Project 3: Multi-modal phenotypic Characterization of marmoset models of Late Onset Alzheimer's Disease

项目3:晚发性阿尔茨海默病狨猴模型的多模式表型表征

基本信息

  • 批准号:
    10494777
  • 负责人:
  • 金额:
    $ 23.72万
  • 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 2027-08-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY PROJECT 3 Project 3: Comparative Multimodal Phenotypic Characterization of Marmoset Models of AD Alzheimer’s Disease (AD), the most common cause of dementia, is a multifactorial neurodegenerative disorder affecting ~6 million Americans. Currently, there are no interventions capable of preventing, stopping, or treating AD. The scarcity of adequate animal models that enable a comprehensive investigation of the pathogenic mechanisms at play in AD has limited our progress towards discovering effective treatments. There is a critical need for enhanced animal models that incorporate genetic variability, optimal lifespan to support age-related research, superior compatibility as a model of human social and cognitive behavior, and the presentation of AD- related pathology. The central premise of our Consortium “Generation, Characterization, and Validation of Marmoset Models of Alzheimer’s Disease” (MARMO-AD) is that the marmoset will reveal the earliest primate- specific cellular and molecular root causes of AD pathogenesis and progression. We postulate that marmosets engineered to harbor genetic risk variants for early- (EOAD) and late-onset AD (LOAD) will reveal clinical disease trajectories that model those of human AD patients and display primate-specific disease pathogenesis that can be detected with a comprehensive phenotypic characterization pipeline. We hypothesize that: (1) the comprehensive 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; and (2) the comparative, longitudinal study of the marmoset LOAD model against the EOAD models and healthy controls will identify emerging phenotypes that precede frank neuropathology and prioritize tractable targets for future therapeutic discovery. The ATP-binding cassette, sub-family A, member 7 (ABCA7) gene was identified by genome-wide association studies (GWAS) as having one of the highest odds ratios for developing LOAD in humans. In this project, we will create a novel genetically engineered marmoset LOAD model incorporating an ABCA7 LOAD variant. Once these animals are born, we will follow them longitudinally to identify emerging phenotypes that deviate from healthy aging ahead of the appearance of frank neuropathology. We will evaluate non-carrier healthy control marmosets to characterize the typical healthy aging trajectory across the lifespan and establish a baseline against which we can contrast our marmoset models of LOAD and EOAD. We will then evaluate the disease trajectory of the ABCA7 marmoset LOAD model relative to the PSEN1 EOAD models via longitudinal, multimodal phenotypic characterization in line with the clinical staging of AD patients. By contrasting our marmoset models of EOAD and LOAD, we hope to identify differential biomarkers of LOAD that can be measured ahead of the emergence of frank neuropathology and prioritize novel targets for therapeutic development. Upon validation of these unique primate AD models, we plan to expand the colony and share this precious resource with the greater AD research community to help accelerate the pace of bringing novel and effective treatments to patients.
项目3 项目3:AD的绒猴模型的比较多模式表型表征 阿尔茨海默病(Alzheimer's Disease,AD)是一种多因素的神经退行性疾病,是痴呆的最常见病因 影响了约600万美国人。目前,没有任何干预措施能够预防、阻止或治疗 AD.缺乏足够的动物模型,使全面调查的致病性 在AD中起作用的机制限制了我们在发现有效治疗方法方面的进展。存在一个临界 需要增强的动物模型,包括遗传变异性,最佳寿命,以支持年龄相关的 研究,作为人类社会和认知行为模型的上级兼容性,以及AD- 相关病理学我们的联盟的中心前提是“生成,表征和验证 阿尔茨海默病的绒猴模型”(MARMO-AD)是绒猴将揭示最早的灵长类动物- AD发病机制和进展的特定细胞和分子根源。我们假设绒猴 设计成携带早发性AD(EOAD)和晚发性AD(LOAD)的遗传风险变体将揭示临床疾病 这些轨迹模拟了人类AD患者的轨迹,并显示了灵长类动物特异性疾病的发病机制, 通过全面的表型表征管道进行检测。我们假设:(1) 综合评估遗传、分子、功能、行为和病理表型, 绒猴将提供人类AD起源和进展的可翻译知识;以及 (2)绒猴LOAD模型与EOAD模型和健康模型的比较、纵向研究 对照组将识别出现在坦率神经病理学之前的新表型,并优先考虑易处理的靶点, 未来的治疗发现ATP结合盒,亚家族A,成员7(ABCA 7)基因被鉴定 全基因组关联研究(GWAS)认为,在发生LOAD的人群中, 人类在这个项目中,我们将创建一个新的基因工程绒猴LOAD模型, ABCA 7 LOAD变体。一旦这些动物出生,我们将纵向跟踪它们, 表型偏离健康老龄化之前的外观坦率的神经病理。我们将评估 非携带者健康对照绒猴,以表征整个生命周期的典型健康衰老轨迹, 建立一个基线,我们可以对照我们的绒猴模型的LOAD和EOAD。然后我们将 评估ABCA 7绒猴LOAD模型相对于PSEN 1 EOAD模型的疾病轨迹, 与AD患者的临床分期一致的纵向多模式表型表征。通过对比 我们的EOAD和LOAD的绒猴模型,我们希望能够识别LOAD的差异生物标志物, 在坦率的神经病理学出现之前进行测量,并优先考虑新的治疗目标。 发展在验证了这些独特的灵长类AD模型后,我们计划扩大殖民地,并分享这些模型。 与更大的广告研究界的宝贵资源,以帮助加快步伐, 有效治疗患者。

项目成果

期刊论文数量(0)
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Afonso C Silva其他文献

脳主幹動脈瘤狭窄閉塞症例に対し脳血流SPECTで脳血管反応性を評価するために用いられるacetazolamide静脈内投与の副作用
静脉注射乙酰唑胺用于通过脑血流SPECT评估脑血管反应性在主脑动脉动脉瘤狭窄和闭塞的情况下的副作用
  • DOI:
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    0
  • 作者:
    河合裕子;青木伊知男;梅田雅宏;樋口敏宏;樋口真人;Afonso C Silva;田中忠蔵;斎藤秀夫
  • 通讯作者:
    斎藤秀夫
Manganese-enhanced MRIを用いた虚血脳における組織変化の検出
使用锰增强 MRI 检测缺血脑中的组织变化
  • DOI:
  • 发表时间:
    2009
  • 期刊:
  • 影响因子:
    0
  • 作者:
    河合裕子;青木伊知男;梅田雅宏;樋口敏宏;樋口真人;Afonso C Silva;田中忠蔵
  • 通讯作者:
    田中忠蔵

Afonso C Silva的其他文献

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{{ truncateString('Afonso C Silva', 18)}}的其他基金

Multimodal Disease Characterization Core
多模式疾病表征核心
  • 批准号:
    10494773
  • 财政年份:
    2022
  • 资助金额:
    $ 23.72万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10494770
  • 财政年份:
    2022
  • 资助金额:
    $ 23.72万
  • 项目类别:
Development and Validation of a Marmoset Model of Late-Onset Alzheimer Disease Based on Tau Seeding
基于 Tau 接种的晚发性阿尔茨海默病狨猴模型的开发和验证
  • 批准号:
    10668407
  • 财政年份:
    2021
  • 资助金额:
    $ 23.72万
  • 项目类别:
Development and Validation of a Marmoset Model of Late-Onset Alzheimer Disease Based on Tau Seeding
基于 Tau 接种的晚发性阿尔茨海默病狨猴模型的开发和验证
  • 批准号:
    10468141
  • 财政年份:
    2021
  • 资助金额:
    $ 23.72万
  • 项目类别:
Development and Validation of a Marmoset Model of Late-Onset Alzheimer Disease Based on Tau Seeding
基于 Tau 接种的晚发性阿尔茨海默病狨猴模型的开发和验证
  • 批准号:
    10281602
  • 财政年份:
    2021
  • 资助金额:
    $ 23.72万
  • 项目类别:
Preclinical investigation of common mechanistic links between aberrant protein aggregation and blood-brain barrier dysfunction in Alzheimer's disease and Alzheimer's related dementias (AD/ADRD)
阿尔茨海默病和阿尔茨海默病相关痴呆 (AD/ADRD) 中异常蛋白聚集与血脑屏障功能障碍之间常见机制联系的临床前研究
  • 批准号:
    10037968
  • 财政年份:
    2020
  • 资助金额:
    $ 23.72万
  • 项目类别:

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