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

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.
项目总体概要 阿尔茨海默病 (AD) 是一种毁灭性的神经退行性疾病,影响着近 600 万美国人和 预计未来几年将会增加。我们对触发机制的了解有限 AD 的出现导致缺乏阻止、预防或充分治疗这种疾病的干预措施。 我们建议将狨猴建立为第一个灵长类动物特异性模型,以揭示最早的细胞和 AD 过程的分子事件,并可以从 AD 开始时绘制图表。为此,我们将绘制 来自一个自给自足的大型研究狨猴群体,拥有专门的兽医和饲养团队, 最先进的体内神经影像和分子检测,以及衰老领域的多学科专家团队 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 表型分析和狨猴基因编辑技术。我们提案的总体目标是发展 狨猴早发性 AD (EOAD) 和晚发性 AD (LOAD) 模型,以便研究 AD 发病机制和进展的潜在细胞和分子根源并支持未来 转化研究。我们相信同时评估遗传、分子、功能、行为、 狨猴的病理表型将提供关于狨猴的起源和进展的可翻译知识 人群中的AD。此外,我们假设基因编辑狨猴模型的综合研究 AD从神经发育到衰老的过程将识别出先于坦率的新兴表型 神经病理学。我们的提案包括 3 个综合研究项目,旨在:(1) 进行 作为 EOAD 研究模型的狨猴 PSEN1 突变的表征和验证,以及 研究与 EOAD 遗传风险相关的 AD 疾病发病机制的早期分子决定因素; (2) 识别并增强近交系和基因工程狨猴中与 LOAD 相关的特征;和(3) 对 AD 狨猴模型进行比较多模式表型表征。这些项目将 由 5 个研究核心支持,专注于项目管理、生物信息学、基因工程、 多模式疾病表征以及兽医和群体管理。这些支撑核心将 整合狨猴和人类基因组特征,并向更广泛的领域提供数据传播和资源 研究社区作为我们致力于开放科学的一部分,生成新颖的基因编辑狨猴模型 AD,根据临床方案制定用于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,从而允许 狨猴模型的完整表征。在这个项目结束时,我们将拥有基因 将三种 AD 风险变异体设计到狨猴模型中,建立了疾病表征流程 全面的表型分析,并与更大的研究界共享这些资源。

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。
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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:
Bioinformatics and Data Integration Core
生物信息学和数据集成核心
  • 批准号:
    10494771
  • 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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Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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骨细胞老化会对骨代谢产生不利影响吗?
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