Generation, Characterization, and Validation of Marmoset Models of Alzheimer's Disease
阿尔茨海默病狨猴模型的生成、表征和验证
基本信息
- 批准号:10819807
- 负责人:
- 金额:$ 77.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAffectAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease riskAmericanBehavioralBioinformaticsBiological AssayBiology of AgingCallithrixClinical ProtocolsCognitiveCommunitiesDedicationsDiseaseDisease ProgressionEarly Onset Alzheimer DiseaseEventFutureGenerationsGenesGeneticGenetic DiseasesGenetic EngineeringGenetic RiskGenomicsGoalsHumanInterventionInvestigationKnowledgeLate Onset Alzheimer DiseaseLifeModelingMolecularMutationNeurodegenerative DisordersOnset of illnessPathogenesisPathologicPatientsPhenotypePopulationPrimatesProcessProtocols documentationResearchResearch Project GrantsResource SharingStudy modelsTechnologyTherapeuticValidationanimal careanimal model developmentcomparativedata disseminationdata resourcegenomic signaturein vivomultidisciplinarymultimodalityneurodevelopmentneuroimagingneuropathologynovelopen datapresenilin-1preventrisk varianttranslational study
项目摘要
PROJECT SUMMARY OVERALL
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting nearly 6 million Americans and
is expected to increase over the next several years. Our limited understanding of the mechanisms that trigger
the emergence of AD has contributed to the lack of interventions that stop, prevent, or fully treat this disease.
We propose to establish the marmoset as the first primate-specific model to reveal the earliest cellular and
molecular events of AD processes and allow charting AD progression from its inception. To do so, we will draw
from a self-sufficient and large colony of research marmosets with dedicated veterinary and husbandry teams,
state-of-the-art in vivo neuroimaging and molecular assays, and a multidisciplinary team of experts in aging
biology, AD genetics and genomics, animal model development and characterization, behavioral and cognitive
phenotyping, and marmoset gene-editing technologies. Our proposal’s overarching goals are to develop
marmoset models of early-onset AD (EOAD) and late-onset AD (LOAD) to enable the investigation of the
underlying cellular and molecular root causes of the pathogenesis and progression of AD and support future
translational studies. We believe that the simultaneous assessment of genetic, molecular, functional, behavioral,
and pathological phenotypes in marmosets will provide translatable knowledge of the origins and progression of
AD in human populations. Furthermore, we posit that the comprehensive study of gene-edited marmoset models
of AD from neurodevelopment through aging will identify emerging phenotypes that precede frank
neuropathology. Our proposal consists of 3 integrated Research Projects that aim to: (1) Conduct
characterization and validation of PSEN1 mutations in marmosets as a model for the study of EOAD, and
investigate early life molecular determinants of AD disease pathogenesis associated with genetic risk for EOAD;
(2) Identify and enhance LOAD-related signatures in outbred and genetically-engineered marmosets; and (3)
Conduct a comparative multimodal phenotypic characterization of marmoset models of AD. These projects will
be supported by 5 Research Cores focused on project administration, bioinformatics, genetic engineering,
multimodal disease characterization, and veterinary and colony management. These supporting cores will
integrate marmoset and human genomic signatures and provide data dissemination and resources to the greater
research community as part of our commitment to open science, generate novel gene-edited marmoset models
of AD, develop optimized protocols for studying disease onset and trajectory in line with clinical protocols,
evaluate therapeutic strategies, and provide specialized animal care and support, respectively, allowing
complete characterization of the marmoset models. At the conclusion of this project, we will have genetically
engineered three AD risk variants into marmoset models, established a disease characterization pipeline for
comprehensive phenotyping, and shared these resources with the greater research community.
项目概要
阿尔茨海默病(AD)是一种破坏性的神经退行性疾病,影响近600万美国人,
预计在未来几年内会增加。我们对触发的机制的有限理解
AD的出现导致缺乏阻止、预防或完全治疗这种疾病的干预措施。
我们建议建立绒猴作为第一个灵长类动物特有的模型,以揭示最早的细胞和
AD过程的分子事件,并允许从一开始就绘制AD进展。为此,我们将绘制
从一个自给自足的大型研究绒猴群体,到专门的兽医和畜牧团队,
最先进的体内神经成像和分子分析,以及多学科的衰老专家团队
生物学,AD遗传学和基因组学,动物模型开发和表征,行为和认知
表型分析和绒猴基因编辑技术。我们提案的首要目标是发展
研究早发性AD(EOAD)和晚发性AD(LOAD)的绒猴模型,以研究
AD发病机制和进展的潜在细胞和分子根本原因,并支持未来
翻译研究我们认为,同时评估遗传,分子,功能,行为,
和病理表型将提供可翻译的知识的起源和发展,
AD在人类中的作用此外,我们认为,基因编辑的绒猴模型的全面研究
从神经发育到衰老的AD的研究将确定在弗兰克之前出现的新表型,
神经病理学我们的建议包括3个综合研究项目,旨在:(1)进行
作为EOAD研究模型的绒猴PSEN 1突变的表征和验证,以及
研究与EOAD遗传风险相关AD发病机制的早期生命分子决定因素;
(2)识别和增强远系繁殖和基因工程绒猴中的LOAD相关特征;以及(3)
对AD的绒猴模型进行比较多模态表型表征。这些项目将
由5个研究核心支持,重点是项目管理,生物信息学,遗传工程,
多模式疾病表征以及兽医和群体管理。这些支撑核心将
整合绒猴和人类基因组特征,并为更大的群体提供数据传播和资源。
作为我们致力于开放科学的一部分,研究社区产生了新的基因编辑的绒猴模型
制定符合临床方案的研究疾病发作和轨迹的优化方案,
评估治疗策略,并分别提供专门的动物护理和支持,
绒猴模型的完整特征。在这个项目结束时,我们将从基因上
将三种AD风险变体设计到绒猴模型中,建立了疾病表征管道,
全面的表型分析,并与更大的研究社区分享这些资源。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Brain Circuits and Dynamics of Curiosity-Driven Behavior in Naturally Curious Marmosets.
天生好奇的狨猴的大脑回路和好奇心驱动行为的动力学。
- DOI:10.1093/cercor/bhab080
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Tian,Xiaoguang;Silva,AfonsoC;Liu,Cirong
- 通讯作者:Liu,Cirong
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Gregory W Carter其他文献
Genetic interactions improve models of quantitative traits
遗传相互作用改进数量性状模型
- DOI:
10.1038/ng.3829 - 发表时间:
2017-03-30 - 期刊:
- 影响因子:29.000
- 作者:
Anna L Tyler;Gregory W Carter - 通讯作者:
Gregory W Carter
Gregory W Carter的其他文献
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{{ truncateString('Gregory W Carter', 18)}}的其他基金
An Explainable Unified AI Strategy for Efficient and Robust Integrative Analysis of Multi-omics Data from Highly Heterogeneous Multiple Studies
一种可解释的统一人工智能策略,用于对来自高度异质性多项研究的多组学数据进行高效、稳健的综合分析
- 批准号:
10729965 - 财政年份:2023
- 资助金额:
$ 77.75万 - 项目类别:
Generation, Characterization, and Validation of Marmoset Models of Alzheimer's Disease
阿尔茨海默病狨猴模型的生成、表征和验证
- 批准号:
10494769 - 财政年份:2022
- 资助金额:
$ 77.75万 - 项目类别:
Project 2: Identify and enhance LOAD-related signatures in outbred and genetically-engineered marmosets
项目 2:识别并增强近交系和基因工程狨猴中与 LOAD 相关的特征
- 批准号:
10494776 - 财政年份:2022
- 资助金额:
$ 77.75万 - 项目类别:
Modeling the Genetic Interaction Between Klotho and APOE Alleles in Alzheimer's Disease
模拟阿尔茨海默病中 Klotho 和 APOE 等位基因之间的遗传相互作用
- 批准号:
10524407 - 财政年份:2022
- 资助金额:
$ 77.75万 - 项目类别:
Open Drug Discovery Center for Alzheimer's Disease
阿尔茨海默病开放药物发现中心
- 批准号:
10250427 - 财政年份:2019
- 资助金额:
$ 77.75万 - 项目类别:
Open Drug Discovery Center for Alzheimer's Disease
阿尔茨海默病开放药物发现中心
- 批准号:
10017132 - 财政年份:2019
- 资助金额:
$ 77.75万 - 项目类别:
IU/JAX/Pitt MODEL-AD: Deep Phenotyping Proteomics Year 1
IU/JAX/Pitt MODEL-AD:深度表型蛋白质组学第 1 年
- 批准号:
10092243 - 财政年份:2016
- 资助金额:
$ 77.75万 - 项目类别:
The IU/JAX Alzheimer's Disease Precision Models Center: Metabolomics
IU/JAX 阿尔茨海默病精密模型中心:代谢组学
- 批准号:
9537115 - 财政年份:2016
- 资助金额:
$ 77.75万 - 项目类别:
The IU/JAX Alzheimer's Disease Precision Models Center: Aging
IU/JAX 阿尔茨海默病精密模型中心:衰老
- 批准号:
9930786 - 财政年份:2016
- 资助金额:
$ 77.75万 - 项目类别:
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