Aged T-cell-derived cytokines impact meningeal lymphatics and contribute to AD
Aged T-cell-derived cytokines impact meningeal lymphatics and contribute to AD
批准号:
10684836
负责人:
Jonathan Kipnis
金额:
$57.94万
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
项目状态:
未结题
起止时间:
2022-08-17 至 2027-04-30
关键词:
AchievementAcuteAddressAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease riskAlzheimer&aposs disease therapyAmyloidAntibodiesAntigen PresentationAntigensAnxietyAtlasesAttentionAttenuatedBehaviorBiological MarkersBlood VesselsBrainBrain DrainsCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCell CountCell physiologyCell secretionCellsCentral Nervous SystemCerebrospinal FluidCognitive deficitsCytokine SignalingDataDeep Cervical Lymph NodeDepositionDeteriorationDisease ProgressionDrainage procedureEquilibriumExcisionGenetic PolymorphismGenetic TranscriptionHLA-DR AntigensIFNGR1 geneIL17 geneImmuneImmune responseImmunityImmunotherapyImpaired cognitionImpairmentIndividualInflammatoryInflammatory ResponseInterferon Type IIInterleukin-4LearningLinkLymphaticLymphatic Endothelial CellsLymphatic functionLymphocyteMediatingMemoryMemory impairmentMeningealMeningeal lymphatic systemMeningesMicrogliaMusNeuronal DysfunctionOutcomePathologicPathologyPathway interactionsPatientsPerfusionPeripheralPhasePhenotypePhysiologicalPopulationProductionRoleRouteSenile PlaquesSignal TransductionSiteSourceT-LymphocyteTestingTherapeuticTherapeutic InterventionTissuesTransgenic Miceabeta depositionadaptive immune responseage relatedage related neurodegenerationagedbrain dysfunctionbrain parenchymacytokinegenome wide association studylymphatic drainagelymphatic dysfunctionlymphatic vasculaturelymphatic vesselmisfolded proteinmouse modelnervous system disorderneurogenesisneuroinflammationneutralizing antibodynew therapeutic targetnoveloverexpressionpreservationpreventreceptorresponserisk variantsingle-cell RNA sequencingtherapeutic targetwasting
中文摘要
项目总结
许多与年龄相关的神经退行性疾病--包括阿尔茨海默病(AD)--与
错误折叠的蛋白质沉积会促进炎症反应、神经元功能障碍和认知障碍。
我们最近发现,衰老和AD都表现出脑膜淋巴功能受损,这
最终导致颈深部淋巴结的脑脊液引流受损,以及脑脊液向颈深部淋巴结的灌流。
脑实质,共同促进废物堆积和A诱导的AD小鼠的病理。我们的预赛
数据表明,衰老也与产生干扰素γ的CD4T细胞和CD8T细胞的积累有关
在硬脑膜中,与脑膜淋巴管密切相关。干扰素γ信号代表一种
衰老脑膜淋巴管的转录特征和幼鼠脑膜淋巴管轴的增强减弱
脑脊液的功能性引流。因此,我们假设在衰老和AD期间,表达上调的
脑膜CD4T细胞和CD8T细胞分泌的干扰素γ通过直接信号转导途径损害脑膜淋巴功能
他们的干扰素γ受体,导致脑膜淋巴恶化。这种恶化后来会导致
脑脊液(CSF)脑灌注,随后导致碎片堆积和恶化
AD的进展。我们进一步假设,使用细胞因子中和抗体,我们可以保存
老年小鼠脑膜淋巴管及预防或减轻增龄相关脑功能障碍和增强
AD患者现有的免疫治疗策略。解决我们对这一提议的假设将有助于
年龄相关性脑膜淋巴功能障碍的机制途径,并确定新的有希望的
旨在减少AD相关病理的治疗干预途径。
英文摘要
PROJECT SUMMARY
Many age-related neurodegenerative diseases—including Alzheimer's disease (AD)—are associated with
misfolded protein deposition that promote inflammatory responses, neuronal dysfunction, and cognitive deficits.
We have recently identified that aging and AD both display impaired meningeal lymphatic function, which
ultimately results in impaired CSF drainage to deep cervical lymph nodes, as well as CSF perfusion into the
brain parenchyma, collectively promoting waste build up and A-induced pathologies in AD mice. Our preliminary
data demonstrate that aging is also associated with the accumulation of IFNγ-producing CD4 and CD8 T cells
in the dural meninges, closely associated with the meningeal lymphatics. IFNγ signaling represents a
transcriptional hallmark of aged meningeal lymphatics and augmentation of this axis in young mice attenuates
their functional drainage of CSF. We therefore hypothesize that during aging and in AD, elevated expression of
IFNγ from meningeal CD4 and CD8 T cells impairs meningeal lymphatic function function via direct signaling on
their IFNγ receptors, leading to meningeal lymphatic deterioration. Such deterioration later results in impaired
brain perfusion by cerebrospinal fluid (CSF), subsequently leading to the accumulation of debris and worsening
progression of AD. We further hypothesize that using cytokine neutralizing antibodies, we can preserve
meningeal lymphatics in aged mice and prevent or reduce the age-associated brain dysfunctions and augment
existing immunotherapy strategies in AD patients. Addressing our hypotheses of this proposal will illuminate
mechanistic pathways underlying age-related meningeal lymphatic dysfunction, and identify new promising
avenues for therapeutic interventions intended to reduce AD-related pathology.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Neuroimmunology of AD and CAA with focus on innate immunity and lymphatics
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批准号:10674670
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项目类别:
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资助金额:$306.33万
-
财政年份:2022
-
负责人:Jonathan Kipnis
-
依托单位:
Aged T-cell-derived cytokines impact meningeal lymphatics and contribute to AD
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批准号:10515246
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项目类别:
-
资助金额:$58.56万
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财政年份:2022
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负责人:Jonathan Kipnis
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依托单位:
Administrative Core
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批准号:10674671
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项目类别:
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资助金额:$19.61万
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财政年份:2022
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负责人:Jonathan Kipnis
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依托单位:
Parenchymal border macrophages in AD and CAA
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批准号:10674673
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项目类别:
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Neural code of the immune responses
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负责人:Jonathan Kipnis
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依托单位:
Neural code of the immune responses
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批准号:9788254
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项目类别:
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资助金额:$112.42万
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财政年份:2018
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负责人:Jonathan Kipnis
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依托单位:
Neural code of the immune responses
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批准号:10218743
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项目类别:
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资助金额:$110.25万
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财政年份:2018
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负责人:Jonathan Kipnis
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依托单位:
Neural code of the immune responses
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批准号:10457300
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项目类别:
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资助金额:$110.25万
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财政年份:2018
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负责人:Jonathan Kipnis
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依托单位:
Meningeal lymphatics and immunity in Alzheimer's disease
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批准号:9428316
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项目类别:
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资助金额:$136.04万
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财政年份:2017
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负责人:Jonathan Kipnis
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依托单位:
Immune response to CNS injury
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批准号:9241450
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项目类别:
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资助金额:$34.29万
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财政年份:2016
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负责人:Jonathan Kipnis
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依托单位:
Immune Response to CNS Injury
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批准号:10228236
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项目类别:
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资助金额:$24.63万
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财政年份:2016
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负责人:Jonathan Kipnis
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依托单位:
Immune response to CNS injury
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批准号:9128161
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项目类别:
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资助金额:$34.29万
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财政年份:2016
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负责人:Jonathan Kipnis
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依托单位:
Phagocytosis of dying cells, adult neurogenesis and depression
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批准号:8382783
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项目类别:
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资助金额:$39.33万
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财政年份:2012
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负责人:Jonathan Kipnis
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依托单位:
Phagocytosis of dying cells, adult neurogenesis and depression
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批准号:8660091
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项目类别:
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资助金额:$39.5万
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财政年份:2012
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负责人:Jonathan Kipnis
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依托单位:
Innate immunity in Rett pathology and repair
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批准号:8419233
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项目类别:
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资助金额:$34.31万
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财政年份:2012
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负责人:Jonathan Kipnis
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依托单位:
Innate immunity in Rett pathology and repair
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批准号:8658866
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项目类别:
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资助金额:$33.97万
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财政年份:2012
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负责人:Jonathan Kipnis
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依托单位:
Innate immunity in Rett pathology and repair
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批准号:8850003
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项目类别:
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资助金额:$34.31万
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财政年份:2012
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负责人:Jonathan Kipnis
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依托单位:
Phagocytosis of dying cells, adult neurogenesis and depression
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批准号:9066808
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项目类别:
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资助金额:$39.5万
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财政年份:2012
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负责人:Jonathan Kipnis
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依托单位:
Phagocytosis of dying cells, adult neurogenesis and depression
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资助金额:$37.92万
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财政年份:2012
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负责人:Jonathan Kipnis
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依托单位:
Innate immunity in Rett pathology and repair
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财政年份:2012
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负责人:Jonathan Kipnis
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依托单位:
海外基金