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
基本信息
- 批准号:10618761
- 负责人:
- 金额:$ 93.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-16 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AgingAlzheimer&aposs disease modelAlzheimer&aposs disease related dementiaAlzheimer&aposs disease riskAmyloid beta-ProteinAmyotrophic Lateral SclerosisApolipoprotein EApolipoproteinsBehavioralBiochemicalBlood - brain barrier anatomyBlood VesselsBody SizeBrainC9ORF72CRISPR/Cas technologyCallithrixCognitiveComplexCraniocerebral TraumaDementiaDevelopmentDiseaseDisease ProgressionDoxycyclineEnvironmentEtiologyEventFunctional Magnetic Resonance ImagingGenesGeneticGoalsHomeostasisHousekeepingHumanImmunologic ReceptorsImpaired cognitionInfectionInflammatory ResponseLewy Body DementiaLigandsLinkLongevityMagnetic Resonance ImagingMaintenanceMammalsMediatingMetabolismMicrogliaModelingMolecularMolecular DiseaseMusMutationNeuraxisNeuronsParkinson DiseasePathologicPathologyPathway interactionsPeptidesPersonal SatisfactionPhasePhenotypePlayPositron-Emission TomographyPreclinical TestingPrimatesProcessResearchRisk FactorsRoleSeriesSignal PathwaySignal TransductionStructureSyndromeTREM2 geneTestingTimeTransgenesTransgenic OrganismsVariantVascular Systemcell typeclinical diagnosiscognitive testingdiagnostic toolearly onsetfluorodeoxyglucose positron emission tomographyfrontotemporal degenerationhuman diseaseimmune functioninducible gene expressionmacrophagemetabolic fitnessmixed dementiamouse modelmutantneuroimagingneuroinflammationneuron lossneuroprotectionnon-geneticnonhuman primatenull mutationoperationpreventpromoterprotein TDP-43reproductiveresponsescreeningsocialsuccesstherapeutic candidatetherapeutic evaluationtherapeutic targettooltransgene expressiontranslational neurosciencevascular cognitive impairment and dementia
项目摘要
Abstract
The long-term goal of this project is to model Alzheimer's Disease related dementias (ADRD) in longer-living
mammals. These multi-dimensional mammalian ADRD models, including frontotemporal degeneration (FTD),
Lewy body dementia (LBD), vascular contributions to cognitive impairment and dementia (VCID), and mixed
etiology dementias, are aimed at informing human ADRD across the disease-relevant stages and serve as
tools to interrogate disease mechanisms and identify therapeutic targets. ADRD develops as a result of a
complex series of events that take place in the brain over a long period of time—the prodromal phase can last
10-20 years in humans—before dementia is clinically diagnosed. Understanding this EARLY stage will be
critically important for developing diagnostic tools (e.g., neuroimaging) and for screening compounds to
prevent or modify disease progression in humans. A variety of ADRD mouse models have been developed to
advance research into the underlying molecular and cellular mechanisms, to identify therapeutic targets, and to
test therapeutic candidates. While existing ADRD mouse models have enabled progress toward each of these
objectives, those available to date do not recapitulate the full spectrum and complexity of the molecular,
cellular, behavioral and cognitive pathology observed in typical dementias. Several lines of evidence suggest
that marmosets have emerged as a non-human primate model for both basic and translational neuroscience
to bridge the gap between mice and humans. First, marmosets and humans have very similar complexity in
brain structures, cognitive/social behavioral repertoires, metabolisms and immune functions. Second, as
compared to other primates, it is highly economical and scalable for understanding brain functions and
preclinical tests because they have a short lifespan, small body size, and high reproductive power. Finally, a
set of gene editing tools is available to generate various types of genetically modified marmosets. Several lines
of evidence led us to elucidate the role of the triggering receptor expressed on myeloid cells 2 (TREM2)
pathways in ADRD. First, homozygous TREM2 null mutations have been linked to a recessive early-onset
dementia syndrome called Nasu–Hakola disease. Several TREM2 variants are pathologic to FTD and a major
risk factor/modifier for AD, Parkinson's disease, and amyotrophic lateral sclerosis (see
https://www.alzforum.org/mutations/trem2). TREM2 mutation precipitates changes in vascular changes and
blood brain barrier damages and may contribute to VCID. Second, microglia have emerged as a key cell type
in the maintenance of central nervous system homeostasis, for which TREM2 mediates multiple critical
signaling pathways. Third, aging is a major risk factor for ADRD. Decreased TREM2 expression during aging
may accelerate ADRD development. Taken together
, TREM2 is poised to influence neuronal and vascular
systems associated with the development of multiple forms of ADRD. To elucidate the role of TREM2 in ADRD,
different genetically modified marmosets will be generated and characterized.
摘要
该项目的长期目标是在更长的寿命中模拟阿尔茨海默病相关痴呆(ADRD)。
哺乳动物这些多维哺乳动物ADRD模型,包括额颞叶变性(FTD),
路易体痴呆(LBD),血管对认知障碍和痴呆的贡献(VCID),以及混合
病因性痴呆,旨在告知人类ADRD跨越疾病相关阶段,并作为
研究疾病机制和确定治疗靶点的工具。ADRD的发展是由于
前驱期是大脑中长时间发生的一系列复杂事件,
在临床诊断痴呆症之前,人类需要10-20年。了解这个早期阶段将是
对于开发诊断工具至关重要(例如,神经成像)和用于筛选化合物,
预防或改变人类疾病的进展。已经开发了多种ADRD小鼠模型,
推进对潜在分子和细胞机制的研究,以确定治疗靶点,并
测试治疗候选人。虽然现有的ADRD小鼠模型已经实现了对每一个的进展,
目标,迄今为止可用的那些并不能概括分子的全部谱和复杂性,
在典型痴呆中观察到的细胞、行为和认知病理学。一些证据表明
绒猴已经成为基础和转化神经科学的非人类灵长类动物模型
来弥合小鼠和人类之间的差距。首先,绒猴和人类有非常相似的复杂性,
大脑结构、认知/社会行为库、代谢和免疫功能。二是作为
与其他灵长类动物相比,它是非常经济和可扩展的了解大脑功能,
临床前试验,因为它们寿命短,体型小,繁殖能力高。最后
一套基因编辑工具可用于生成各种类型的转基因绒猴。几行
的证据使我们阐明了触发受体表达的髓样细胞2(TREM 2)的作用,
ADRD中的路径。首先,纯合子TREM 2无效突变与隐性早发性
痴呆综合症称为纳苏-哈科拉病。几种TREM 2变体是FTD的病理性变体,
AD、帕金森病和肌萎缩侧索硬化症的危险因素/修饰因子(见
https://www.alzforum.org/mutations/trem2). TREM 2突变可促进血管变化,
血脑屏障损伤,可能导致VCID。其次,小胶质细胞已经成为一种关键的细胞类型,
在维持中枢神经系统稳态中,TREM 2介导多种关键的
信号通路第三,衰老是ADRD的主要危险因素。衰老过程中TREM 2表达减少
可能加速ADRD的发展。两者合计
TREM 2有望影响神经元和血管
与多种形式ADRD发展相关的系统。为了阐明TREM 2在ADRD中的作用,
将产生和表征不同的遗传修饰的绒猴。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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:
$ 93.72万 - 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:
$ 93.72万 - 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:
$ 93.72万 - 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:
$ 93.72万 - 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:
$ 93.72万 - 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:
$ 93.72万 - 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:
$ 93.72万 - 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:
$ 93.72万 - 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:
$ 93.72万 - 项目类别: