Antiviral response coupled with transposon derepression in Alzheimer's disease and aging
抗病毒反应与转座子去抑制在阿尔茨海默病和衰老中的作用
基本信息
- 批准号:10629440
- 负责人:
- 金额:$ 64.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-15 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AchievementAffectAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease riskAmyloid beta-ProteinAntiviral ResponseBiogenesisBrainBrain MappingBrain regionCellsCentral Nervous SystemChronicClinicCoupledDNA Transposable ElementsDefense MechanismsElementsEncephalitisEpigenetic ProcessEventGenetic PolymorphismGenetic TranscriptionGenomeGenomic InstabilityGenomicsGliosisGoalsHeterochromatinHumanImmuneImmune responseImmune signalingIn VitroInflammagingInflammationInnate Immune ResponseInterferonsInvadedKineticsLate Onset Alzheimer DiseaseMediatingMediatorMethylationMicrogliaModelingModificationMolecularMusNatural ImmunityNerve DegenerationNeurogliaNeuronsNucleic AcidsOutcomeParasitesPathogenesisPathologyPathway interactionsPhenotypePlayPopulationProcessProductionReactionRelaxationReporterReportingRetroelementsRetrotranspositionRoleSenile PlaquesSignal TransductionStagingSting InjurySynapsesTauopathiesTestingTherapeutic InterventionViralViral GenomeVirusagedaging brainbrain cellcell typecohortcytokinederepressionepigenomein vivoin vivo Modelinnate immune pathwaysinsightmolecular targeted therapiesneuroinflammationnoveloverexpressionphenotypic biomarkerresponsesenescencesensortau Proteinstransgene expressionviral detection
项目摘要
Project Summary/Abstract
Alzheimer's disease (AD) significantly impacts aging populations worldwide. Inflammation, at cell and organismic
levels, often accompanies aging process; whereas in sporadic AD, neuroinflammation is increasingly recognized
as a major contributor. However, the molecular triggers for neuroinflammatory response and factors mediating
and regulating the process remains enigmatic. Antiviral defense mechanisms control nucleic acid-based
parasites, most noticeably the invading viruses. Type I IFN (IFN) cytokines, a key component of antiviral innate
immunity, is a product of signaling activation of mammalian nucleic acid innate immune sensors that detect viral
genomes or their replication products. We recently reported that plaque-associated microglia innately reacted to
nucleic acid-containing amyloid β (Aβ) plaques and promote chronic gliosis and synapse loss in various Aβ
models. While grossly upregulated in clinic AD, IFN pathway unexpectedly escalates with increased BRAAK
staging, which implies an idiosyncratic IFN response in association with human tau pathology. We have since
confirmed a prominent IFN pathway activation in different murine tauopathy models. Genomic instability is a core
hallmark of aging. Senescent cells dysregulate their epigenome and derepress transposable elements (TE or
transposons), endogenous parasites widely distributed in the genome. Consequently, activation of L1
retrotransposable element triggers an antiviral innate immune response, resulting in IFN production. In parallel,
we found that tau overexpression relaxed neuronal heterochromatin, which is correlated with elevated
transcription of L1 and other TEs in tauopathy brains. Remarkably, IFN signaling is activated in aging brain and
polymorphisms of several ISGs as a group impose as a risk factor for AD. Based on these intriguing findings,
we seek to investigate how antiviral immune response is coupled to derepressed transposon activity during AD
pathogenesis in this proposal. Specifically, we plan to examine the involvement of L1 and retroelements in
conjunction with the onset of neuroinflammation under tauopathy and aging conditions (aim 1), identify the key
signaling mediators facilitating tau-stimulated antiviral response in the brain (aim 2) and elucidate epigenetic
influence on transposon derepression and antiviral inflammation in tauopathy and brain aging (aim 3).
项目摘要/摘要
阿尔茨海默病(AD)严重影响全球老龄化人口。炎症,在细胞和组织中
水平,通常伴随着衰老过程;而在散发性AD中,神经炎症越来越被认识到
作为主要贡献者。然而,神经炎性反应的分子触发因素和中介因子
监管这一过程仍然是个谜。抗病毒防御机制控制基于核酸的
寄生虫,最引人注目的是入侵的病毒。I型干扰素细胞因子,先天抗病毒的关键成分
免疫,是哺乳动物检测病毒的核酸天然免疫传感器信号激活的产物
基因组或其复制产物。我们最近报道斑块相关的小胶质细胞先天对
核酸淀粉样蛋白β(A-β)斑块与各种A-β的慢性胶质增生和突触丢失
模特们。虽然在临床AD中大量上调,但随着Braak的增加,干扰素途径意外地升级
分期,这意味着与人类tau病理相关的特殊的干扰素反应。从那以后我们就
证实在不同的小鼠共济失调模型中有显著的干扰素途径激活。基因组不稳定性是一个核心
这是衰老的标志。衰老细胞失调其表观基因组,并降低转座元件(TE或
转座子),内生寄生虫广泛分布在基因组中。因此,L1的激活
逆转录转座元件可触发抗病毒的先天免疫反应,导致干扰素的产生。同时,
我们发现,tau的过度表达松弛了神经元异染色质,这与升高的
脊椎病患者脑内L1和其他TES的转录。值得注意的是,干扰素信号在老化的大脑和
作为一个群体,几个ISG基因的多态性是AD的危险因素。基于这些有趣的发现,
我们试图研究AD期间抗病毒免疫反应与去抑制转座子活性之间的关系
发病机制在这一建议中。具体地说,我们计划研究L1和逆转录因子在
结合肌萎缩侧索硬化症和衰老条件下的神经炎症发作(目标1),找出关键
促进tau刺激的脑内抗病毒反应的信号介质(Aim 2)和阐明表观遗传学
转座子去抑制和抗病毒炎症在紧张症和脑老化中的影响(目标3)。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Glial interference: impact of type I interferon in neurodegenerative diseases.
- DOI:10.1186/s13024-022-00583-3
- 发表时间:2022-11-26
- 期刊:
- 影响因子:15.1
- 作者:
- 通讯作者:
IFN-Aging: Coupling Aging With Interferon Response.
- DOI:10.3389/fragi.2022.870489
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Cao, Wei
- 通讯作者:Cao, Wei
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{{ truncateString('Wei Cao', 18)}}的其他基金
Antiviral response coupled with transposon derepression in Alzheimer's disease and aging
抗病毒反应与转座子去抑制在阿尔茨海默病和衰老中的作用
- 批准号:
10612174 - 财政年份:2021
- 资助金额:
$ 64.75万 - 项目类别:
Antiviral response coupled with transposon derepression in Alzheimer’s disease and aging
抗病毒反应与转座子去抑制在阿尔茨海默病和衰老中的作用
- 批准号:
10302003 - 财政年份:2021
- 资助金额:
$ 64.75万 - 项目类别:
Hypoxia inducible factors in shaping neuroinflammation and Alzheimer's pathogenesis
缺氧诱导因素影响神经炎症和阿尔茨海默病发病机制
- 批准号:
10709109 - 财政年份:2020
- 资助金额:
$ 64.75万 - 项目类别:
Receptors Of Plasmacytoid Dendritic Cells And Their Ligands
浆细胞样树突状细胞受体及其配体
- 批准号:
7297238 - 财政年份:2007
- 资助金额:
$ 64.75万 - 项目类别:
Receptors Of Plasmacytoid Dendritic Cells And Their Ligands
浆细胞样树突状细胞受体及其配体
- 批准号:
7667846 - 财政年份:2007
- 资助金额:
$ 64.75万 - 项目类别:
Receptors Of Plasmacytoid Dendritic Cells And Their Ligands
浆细胞样树突状细胞受体及其配体
- 批准号:
8118115 - 财政年份:2007
- 资助金额:
$ 64.75万 - 项目类别:
Receptors Of Plasmacytoid Dendritic Cells And Their Ligands
浆细胞样树突状细胞受体及其配体
- 批准号:
7906750 - 财政年份:2007
- 资助金额:
$ 64.75万 - 项目类别:
Receptors Of Plasmacytoid Dendritic Cells And Their Ligands
浆细胞样树突状细胞受体及其配体
- 批准号:
7475049 - 财政年份:2007
- 资助金额:
$ 64.75万 - 项目类别:
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