Alveolar Macrophages as Age-Related Drivers of Disordered Tissue Repair
肺泡巨噬细胞作为紊乱组织修复的年龄相关驱动因素
基本信息
- 批准号:10417059
- 负责人:
- 金额:$ 39.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-07-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AgingAirAlveolarAlveolar MacrophagesAlzheimer&aposs DiseaseAnimalsAreaAwardCaenorhabditis elegansCause of DeathCellsCessation of lifeChronic Kidney FailureClinicalCommunicable DiseasesComplexDataDementiaDiseaseEffector CellElderlyElectron TransportEpithelialFlow CytometryFriendsFunctional disorderFunding OpportunitiesGenesGeneticGenetic TranscriptionHealthcareHospitalsImmuneImmune System DiseasesImpaired cognitionImpairmentInfectionInfluenza A virusInhalationInjuryInstructionLinkLungMediatingMetforminMitochondriaMitochondrial Electron Transport Complex IModernizationMorbidity - disease rateMusMyocardial InfarctionPathway interactionsPlayPneumoniaPopulationPredispositionProteomicsRecoveryResearchRiskRoleSentinelSkeletal MuscleStressSurvivorsTestingTissuesToxinTranscriptional ActivationTranslational RepressionWorkactivating transcription factoractivating transcription factor 4age relatedagedbiological adaptation to stressend of lifeexperimental studyhealthspanimprovedinfluenza A pneumoniainhibitorinjury and repairjuvenile animallung injurylung repairmacrophagemanmonocytemortalityolder patientparticlepathogenproteostasisrecruitrepair functionrepairedresilienceresponsescavenger receptorsingle-cell RNA sequencingsmall molecule inhibitortissue repairtranscriptomics
项目摘要
Abstract
One of the most important clinical manifestations of age-related immune dysfunction is an enhanced
susceptibility to and mortality from pneumonia, the most common cause of death from an infectious disease
worldwide. In the year after hospital discharge older pneumonia survivors have an increased risk of developing
age-related disorders including persistent lung injury, skeletal muscle dysfunction leading to immobility,
myocardial infarction, chronic kidney disease, dementia and cognitive impairment. As such, pneumonia is a
gateway for the compounding morbidity that limits healthspan at the end of life. Alveolar macrophages are the
most abundant resident immune population in the alveolar space, where they serve as sentinel and effector cells
that respond to inhaled particles, toxins and pathogens in the ambient air. We used a combination of causal
genetic experiments targeting macrophages and unbiased transcriptomic and proteomic analyses of flow-sorted
cell populations from the lungs of influenza A infected mice to suggest that the reparative function of alveolar
macrophages is reduced during aging. These findings converge with the concept of mitochondrial hormesis that
emerged from Dr. Morimoto and Dr. Chandel's work (Project 2). They found that low level inhibition of
mitochondrial electron transport in C. elegans induced a proteostasis-protective response that enhanced the
resilience of aging animals, while more dramatic inhibition of electron transport was toxic. In mice, we found
that metformin inhibits mitochondrial electron transport at complex I in alveolar macrophages to induce the
expression of proteostasis protective genes in response to environmental stress. Mitochondrial electron
transport is linked with proteostasis through the integrated stress response and activation of the transcription
factor ATF4. Consistently, we found a small molecule inhibitor of the integrated stress response, ISRIB,
accelerated lung repair after influenza A infection in aged mice. These data support our hypothesis that age-
related impairments in the reparative function of alveolar macrophages can be reversed by transient low level
inhibition of electron transport with complex I inhibitors via the ISR and ATF4, while smoldering activation of
these pathways during aging precludes normal repair. We will test this hypothesis in three interrelated Specific
Aims:
Aim 1. To determine whether deficiency of the scavenger receptor Mertk in aged alveolar macrophages
impairs lung repair after influenza A-induced injury.
Aim 2. To determine whether metformin can restore the reparative function of alveolar macrophages via
inhibition of complex I of mitochondrial electron transport during aging.
Aim 3. To determine whether mitochondrial activation of proteostasis through eIF2?-mediated
translational inhibition and/or ATF4 improves lung repair after injury during aging.
摘要
项目成果
期刊论文数量(0)
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GR Scott Budinger其他文献
GR Scott Budinger的其他文献
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{{ truncateString('GR Scott Budinger', 18)}}的其他基金
Targeting abnormal alveolar immune activation and failed epithelial repair in COVID-19
针对 COVID-19 中异常的肺泡免疫激活和失败的上皮修复
- 批准号:
10596990 - 财政年份:2022
- 资助金额:
$ 39.91万 - 项目类别:
Microglia mediate cognitive dysfunction in elderly survivors of pneumonia
小胶质细胞介导老年肺炎幸存者的认知功能障碍
- 批准号:
10354214 - 财政年份:2022
- 资助金额:
$ 39.91万 - 项目类别:
Targeting abnormal alveolar immune activation and failed epithelial repair in COVID-19
针对 COVID-19 中异常的肺泡免疫激活和失败的上皮修复
- 批准号:
10391970 - 财政年份:2022
- 资助金额:
$ 39.91万 - 项目类别:
Project 3: Targeting linear ubiquitination to attenuate inflammation and promote repair after viral pneumonia
项目3:靶向线性泛素化以减轻病毒性肺炎后的炎症并促进修复
- 批准号:
10696965 - 财政年份:2021
- 资助金额:
$ 39.91万 - 项目类别:
Project 3: Targeting linear ubiquitination to attenuate inflammation and promote repair after viral pneumonia
项目3:靶向线性泛素化以减轻病毒性肺炎后的炎症并促进修复
- 批准号:
10269676 - 财政年份:2021
- 资助金额:
$ 39.91万 - 项目类别:
Disordered Proteostasis as a Driver of Disease in the Aging Lung
蛋白质稳态紊乱是衰老肺疾病的驱动因素
- 批准号:
10208506 - 财政年份:2015
- 资助金额:
$ 39.91万 - 项目类别:
Disordered Proteostasis as a Driver of Disease in the Aging Lung
蛋白质稳态紊乱是衰老肺疾病的驱动因素
- 批准号:
10197736 - 财政年份:2015
- 资助金额:
$ 39.91万 - 项目类别:
Alveolar Macrophages as Age-Related Drivers of Disordered Tissue Repair
肺泡巨噬细胞作为紊乱组织修复的年龄相关驱动因素
- 批准号:
10197742 - 财政年份:2015
- 资助金额:
$ 39.91万 - 项目类别:
Disordered Proteostasis as a Driver of Disease in the Aging Lung
蛋白质稳态紊乱是衰老肺疾病的驱动因素
- 批准号:
9751135 - 财政年份:2015
- 资助金额:
$ 39.91万 - 项目类别:
Disordered Proteostasis as a Driver of Disease in the Aging Lung
蛋白质稳态紊乱是衰老肺疾病的驱动因素
- 批准号:
9779491 - 财政年份:2015
- 资助金额:
$ 39.91万 - 项目类别:
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