Investigating Mechanisms of Neurodegeneration in Transgenic Mouse Models of Tauopathies
研究 Tau蛋白病转基因小鼠模型中神经变性的机制
基本信息
- 批准号:10372933
- 负责人:
- 金额:$ 4.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-08 至 2025-03-07
- 项目状态:未结题
- 来源:
- 关键词:3xTg-AD mouseAD transgenic miceAffectAgeAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease patientAnimal ModelAntibodiesBiochemistryBiological MarkersBrainBrain regionCell CountClinicalCognitive deficitsCryoelectron MicroscopyCultured CellsDiseaseDisease ProgressionFellowshipFrontotemporal DementiaGenesGoalsGolgi ApparatusHippocampus (Brain)HistopathologyHumanImmunotherapyImpaired cognitionLongevityMemory LossMemory impairmentModelingMolecularMonoclonal AntibodiesMosaicismMotorMusMutationNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesNeuronsPathogenicityPathologyPersonsPharmacotherapyPhenotypePhosphorylationPick bodyRapid screeningReproducibilityResearch ProposalsRoleSeveritiesStainsStructureSymptomsTauopathiesTestingTherapeuticTherapeutic StudiesTimeTrainingTransgenic MiceTranslational Researchbasebehavior testcerebral atrophyclinical predictorsdisease mechanisms studydisease phenotypedisease-causing mutationeffectiveness testingfamilial Alzheimer diseasehyperphosphorylated tauinterdisciplinary approachmouse modelneurotoxicitynovelnovel therapeuticsscreeningtau Proteinstau aggregationtau expressiontau mutationtau phosphorylationtau-1transmission processuptake
项目摘要
Project Summary/Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disease that affects over 25 million people
worldwide. In AD, hyperphosphorylated tau inclusions like neurofibrillary tangles are one of the earliest changes
and can predict clinical severity. As tau inclusions increase, cognitive decline and memory loss worsen over time.
Since familial and sporadic AD share the same pathology and clinical symptoms, transgenic mice that express
human tau can effectively model AD. However, many existing tau mouse models do not develop both cognitive
deficits and robust pathology in the cortex and hippocampus, which are the primary regions of neurodegeneration
in AD. In the field, there is a compelling need to develop an effective animal model of tauopathies for mechanistic
and therapeutic studies. A good model of tauopathies must meet at least four criteria: 1) develops progressive
phosphorylated tau inclusions; 2) affects the primary brain regions of cortex and hippocampus like in AD patients;
3) causes cognitive deficits; and 4) is reproducible with stable germline transmission.
To meet this demand, my main translational research goal is to develop a robust animal model for 1. studying
disease mechanisms of tau aggregation and hyperphosphorylation and for 2. rapid screening of drugs and
therapies. Given that mice have much shorter lifespans, expression of a single disease-causing mutation may
not be sufficient to induce a robust disease phenotype. In the field of neurodegeneration, multiple pathogenic
mutations are commonly used to accelerate disease phenotypes in transgenic mice. For example, 3XTg-AD and
5XFAD mouse models use three and five different mutations of multiple genes respectively. As a result, I chose
to enhance tau neurotoxicity by combining two disease-causing mutations (P301S/S320F) in the same gene.
For this research proposal, my lab and I used pronuclear integration to generate novel transgenic mice for stable
germline expression of the tau mutations P301S/S320F. With this unprecedent mouse model, I will determine
the role of tau hyperphosphorylation in promoting tau aggregation, cognitive deficits and brain atrophy in Specific
Aims 1 and 2. In Specific Aim 3, I will use this novel mouse model to screen phospho-tau immunotherapies.
Upon completion of this study, I will fulfill my fellowship training goals of studying disease mechanisms of tau-
induced neurodegeneration and developing novel immunotherapies for the treatment of AD.
项目总结/文摘
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)
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Yuxing Xia其他文献
Yuxing Xia的其他文献
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{{ truncateString('Yuxing Xia', 18)}}的其他基金
Investigating Mechanisms of Neurodegeneration in Transgenic Mouse Models of Tauopathies
研究 Tau蛋白病转基因小鼠模型中神经变性的机制
- 批准号:
10617695 - 财政年份:2021
- 资助金额:
$ 4.43万 - 项目类别:
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