Novel role of β-arrestins in Tauopathy
Novel role of β-arrestins in Tauopathy
批准号:
10373926
负责人:
JungA Alexa Woo
金额:
$40.25万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-05-15 至 2024-01-31
关键词:
Abeta synthesisAblationAddressAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAmyloid beta-ProteinArrestinsAutophagocytosisAutophagosomeAxonAxonal TransportBehavioralBindingBiochemicalBiologicalBrainCellsComplexDataDefectDepositionDistalElectrophysiology (science)FutureG-Protein-Coupled ReceptorsGPR3 geneGeneticIL8RB geneImpaired cognitionImpairmentIn VitroLearningLinkLysosomesMeasuresMediatingMemory impairmentMicrofluidic MicrochipsMicrotubule DepolymerizationMicrotubulesMitochondriaModelingMolecularMolecular ConformationMusNerve DegenerationNeuritesNeurodegenerative DisordersNeuronsOutcomePathogenesisPathogenicityPathologicPathologyPathway interactionsPlayProteinsReceptor SignalingRecombinant adeno-associated virus (rAAV)Recovery of FunctionReporterRoleSignal TransductionSolidSynapsesSynaptic plasticityTauopathiesTestingTherapeuticTransgenic MiceViralabeta accumulationbasebeta-arrestindesensitizationgamma secretasehyperphosphorylated tauin vivoindexinginsightinterdisciplinary approachneuroinflammationneuronal cell bodyneurotransmissionnovelreceptor bindingreceptor internalizationretrograde transportscaffoldtau Proteinstherapeutic targettooltrafficking
中文摘要
阿尔茨海默病(AD)的主要病理特征是
淀粉样蛋白β(Aβ)和过度磷酸化的tau。多个GPCR(即β2AR、GPR3、AT2R、CXCR2、
&NMDARs)在AD发病机制中起着不可或缺的作用。然而,目前还不清楚
不同的GPCR阵列如何都对β和tau的发病机制产生积极影响
阿尔茨海默病的神经退行性变。鉴于GPCR通过β-arrestin共享共同的行动机制
作为信号复合体的支架,中心假说是β阻滞素的作用
GPCRs下游直接影响AD的发病机制。β-逮捕存在于三个不同的状态
在细胞中;1)游离的,2)gpr结合的,3)微管结合的,每一个都有不同的信号
能力。先前的研究表明,β-arrestins在AD大脑中上调,而β--
抑制素促进A-β的发病。然而,目前尚不清楚β-arrestins是否以及如何
对阿尔茨海默病和神经退行性变的病理性影响。初步数据显示,
β-arrestin寡聚体通过两种不同的机制促进转位性病变:1)与tau直接竞争
用于与微管(MT)结合,从而解除对MT动力学的调控;2)抑制tau清除
通过放松对自噬机制的管制。
通过利用分子、细胞生物学、生化、电生理、行为、病毒和
组织化学工具,这项提议将1)验证β-arrestins在活体中的作用,2)
验证β-arrestins在tau/微管动力学中的作用,以及3)研究β-
P62介导的自噬和tau翻转中的拦阻蛋白。这份提案将验证β是否-
抑制素及其寡聚体状态有望成为缓解tau的治疗靶点
发病机制。
英文摘要
The major defining pathological hallmarks of Alzheimer’s disease (AD) are the accumulation of
amyloid β (Aβ) and hyperphosphorylated tau. Multiple GPCRs (i.e, β2AR, GPR3, AT2R, CXCR2,
& NMDARs) have been shown to play integral roles in AD pathogenesis. However, it is unclear
as to how a diverse array of GPCRs all positively impinge on Aβ and tau pathogenesis as well as
neurodegeneration in AD. Given that GPCRs share a common mechanism of action via β-arrestin
scaffolding signaling complexes, the central hypothesis is that the actions of β-arrestins
downstream of GPCRs directly impact AD pathogenesis. β-arrestins exist in three distinct states
in cells; 1) free unbound, 2) GPCR-bound, and 3) microtubule-bound, each with different signaling
capability. Previous studies have shown that β-arrestins are upregulated in AD brains and that β-
arrestins promote Aβ pathogenesis. However, it is unknown whether and how β-arrestins
pathogenically impinge on tauopathy and neurodegeneration in AD. Preliminary data indicate that
β-arrestin oligomers promote tauopathy via 2 distinct mechanisms: 1) directly competing with tau
for binding to microtubules (MT), thereby deregulating MT dynamics; 2) inhibiting tau clearance
by deregulating the autophagy machinery.
By utilizing molecular, cell biological, biochemical, electrophysiological, behavioral, viral, and
histochemical tools, this proposal will 1) validate the role of β-arrestins in tauopathy in vivo, 2)
validate the role of β-arrestins in tau/microtubule dynamics, and 3) investigate the role of β-
arrestins in p62-mediated autophagy and tau turnover. This proposal will validate whether β-
arrestins and their oligomeric status serve as promising therapeutic targets to mitigate tau
pathogenesis.
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Novel role of β-arrestins in Tauopathy
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批准号:10548201
-
项目类别:
-
资助金额:$40.25万
-
财政年份:2019
-
负责人:JungA Alexa Woo
-
依托单位:
Novel role of β-arrestins in Tauopathy
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批准号:10094176
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项目类别:
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资助金额:$37.38万
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财政年份:2019
-
负责人:JungA Alexa Woo
-
依托单位:
海外基金