资助金额:
$ 63.73万 - 项目类别:
Macrophage Pathogen Interactions in Regional Cystic Fibrosis Lung Inflammation
巨噬细胞病原体在局部囊性纤维化肺部炎症中的相互作用
- 批准号:
10404969 - 财政年份:2020
- 资助金额:
$ 63.73万 - 项目类别:
Macrophage Pathogen Interactions in Regional Cystic Fibrosis Lung Inflammation
巨噬细胞病原体在局部囊性纤维化肺部炎症中的相互作用
- 批准号:
10207764 - 财政年份:2020
- 资助金额:
$ 63.73万 - 项目类别:
Macrophage Pathogen Interactions in Regional Cystic Fibrosis Lung Inflammation
巨噬细胞病原体在局部囊性纤维化肺部炎症中的相互作用
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10055030 - 财政年份:2020
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$ 63.73万 - 项目类别:
Regional Hypoxia Impacts the Heterogeneity of Inflammatory Lung Disease
区域缺氧影响炎症性肺病的异质性
- 批准号:
8881421 - 财政年份:2015
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$ 63.73万 - 项目类别:
Regional Hypoxia Impacts the Heterogeneity of Inflammatory Lung Disease
区域缺氧影响炎症性肺病的异质性
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9307968 - 财政年份:2015
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