Role of stromal inflammatory signaling in the aging of lung resident lymphocytes
基质炎症信号在肺驻留淋巴细胞衰老中的作用
基本信息
- 批准号:10723431
- 负责人:
- 金额:$ 16.9万
- 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:2023-08-15 至 2028-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAgeAge FactorsAgingAlveolusAntibodiesAutomobile DrivingBasal CellBiological AssayBiologyCD8-Positive T-LymphocytesCD8B1 geneCDKN2A geneCell AgingCell CommunicationCell CycleCell Cycle ArrestCellsCellular StressChronic Obstructive Pulmonary DiseaseCirculationCoculture TechniquesComplexDasatinibDataDevelopmentDiseaseElderlyExhibitsFibroblastsFibrosisGene Expression ProfileGenetic ModelsGenetic TranscriptionGoalsHealthHistologyHomeostasisHydroxyprolineI Kappa B-AlphaImmuneImmune System DiseasesImmune systemImmunohistochemistryImpairmentIn VitroInfectionInflammationInflammatoryInfluenzaK-Series Research Career ProgramsKineticsLungLung diseasesLung infectionsLymphocyteLymphoidMentorshipMesenchymalMesenchymeMorbidity - disease rateMusNamesNuclearPathogenesisPathologicPhenotypePhysiciansPlayPneumoniaPopulationProductionPulmonary FibrosisQuercetinReporterResearchRoleScientistSignal InductionSignal TransductionSourceT-LymphocyteTestingTissuesTrainingTransplantationUncertaintyUp-RegulationViralViral Load resultViral PneumoniaVirus Diseasesadaptive immunityage relatedagedanti-PD-1careerchemokinecytokinedifferential expressionemerging adultepithelial stem cellexhaustionexperienceimprovedin vitro testingin vivoin vivo evaluationinhibitorknock-downlung healthlung repairmortalitymouse modelneutralizing antibodynovelprogrammed cell death protein 1recruitsenescencesingle-cell RNA sequencingsymposiumtherapeutic targettherapy developmenttissue injurytissue repairtranscriptome sequencing
项目摘要
PROJECT SUMMARY
Immune system dysfunction has been implicated in the pathogenesis of several age-related lung diseases.
Interestingly, multiple recent studies have identified the tissue microenvironment as playing a critical role in the
pathogenesis of some of these age-related immune system changes. The lung mesenchyme provides a
supportive niche for the resident immune system. Therefore, to identify aging-related changes in the lung
mesenchyme that might contribute to immune system dysfunction, we performed single-cell RNA-sequencing
of lung mesenchyme from aged versus young mice, identifying evidence of nuclear-factor kappa-B (NF-kB)
activation in aged relative to young adventitial fibroblasts. NF-kB is an important regulator of inflammation and
cellular senescence, a multifaceted cellular stress response characterized by several features including
permanent cell cycle arrest, expression of the cell cycle inhibitor 16INK4a, and a complex secretory profile known
as the senescence-associated secretory phenotype. Using a novel p16INK4a reporter mouse to identify cells with
senescent features in vivo, we found that p16INK4a+ lung fibroblasts were enriched for NF-kB activation and
accumulated in the parenchyma with age. Therefore, to study the effects of mesenchymal NF-kB activation in
regulating the immune system, we used a genetic model to conditionally delete Tnfaip3, which encodes an
important negative regulator of NF-kB signaling, from the mesenchyme. Preliminary data in this proposal
demonstrates that mesenchymal deletion of Tnfaip3 leads to the accumulation of CD8+ T cells within the lung
adventitial mesenchyme of young mice, and that these T cells transcriptionally resemble an aging-associated
CD8+ T cell population (Taa). Therefore, the central hypothesis of this proposal is that NF-kB activation
within senescent fibroblasts plays a direct role in driving lung Taa accumulation. Aim 1 is to identify the
contribution of lung fibroblast senescence to Taa formation using our novel p16INK4a+ reporter mouse. Aim 2
focuses on identifying the mechanism by which mesenchymal NF-kB drives Taa formation, and Aim 3 will
determine the functional consequences of Taa formation in the setting of viral pneumonia.
The training plan for this proposal has been developed to achieve Dr. Allen’s goal of becoming an
independent physician-scientist studying the interactions between the lung mesenchyme and immune system
in health and disease. The plan involves formal didactics, conferences, mentorship, and hands-on experience
though which Dr. Allen will develop expertise in cellular senescence, adaptive immunity, mouse models of
pulmonary infection, the lung mesenchyme and associated epithelial stem cell nice, as well as responsible and
effective research practices. She will be supported by a strong mentorship team with expertise spanning lung
biology, cellular senescence, tissue resident lymphocytes, and NF-kB signaling. With completion of this Career
Development Award Dr. Allen will have made valuable contributions to the understanding of lung immune
system aging, and will be well-prepared to launch her independent career.
项目摘要
免疫系统功能障碍与几种与年龄相关的肺部疾病的发病机制有关。
有趣的是,最近的多项研究已经确定,组织微环境在肿瘤的发生中起着关键作用。
这些年龄相关的免疫系统变化的发病机制。肺间质提供了一个
为居民免疫系统提供支持。因此,为了确定与年龄相关的肺部变化,
间充质可能有助于免疫系统功能障碍,我们进行了单细胞RNA测序
老年小鼠与年轻小鼠的肺间充质比较,确定核因子kappa-B(NF-kB)的证据
相对于年轻的外膜成纤维细胞,老年人中的活化。NF-kB是炎症的重要调节因子,
细胞衰老是一种多方面的细胞应激反应,其特征包括
永久的细胞周期停滞,细胞周期抑制剂16 INK 4a的表达,以及已知的复杂的分泌特征,
作为衰老相关的分泌表型。使用新型p16 INK 4a报告小鼠鉴定具有
我们发现p16 INK 4a+肺成纤维细胞富含NF-κ B活化,
随着年龄的增长在薄壁组织中积累。因此,为了研究间充质NF-kB活化在人骨髓瘤中的作用,
调节免疫系统,我们使用遗传模型有条件地删除Tnfaip 3,它编码一种
NF-kB信号传导的重要负调节因子,来自间充质。本提案中的初步数据
证明Tnfaip 3的间充质缺失导致CD 8 + T细胞在肺内的积累
年轻小鼠的外膜间充质,这些T细胞在转录上类似于衰老相关的
CD 8 + T细胞群(Taa)。因此,该提议的中心假设是NF-kB激活
在衰老成纤维细胞内的Taa在驱动肺Taa积累中起直接作用。目标1是确定
使用我们的新型p16 INK 4a+报告小鼠,肺成纤维细胞衰老对Taa形成的贡献。目的2
重点是确定间充质NF-kB驱动Taa形成的机制,Aim 3将
确定病毒性肺炎背景下Taa形成的功能后果。
本提案的培训计划旨在实现艾伦博士的目标,
研究肺间质和免疫系统之间相互作用的独立医生-科学家
健康和疾病。该计划包括正式的教学法,会议,指导和实践经验
尽管如此,艾伦博士将在细胞衰老、适应性免疫、
肺部感染,肺间充质和相关的上皮干细胞尼斯,以及负责,
有效的研究实践。她将得到一个强大的导师团队的支持,
生物学、细胞衰老、组织驻留淋巴细胞和NF-κ B信号传导。随着这一职业生涯的结束,
发展奖艾伦博士将对肺免疫的理解做出宝贵贡献
系统老化,并将充分准备推出她的独立职业生涯。
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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Nancy Christine Allen其他文献
Nancy Christine Allen的其他文献
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{{ truncateString('Nancy Christine Allen', 18)}}的其他基金
Mesenchymal inflammatory signaling in regulation of the immune response and tissue dysfunction during lipopolysaccharide-induced acute lung injury
间充质炎症信号在脂多糖诱导的急性肺损伤期间调节免疫反应和组织功能障碍
- 批准号:
10389796 - 财政年份:2022
- 资助金额:
$ 16.9万 - 项目类别:
Mesenchymal inflammatory signaling in regulation of the immune response and tissue dysfunction during lipopolysaccharide-induced acute lung injury
间充质炎症信号在脂多糖诱导的急性肺损伤期间调节免疫反应和组织功能障碍
- 批准号:
10806558 - 财政年份:2022
- 资助金额:
$ 16.9万 - 项目类别:
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