Mechanisms of regulation of amyloid-beta metabolism by CALHM1
CALHM1 调节淀粉样蛋白代谢的机制
基本信息
- 批准号:8731789
- 负责人:
- 金额:$ 34.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-15 至 2017-06-30
- 项目状态:已结题
- 来源:
- 关键词:APP-PS1AdultAffectAgeAging-Related ProcessAllelesAlzheimer&aposs DiseaseAmyloid beta-ProteinAmyloid depositionAtrophicBrainBrain DiseasesC-terminalCalciumCalcium ChannelCandidate Disease GeneCell Culture SystemCellsCellular biologyCerebral cortexCerebrospinal FluidCerebrumCodeCognitive deficitsCollaborationsDNADataDefectDepositionDevelopmentDiseaseEmbryonic DevelopmentEventGene Expression ProfileGene Expression ProfilingGenesGoalsHippocampus (Brain)HomeostasisHumanImmunohistochemistryImpairmentIn VitroInsulinInsulin ReceptorInsulinaseIon ChannelKnock-outKnockout MiceLaboratoriesLiteratureMeasurementMediatingMemoryMemory impairmentMetabolismMethodsMindModelingMolecularMolecular BiologyMusNeurodegenerative DisordersNeuronsPathogenesisPathologic ProcessesPeptide HydrolasesPhosphorylationPlayProductionProteinsPublishingReceptor SignalingRegulationRoleSenile PlaquesSignal TransductionStaining methodStainsSynapsesTestingTranscriptional RegulationTransgenic MiceWorkactivating transcription factoramyloid formationbasebeta-site APP cleaving enzyme 1calcium metabolismcerebral atrophyconditioned feargenome-widein vivoinsightknockout animalmorris water mazemouse modelmutantneuron lossnext generation sequencingnovelobject recognitionpeptide Apreventprotein aggregateyoung adult
项目摘要
DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by A¿ peptide deposition into cerebral senile plaques. CALHM1 is a recently identified neuronal calcium channel controlling AD age-at-onset and A¿ levels both in vitro in cell culture systems and in vivo in human cerebrospinal fluid (Dreses-Werringloer et al, Cell 2008; Koppel et al., Mol Med 2011). These results strongly support the notion that CALHM1, via an unknown mechanism, controls A¿ metabolism and AD pathogenesis. In order to gain insight into the mechanism by which CALHM1 controls A¿ metabolism, we recently generated a CALHM1 knockout (KO) mouse model. In these KO mice, we found that CALHM1 was required for the expression of insulin-degrading enzyme (IDE), a protease controlling A¿ clearance in vivo. Preliminary results also showed that CALHM1 KO mice have elevated levels of brain A¿ and develop significant deficits in memory formation. The long-term goal of this application is to test the working model that CALHM1 influences A¿ levels by controlling cerebral IDE expression, a mechanism that, when impaired, leads to A¿-dependent cognitive deficits in mice. In CALHM1 KO mice, we will first determine whether CALHM1 deficiency affects neuronal integrity and leads to amyloid deposition in the mouse brain. We will also determine the extent to which CALHM1 deficiency leads to A¿-dependent cognitive deficits in mice. Finally using cell and molecular biology methods, we will elucidate the
molecular mechanism by which CALHM1 controls IDE expression.
描述(由申请人提供):阿尔茨海默病(AD)是一种进行性神经退行性疾病,其特征是A肽沉积到大脑老年斑中。CALHM 1是最近鉴定的神经元钙通道,其在体外细胞培养系统中和体内人脑脊液中控制AD发病年龄和A水平(Dreses-Werringloer等人,Cell 2008; Koppel等人,Mol Med 2011)。这些结果强烈支持CALHM 1通过未知机制控制A?代谢和AD发病机制的观点。为了深入了解CALHM 1控制A?代谢的机制,我们最近建立了CALHM 1敲除(KO)小鼠模型。在这些KO小鼠中,我们发现CALHM 1是胰岛素降解酶(IDE)表达所必需的,IDE是一种控制体内A?清除的蛋白酶。初步结果还表明,CALHM 1 KO小鼠的大脑A水平升高,记忆形成明显不足。该应用的长期目标是测试CALHM 1通过控制大脑IDE表达来影响A?水平的工作模型,这是一种在受损时导致小鼠A?依赖性认知缺陷的机制。在CALHM 1基因敲除小鼠中,我们将首先确定CALHM 1缺陷是否影响神经元的完整性并导致小鼠大脑中的淀粉样蛋白沉积。我们还将确定CALHM 1缺乏导致小鼠A?依赖性认知缺陷的程度。最后,利用细胞和分子生物学方法,我们将阐明
CALHM 1控制IDE表达的分子机制。
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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PHILIPPE MARAMBAUD其他文献
PHILIPPE MARAMBAUD的其他文献
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10689797 - 财政年份:2020
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mTOR and VEGFR2 pathways in HHT pathogenesis
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mTOR and VEGFR2 pathways in HHT pathogenesis
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10473796 - 财政年份:2020
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$ 34.54万 - 项目类别:
Mechanisms of regulation of amyloid-beta metabolism by CALHM1
CALHM1 调节淀粉样蛋白代谢的机制
- 批准号:
8346353 - 财政年份:2013
- 资助金额:
$ 34.54万 - 项目类别:
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