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)的主要病理学标志是
淀粉样蛋白β(Aβ)和过度磷酸化的tau蛋白。多个GPCR(即β2AR、GPR 3、AT 2 R、CXCR 2、
和NMDAR)在AD发病机制中起重要作用。但目前尚不清楚
关于各种GPCR如何对Aβ和tau发病机制产生积极影响,
AD中的神经变性。鉴于GPCR通过β-抑制蛋白具有共同的作用机制,
支架信号复合物,中心假设是β-抑制蛋白的作用,
GPCR的下游直接影响AD的发病机制。β-抑制蛋白存在三种不同的状态
在细胞中; 1)游离的未结合的,2)GPCR结合的,和3)微管结合的,各自具有不同的信号传导
能力。先前的研究表明,β-arrestins在AD脑中上调,β-arrestins在AD脑中上调。
抑制蛋白促进Aβ发病。然而,β-arrestins是否以及如何与
在AD中的tau蛋白病和神经变性的病理学上起作用。初步数据表明
β-抑制蛋白寡聚体通过2种不同的机制促进tau蛋白病:1)直接与tau蛋白竞争
用于结合微管(MT),从而解除MT动力学的调节; 2)抑制tau清除
通过解除自噬机制的调节。
通过利用分子、细胞生物学、生物化学、电生理学、行为学、病毒和
组织化学工具,该提议将1)验证β-抑制蛋白在体内tau蛋白病中的作用,2)
验证β-arrestins在tau/微管动力学中的作用,以及3)研究β-arrestins在tau/微管动力学中的作用。
抑制蛋白在p62介导的自噬和tau蛋白转换中的作用。该提案将验证β-
抑制蛋白和它们的寡聚状态作为有希望的治疗靶点来减轻tau蛋白
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
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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
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负责人:JungA Alexa Woo
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依托单位:
海外基金