ApoE: Cellular and Molecular Mechanisms Controlling Neuronal Viability
ApoE: Cellular and Molecular Mechanisms Controlling Neuronal Viability
批准号:
9255575
负责人:
Kelly M Lohr
金额:
$5.63万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-03-01 至 2020-02-29
关键词:
ActinsAddressAdultAffectAgingAlzheimer&aposs DiseaseAmyloid beta-ProteinAnimalsApolipoprotein EAstrocytesAutopsyBehaviorBiochemicalBrainCellsCellular biologyCholesterol HomeostasisComplementCytoskeletonDataDiseaseDrosophila genusF-ActinFutureGene DosageGenesGeneticGenotypeGoalsHippocampus (Brain)HumanImpairmentIndividualInjuryLaboratoriesLipidsLipoprotein (a)MassachusettsMediatingMediator of activation proteinMitochondriaModelingMolecularMolecular BiologyNerve DegenerationNeurodegenerative DisordersNeurogliaNeuronsOutcomeOxidative StressPathogenesisPathologicPathway interactionsPatientsPrevalenceProtein IsoformsProteinsResearchRoleSamplingSourceStressSystemTauopathiesTechniquesTherapeuticTherapeutic InterventionTimeTissuesToxic effectTrainingTraumatic Brain InjuryUnited StatesWorkapolipoprotein E-3apolipoprotein E-4basebrain tissuecareerexperimental studyflygenetic manipulationgenetic risk factorhuman diseasehuman tissuein vivoinsightmitochondrial dysfunctionneuron lossneuropathologyneurotoxicneurotoxicitynovelreceptor mediated endocytosistau Proteinstool
中文摘要
项目摘要
载脂蛋白E(ApoE)e4是散发性阿尔茨海默病(AD)的最强遗传风险因子,
也与创伤性脑损伤后的不良结局有关。 ApoE通常在星形胶质细胞中表达,
通过受体介导的内吞作用进入神经元。神经元在受伤和应激时也表达ApoE
它会导致神经毒性级联反应,最终导致神经退行性变。尽管我们的成长
了解AD发病机制中的其他蛋白质,ApoE 4促进AD发病的机制,
神经毒性还不太清楚。 果蝇遗传学的最新进展使我们能够评估
ApoE细胞源通过独立操作对神经变性和行为的贡献
神经胶质和神经元表达。 初步数据表明,神经元ApoE表达诱导ApoE 4
在我们果蝇tau蛋白病模型中同种型-β-特异性神经变性。此外,ApoE 4表达导致
细胞骨架和线粒体异常的成年果蝇大脑。基于这些结果,我们假设
ApoE 4的神经毒性是通过其细胞来源和稳定肌动蛋白和损害
线粒体双染色质通过使用遗传工具在果蝇和检查死后
在人类组织中,我们的建议旨在1)比较神经元与神经胶质ApoE的神经变性
表达,2)研究肌动蛋白稳定性和线粒体异常在ApoE 4-β特异性
神经变性,和3)在ApoE 4-β 1阳性人AD组织中检查这些相同的变化。基于
我们实验室以前的工作定义了细胞骨架稳定和线粒体功能障碍的重要性,
退行性tau蛋白病模型,我们相信,这些初步数据提供了一个新的机制的见解
ApoE 4介导的神经变性。这些研究将突出其在细胞和分子中的作用,
毒性,以填补我们对这一重要的广告播放器的理解的根本空白。 我的提议还包括
各种实验方法的优势,包括遗传学,分子生物学,细胞生物学,
人类神经病理学 最后,这些目标和方法将使我接触到新的研究问题,
技术,以补充我以前的培训,并准备我的独立,因为我在我的前进,
事业
英文摘要
PROJECT SUMMARY
The apolipoprotein E (ApoE) e4 is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD) and is
also associated with poor outcome after traumatic brain injury. ApoE is commonly expressed in astrocytes,
entering neurons via receptor-mediated endocytosis. Neurons also express ApoE in times of injury and stress
where it contributes to a neurotoxic cascade that eventually leads to neurodegeneration. Despite our growing
understanding of other proteins in the pathogenesis of AD, the mechanisms by which ApoE4 contributes to
neurotoxicity are not well understood. Recent advances in Drosophila genetics now allow us to assess the
contributions of ApoE cellular source to neurodegeneration and behavior through independent manipulation of
glial and neuronal expression. Preliminary data suggest that neuronal ApoE expression induces an ApoE4
isoform-specific neurodegeneration in our Drosophila tauopathy model. Additionally, ApoE4 expression causes
cytoskeletal and mitochondrial abnormalities in adult Drosophila brain. Based on these results, we hypothesize
that ApoE4 neurotoxicity is controlled through its cellular source and ability to stabilize actin and impair
mitochondrial dyanmics. Through the use of genetic tools in Drosophila and examination of postmortem
human tissue, our proposal aims to 1) compare neurodegeneration from neuronal vs. glial ApoE
expression, 2) investigate actin stabilization and mitochondrial abnormalities in ApoE4-specific
neurodegeneration, and 3) examine these same changes in ApoE4-positive human AD tissue. Based on
previous work from our lab defining the importance of cytoskeletal stabilization and mitochondrial dysfunction in
degenerative tauopathy models, we are confident that these preliminary data provide a novel mechanistic insight
into ApoE4-mediated neurodegeneration. These studies will highlight both the cellular and molecular roles of its
toxicity to fill fundamental gaps in our understanding of this important AD player. My proposal also takes
advantage of a variety of experimental approaches, including genetics, molecular biology, cell biology, and
human neuropathology. Finally, these goals and approaches will expose me to new research questions and
techniques to complement my previous training and prepare me for independence as I move forward in my
career.
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会议论文
VMAT2-mediated rescue of Parkinsons disease pathology and behavior
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批准号:8896082
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项目类别:
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资助金额:$1.07万
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财政年份:2013
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负责人:Kelly M Lohr
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依托单位:
VMAT2-mediated rescue of Parkinsons disease pathology and behavior
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批准号:8595938
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项目类别:
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资助金额:$3.09万
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财政年份:2013
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负责人:Kelly M Lohr
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依托单位:
VMAT2-mediated rescue of Parkinsons disease pathology and behavior
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批准号:8703547
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项目类别:
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资助金额:$3.14万
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财政年份:2013
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负责人:Kelly M Lohr
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依托单位:
海外基金