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:
    10669078
  • 负责人:
  • 金额:
    $ 147.64万
  • 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

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.
抽象的 该项目的长期目标是开发、表征和验证转基因狨猴 散发性阿尔茨海默病(AD)模型将作为研究分子和细胞的工具 疾病机制,并确定治疗靶点。 AD 是痴呆症最常见的原因, 大多数病例(~95%)似乎是散发的,这是由之间复杂的相互作用引起的 多种基因变异和环境因素。已经开发了许多 AD 模型(例如小鼠); 这些模型主要关注 AD 的家族形式,并在这方面取得了重大进展 了解AD,但他们未能概括分子、细胞、行为和认知的全部范围 在 AD 中观察到的病理现象在尝试将研究结果转化为人类时提供的预测价值很差 临床试验。多项证据表明狨猴可以有效地弥合小鼠之间的差距 以及人类的基础和转化神经科学研究。首先,狨猴和人类有非常 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,狨猴寿命短、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狨猴。 载脂蛋白 E (APOE) 是迟发性、散发性 AD 的最强危险因素,并且还会增加年龄 单基因家族性 AD 的相关风险和女性 AD 的发病率。 APOE 共有 3 个等位基因 携带 APOE*ε4 等位基因的人类会增加风险,携带 APOE*ε2 等位基因会降低风险 相对于常见的 APOE*ε3 等位基因。 APOE 亚型差异调节淀粉样蛋白-β (Aβ) 依赖性 和 Aβ 独立途径影响大脑稳态,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。 这三个 APOE 等位基因在第 112 位和第 112 位的半胱氨酸 (C) 和精氨酸 (R) 氨基酸方面有所不同。 158(APOE2 中的 C112/C158;APOE3 中的 C112/R158;以及 APOE4 中的 R112/R158)。几行证据 证明 R61 对于 APOE4 介导的 AD 风险至关重要。狨猴 APOE (mAPOE) 是由 单个等位基因,包含 R112 和 R158 的等价物,但缺少关键的 R61 等价物(它包含 T 相反),表明它的行为类似于人类 APOE3。为了验证这一假设,mAPOE T61R 突变蛋白 旨在测试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 T61R 变体产生了更强烈的反应。类似的结果 当使用人类 APOE4 时发现 (APOE4>APOE3)。综合起来,这些初步结果 表明 mAPOE T61R 在功能上等同于人类 APOE4。此外,几对 CRISPR 用于产生 APOE 无效突变的 gRNA 已被鉴定。研究 APOE 在 将生成狨猴、APOE 缺失和 T61R 突变狨猴中的散发性 AD 并进行表征。

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)
A central alarm system that gates multi-sensory innate threat cues to the amygdala.
  • DOI:
    10.1016/j.celrep.2022.111222
  • 发表时间:
    2022-08-16
  • 期刊:
  • 影响因子:
    8.8
  • 作者:
    Kang, Sukjae J.;Liu, Shijia;Ye, Mao;Kim, Dong-Il;Pao, Gerald M.;Copits, Bryan A.;Roberts, Benjamin Z.;Lee, Kuo-Fen;Bruchas, Michael R.;Han, Sung
  • 通讯作者:
    Han, Sung
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KUO-FEN LEE其他文献

KUO-FEN LEE的其他文献

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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:
    $ 147.64万
  • 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:
    $ 147.64万
  • 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:
    $ 147.64万
  • 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:
    $ 147.64万
  • 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:
    $ 147.64万
  • 项目类别:
Marmoset Bioscience Meeting
狨猴生物科学会议
  • 批准号:
    10318680
  • 财政年份:
    2019
  • 资助金额:
    $ 147.64万
  • 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:
    $ 147.64万
  • 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:
    $ 147.64万
  • 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:
    $ 147.64万
  • 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:
    $ 147.64万
  • 项目类别:

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