Genetic models of sporadic Alzheimers Disease in the marmoset
狨猴散发性阿尔茨海默病的遗传模型
基本信息
- 批准号:10281948
- 负责人:
- 金额:$ 141.04万
- 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:2021-09-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAgingAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease riskAmino AcidsAmyloid beta-ProteinAmyloid beta-Protein PrecursorAnimalsApolipoprotein EApolipoproteins AArginineBehavioralBiochemicalBiological ModelsBody SizeBrainBrain PathologyCallithrixClinicalClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCognitiveComplexCysteineDementiaDementia with Lewy BodiesDiseaseEnvironmental Risk FactorExhibitsFishesGenesGenetic ModelsGenomicsGenotypeGoalsGuide RNAHomeostasisHumanIncidenceInfectionInflammationInflammatory ResponseLinkLipid BindingLipopolysaccharidesLongevityMagnetic Resonance ImagingMediatingMeta-AnalysisMetabolismMicrogliaModelingMolecularMolecular DiseaseMusMutationNerve DegenerationNeurosciences ResearchParkinson&aposs DementiaPathologyPathway interactionsPhenotypePoint MutationPositioning AttributePositron-Emission TomographyPredictive ValuePrimatesProtein IsoformsProteinsRelative RisksReproducibilityResearchRiskRisk FactorsRoleSignal TransductionStructureSynapsesTauopathiesTestingThreonineTransgenic MiceTranslatingVariantWomanage relatedapolipoprotein E-3cerebrovascularcognitive testingearly onsetfamilial Alzheimer diseaseflygain of functiongenetic linkage analysisgenetic variantgenome wide association studyglucose metabolismimmune functionlipid transportlipidomicsmouse modelmutantneuroimagingnonhuman primatenull mutationoverexpressionpresenilin-1presenilin-2protective alleleprotein TDP-43reproductiveresponserisk variantsexsocialtau Proteinstherapeutic targettooltransgenic model of alzheimer diseasetranslational neuroscience
项目摘要
Abstract
The long-term goal of this project is to develop, characterize, and validate genetically modified marmoset
models of sporadic Alzheimer's Disease (AD) that will serve as tools for investigating molecular and cellular
disease mechanisms, and for identifying therapeutic targets. AD is the most common cause of dementia, with
the majority of cases (~95%) appearing to be sporadic, which is caused by complex interactions between
multiple gene variants and environmental factors. Numerous models of AD have been developed (e.g., mice);
these models are primarily focused on familial forms of AD and have enabled significant progress toward
understanding AD, but they fail to recapitulate the full spectrum of molecular, cellular, behavioral, and cognitive
pathologies observed in AD and provide poor predictive value when trying to translate findings to human
clinical trials. Several lines of evidence suggest that marmosets may effectively bridge the gap between mice
and humans for both basic and translational neuroscience research. First, marmosets and humans have very
similar brain structures, cognitive/social behavioral repertoires, metabolism, and immune functions. Second,
compared to other primates, marmosets have short lifespan, small body size, and high reproductive power.
Finally, gene editing tools are now available to generate various types of genetically modified marmosets.
Apolipoprotein E (APOE) is the strongest risk factor for late-onset, sporadic AD and also increases the age-
dependent risk of monogenic familial AD and incidence of AD in women. There are three APOE alleles in
humans with the APOE*ε4 allele conferring increased risk and the APOE*ε2 allele conferring decreased risk
relative to the common APOE*ε3 allele. APOE isoforms differentially modulate both amyloid-β (Aβ)-dependent
and Aβ-independent pathways to affect brain homeostasis, including tau-mediated neurodegeneration,
microglial inflammation, lipid transport, synaptic integrity, glucose metabolism and cerebrovascular function.
These three APOE alleles differ with regard to cysteine (C) and arginine (R) amino acids at positions 112 and
158 (C112/C158 in APOE2; C112/R158 in APOE3; and R112/R158 in APOE4). Several lines of evidence
demonstrate that R61 is critical for APOE4-mediated AD risk. Marmoset APOE (mAPOE) is encoded by a
single allele and contains the equivalent of R112 and R158, but lacks the critical R61 equivalent (it contains T
instead), suggesting that it behaves like human APOE3. To test this hypothesis, mAPOE T61R mutant protein
was generated to test the effect on inflammatory responses induced by lipopolysaccharides in microglial cells.
The mAPOE T61R variant resulted in a more robust response compared to wild type mAPOE. Similar results
were found when human APOE4 was used (APOE4>APOE3). Taken together, these preliminary results
indicate that mAPOE T61R is functionally equivalent to human APOE4. Further, several pairs of CRISPR
gRNAs for generating an APOE null mutation have been identified. To investigate the role of APOE in
sporadic AD in the marmoset, APOE null and T61R mutant marmosets will be generated and characterized.
摘要
项目成果
期刊论文数量(0)
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专利数量(0)
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{{ truncateString('KUO-FEN LEE', 18)}}的其他基金
Atlas for neuronal and glial cell types selectively vulnerable to proteinopathies during progression of Alzheimer's Disease
在阿尔茨海默病进展过程中选择性易受蛋白质病影响的神经元和神经胶质细胞类型图谱
- 批准号:
10667245 - 财政年份:2023
- 资助金额:
$ 141.04万 - 项目类别:
Genetic models of sporadic Alzheimers Disease in the marmoset
狨猴散发性阿尔茨海默病的遗传模型
- 批准号:
10472633 - 财政年份:2021
- 资助金额:
$ 141.04万 - 项目类别:
Genetic models of sporadic Alzheimers Disease in the marmoset
狨猴散发性阿尔茨海默病的遗传模型
- 批准号:
10669078 - 财政年份:2021
- 资助金额:
$ 141.04万 - 项目类别:
Modeling Alzheimer's Disease Related Dementias in the Marmoset
模拟狨猴中与阿尔茨海默病相关的痴呆症
- 批准号:
10618761 - 财政年份:2019
- 资助金额:
$ 141.04万 - 项目类别:
High-throughput mapping of selectively vulnerable cell types and projections in aging and Alzheimer's Disease
选择性脆弱细胞类型的高通量绘图以及衰老和阿尔茨海默氏病的预测
- 批准号:
9803745 - 财政年份:2019
- 资助金额:
$ 141.04万 - 项目类别:
Modeling Alzheimer's Disease Related Dementias in the Marmoset
模拟狨猴中与阿尔茨海默病相关的痴呆症
- 批准号:
10705182 - 财政年份:2019
- 资助金额:
$ 141.04万 - 项目类别:
Modeling Alzheimer's Disease Related Dementias in the Marmoset
模拟狨猴中与阿尔茨海默病相关的痴呆症
- 批准号:
9903123 - 财政年份:2019
- 资助金额:
$ 141.04万 - 项目类别:
Development of marmoset models of neurodegenerative disease using embryonic stem cell-based gene-editing approaches
使用基于胚胎干细胞的基因编辑方法开发狨猴神经退行性疾病模型
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项目 1 - 索尔克生物研究所 NINDS 中心核心资助
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8867295 - 财政年份:2015
- 资助金额:
$ 141.04万 - 项目类别:
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