RETROMER TRAFFICKING AND ALZHEIMER'S DISEASE IN DROSOPHILA
果蝇中的逆转录酶贩运和阿尔茨海默氏病
基本信息
- 批准号:8664316
- 负责人:
- 金额:$ 20.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:Alzheimer&aposs DiseaseAmyloid beta-Protein PrecursorBiochemicalBiological AssayBrainCessation of lifeComplexDataDefectDrosophila genusElectrophysiology (science)EndosomesEnzymesGenetic ModelsGenetic VariationHippocampus (Brain)HumanLate Onset Alzheimer DiseaseLeadLinkLocomotionLongevityMammalian CellMeasuresMediatingMemoryModelingMolecularMolecular ProfilingMusNerve DegenerationNeurologicNeuronsPathologyPathway interactionsPatientsPeptidesProteinsRecyclingRegulationResearchRiskSignal PathwaySignal TransductionSorting - Cell MovementTestingTransgenic OrganismsUniversitiesVacuolar Protein Sortingbasebeta-site APP cleaving enzyme 1designflyglycogen synthase kinase 3 betamemberneurodegenerative phenotypeneuron lossnoveloverexpressionreceptorreceptor bindingresponsesecretasesortilintau Proteinstau aggregationtau phosphorylationtau-1traffickingtrans-Golgi Network
项目摘要
Late-Onset Alzheimer's disease (LOAD) is biochemically characterized by abnormal elevations of AB peptide and increased tau phosphorylation. Recently, reduced activity ofthe Retromer complex, which is important for the recycling of transmembrane receptors from endosomes to the Trans-Golgi Network (TGN), has been implicated in the pathology of LOAD from human patient expression profiling. The importance of retromer
trafficking to LOAD is supported by several studies including both mouse and Drosophila genetic models of retromer deficiency, which have increased levels of Ap peptide, neurological deficits, and in the fly, extensive neurodegeneration. Defective retromer trafficking also inhibits Wnt signaling, suggesting a pathway via glycogen synthase kinase 3 beta (GSKSp) through which retromer could alter tau phosphorylation. We hypothesize that defective retromer sorting is central to both elevated AB peptide levels and increased tau phosphorylation in LOAD and that modulating retromer trafficking levels will have a positive impact on neurodegeneration. We will test this hypothesis in transgenic Drosophila models of LOAD where human Amyloid Precursor Protein (APP) and Amyloid Precursor Protein li-secretase (BACE) or human Tau are expressed. Our specific aims are designed to determine the molecular pathway that connects retromer deficiency to neurodegeneration and characterize novel interacting proteins that could promote retromer stability.
晚发性阿尔茨海默病(LOAD)的生化特征是AB肽异常升高和tau磷酸化增加。最近,Retromer复合物的活性降低,这是重要的跨膜受体从内体到跨高尔基体网络(TGN)的再循环,已被牵连在从人类患者的表达谱的LOAD的病理。Retromer的重要性
几项研究支持了向LOAD的运输,包括逆转录酶缺乏的小鼠和果蝇遗传模型,其具有增加的A β肽水平、神经缺陷和在果蝇中广泛的神经变性。缺陷的逆转录分子运输也抑制Wnt信号传导,表明通过糖原合成酶激酶3 β(GSKSp)的途径,逆转录分子可以通过该途径改变tau磷酸化。我们假设,有缺陷的retromer分选是核心的AB肽水平升高和增加的tau磷酸化在负载和调节retromer运输水平将有积极的影响神经退行性变。我们将在LOAD的转基因果蝇模型中检验这一假设,其中表达人淀粉样前体蛋白(APP)和淀粉样前体蛋白li-secretase(BACE)或人Tau。我们的具体目标是确定连接retromer缺乏神经变性的分子途径,并表征可以促进retromer稳定性的新型相互作用蛋白。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Brian D McCabe其他文献
Brian D McCabe的其他文献
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{{ truncateString('Brian D McCabe', 18)}}的其他基金
Deciphering the Genetics of Synapse Development by Whole Genome Sequencing
通过全基因组测序解读突触发育的遗传学
- 批准号:
8269869 - 财政年份:2011
- 资助金额:
$ 20.05万 - 项目类别:
Deciphering the Genetics of Synapse Development by Whole Genome Sequencing
通过全基因组测序解读突触发育的遗传学
- 批准号:
8164693 - 财政年份:2011
- 资助金额:
$ 20.05万 - 项目类别:
RETROMER TRAFFICKING AND ALZHEIMER'S DISEASE IN DROSOPHILA
果蝇中的逆转录酶贩运和阿尔茨海默氏病
- 批准号:
8441031 - 财政年份:1997
- 资助金额:
$ 20.05万 - 项目类别:
RETROMER TRAFFICKING AND ALZHEIMER'S DISEASE IN DROSOPHILA
果蝇中的逆转录酶贩运和阿尔茨海默氏病
- 批准号:
8014567 - 财政年份:
- 资助金额:
$ 20.05万 - 项目类别:
RETROMER TRAFFICKING AND ALZHEIMER'S DISEASE IN DROSOPHILA
果蝇中的逆转录酶贩运和阿尔茨海默氏病
- 批准号:
8574150 - 财政年份:
- 资助金额:
$ 20.05万 - 项目类别:
RETROMER TRAFFICKING AND ALZHEIMER'S DISEASE IN DROSOPHILA
果蝇中的逆转录酶贩运和阿尔茨海默氏病
- 批准号:
8573796 - 财政年份:
- 资助金额:
$ 20.05万 - 项目类别:
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