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:10472633
- 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
这个项目的长期目标是开发、表征和验证转基因绒猴
散发性阿尔茨海默病(AD)的模型,将作为研究分子和细胞的工具,
疾病机制,并确定治疗目标。AD是痴呆症最常见的原因,
大多数病例(~95%)似乎是散发性的,这是由以下因素之间的复杂相互作用引起的:
多种基因变异和环境因素。已经开发了许多AD模型(例如,mice);
这些模型主要集中在家族性AD,
了解AD,但他们未能概括分子,细胞,行为和认知的全谱
在AD中观察到的病理学,并且当试图将发现转化为人类时,
临床试验几条证据表明,绒猴可能有效地弥合小鼠之间的差距
和人类的基础和转化神经科学研究。首先,绒猴和人类
相似的大脑结构、认知/社会行为、新陈代谢和免疫功能。第二、
与其他灵长类动物相比,绒猴寿命短,体型小,繁殖能力强。
最后,基因编辑工具现在可用于生成各种类型的转基因绒猴。
载脂蛋白E(APOE)是迟发性、散发性AD最强的危险因素,也会增加年龄,
单基因家族性AD的相关风险和女性AD的发病率有三个APOE等位基因,
具有赋予风险增加的APOE*ε4等位基因和赋予风险降低的APOE*ε2等位基因的人
相对于常见的APOE*ε3等位基因。APOE亚型差异调节淀粉样β(Aβ)依赖性
和Aβ非依赖性途径影响脑内稳态,包括tau介导的神经变性,
小胶质细胞炎症、脂质转运、突触完整性、葡萄糖代谢和脑血管功能。
这三种APOE等位基因在位置112和114的半胱氨酸(C)和精氨酸(R)氨基酸方面不同。
158(APOE 2中的C112/C158; APOE 3中的C112/R158;和APOE 4中的R112/R158)。若干条证据
证明R61对APOE 4介导的AD风险至关重要。绒猴APOE(mAPOE)是由一个
一个等位基因,含有R112和R158的等价物,但缺乏关键的R61等价物(它含有T
相反,这表明它的行为与人类APOE 3相似。为了验证这一假设,mAPOE T61 R突变蛋白
以测试对小胶质细胞中脂多糖诱导的炎症反应的影响。
与野生型mAPOE相比,mAPOE T61 R变体导致更稳健的应答。类似的结果
当使用人APOE 4时,发现(APOE 4> APOE 3)。综合来看,这些初步结果
表明mAPOE T61 R在功能上等同于人APOE 4。此外,几对CRISPR
已经鉴定了用于产生APOE无效突变的gRNA。研究APOE在
将产生并表征绒猴、APOE缺失和T61 R突变绒猴中的散发性AD。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
KUO-FEN LEE其他文献
KUO-FEN LEE的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
10281948 - 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
- 批准号:
9209904 - 财政年份:2017
- 资助金额:
$ 141.04万 - 项目类别:
Project 1 - Salk Institute for Biological Studies NINDS Center Core Grant
项目 1 - 索尔克生物研究所 NINDS 中心核心资助
- 批准号:
8867295 - 财政年份:2015
- 资助金额:
$ 141.04万 - 项目类别:
相似海外基金
Interplay between Aging and Tubulin Posttranslational Modifications
衰老与微管蛋白翻译后修饰之间的相互作用
- 批准号:
24K18114 - 财政年份:2024
- 资助金额:
$ 141.04万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The Canadian Brain Health and Cognitive Impairment in Aging Knowledge Mobilization Hub: Sharing Stories of Research
加拿大大脑健康和老龄化认知障碍知识动员中心:分享研究故事
- 批准号:
498288 - 财政年份:2024
- 资助金额:
$ 141.04万 - 项目类别:
Operating Grants
EMNANDI: Advanced Characterisation and Aging of Compostable Bioplastics for Automotive Applications
EMNANDI:汽车应用可堆肥生物塑料的高级表征和老化
- 批准号:
10089306 - 财政年份:2024
- 资助金额:
$ 141.04万 - 项目类别:
Collaborative R&D
Baycrest Academy for Research and Education Summer Program in Aging (SPA): Strengthening research competencies, cultivating empathy, building interprofessional networks and skills, and fostering innovation among the next generation of healthcare workers t
Baycrest Academy for Research and Education Summer Program in Aging (SPA):加强研究能力,培养同理心,建立跨专业网络和技能,并促进下一代医疗保健工作者的创新
- 批准号:
498310 - 财政年份:2024
- 资助金额:
$ 141.04万 - 项目类别:
Operating Grants
関節リウマチ患者のSuccessful Agingに向けたフレイル予防対策の構築
类风湿性关节炎患者成功老龄化的衰弱预防措施的建立
- 批准号:
23K20339 - 财政年份:2024
- 资助金额:
$ 141.04万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Life course pathways in healthy aging and wellbeing
健康老龄化和福祉的生命历程路径
- 批准号:
2740736 - 财政年份:2024
- 资助金额:
$ 141.04万 - 项目类别:
Studentship
I-Corps: Aging in Place with Artificial Intelligence-Powered Augmented Reality
I-Corps:利用人工智能驱动的增强现实实现原地老龄化
- 批准号:
2406592 - 财政年份:2024
- 资助金额:
$ 141.04万 - 项目类别:
Standard Grant
NSF PRFB FY 2023: Connecting physiological and cellular aging to individual quality in a long-lived free-living mammal.
NSF PRFB 2023 财年:将生理和细胞衰老与长寿自由生活哺乳动物的个体质量联系起来。
- 批准号:
2305890 - 财政年份:2024
- 资助金额:
$ 141.04万 - 项目类别:
Fellowship Award
虚弱高齢者のSuccessful Agingを支える地域課題分析指標と手法の確立
建立区域问题分析指标和方法,支持体弱老年人成功老龄化
- 批准号:
23K20355 - 财政年份:2024
- 资助金额:
$ 141.04万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
「ケア期間」に着目したbiological aging指標の開発
开发聚焦“护理期”的生物衰老指数
- 批准号:
23K24782 - 财政年份:2024
- 资助金额:
$ 141.04万 - 项目类别:
Grant-in-Aid for Scientific Research (B)