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Mapping protein interactome of TREM2 and its variants to probe the etiology of Alzheimer's Disease

Mapping protein interactome of TREM2 and its variants to probe the etiology of Alzheimer's Disease
绘制 TREM2 及其变体的蛋白质相互作用组图以探讨阿尔茨海默病的病因
批准号:
10370642
负责人:
Jie Gao
金额:
$19.69万
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
项目状态:
已结题
起止时间:
2022-06-15 至 2024-03-31

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中文摘要
翻译
项目总结 触发髓样细胞上表达的受体2(TREM2)最近成为一种主要的 免疫信号中枢,对维持小胶质细胞对AD病理的反应至关重要,以及 使小胶质细胞转变为疾病相关的小胶质细胞(DAM)状态。稀有变种R47H TREM2和R62H显著增加了晚发性阿尔茨海默病(AD)的风险, 提示TREM2信号的改变足以推动AD的病理。 尽管有令人兴奋的基因研究将TREM2变异与AD病因学联系起来,但分子 这种基因型-表型关系的潜在机制仅被部分解释。 蛋白质-蛋白质相互作用(PPI)是细胞信号和蛋白质的正常功能的核心 经常观察到监管过程以及PPI正常模式的中断 与人类遗传病有关。因此,绘制与TREM2相互作用的蛋白质图 系统水平是理解TREM2途径分子机制的基础 并解剖在AD相关的TREM2变体中改变的特定小胶质细胞信号。在……里面 在这一应用中,我们建议使用TurboID-1定位TREM2蛋白在小胶质细胞中的相互作用组。 基于邻近标记方法(Aim 1),并描述TREM2相互作用体的变化 由AD相关变异R47H和R62H引起(目标2)。完成后,我们的研究将 确定TREM2信号的新调节因子,并深入了解TREM2信号转导的原因 AD中的TREM2变种。从这个项目中产生的知识也将有助于设计小说 针对TREM2的治疗策略用于AD的治疗。
英文摘要
Project summary Triggering receptor expressed on myeloid cells 2 (TREM2) recently emerged as a major immune signaling hub that is essential to sustain the microglial response to AD pathology, and enable microglial transition to a disease-associated microglia (DAM) status. Rare variants R47H and R62H in TREM2 significantly increase risks for late-onset Alzheimer’s disease (AD), indicating altered TREM2 signaling is sufficient to drive AD pathology. Despite the exciting genetic studies linking TREM2 variants to AD etiology, the molecular mechanisms underlying this genotype-phenotype relationship are only partially explained. Protein-protein interactions (PPIs) are central to the proper functioning of cellular signaling and regulatory processes, and disruptions of the normal patterns of PPIs are often observed and implicated in human genetic diseases. As such, mapping proteins that interact with TREM2 on a system-wide level is fundamental for understanding molecular machinery of TREM2 pathway and dissecting specific microglial signaling that is altered in AD-associated TREM2 variants. In this application, We propose to map TREM2 protein interactome in microglia use TurboID- based proximity labeling approach (Aim 1), and to profile the change of TREM2 interactome caused by AD-associated variations R47H and R62H (Aim 2). Upon completion, our study will identify novel regulators of TREM2 signaling, and bring insights into the causal mechanisms of TREM2 variants in AD. Knowledge generated from this project will also help design novel therapeutic strategies targeting TREM2 for the treatment of AD.
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Mapping protein interactome of TREM2 and its variants to probe the etiology of Alzheimer's Disease
  • 批准号:
    10642677
  • 项目类别:
  • 资助金额:
    $23.63万
  • 财政年份:
    2022
  • 负责人:
    Jie Gao
  • 依托单位:
Targeting IDOL-ApoE receptor pathway in Alzheimer's disease
  • 批准号:
    10461318
  • 项目类别:
  • 资助金额:
    $39.38万
  • 财政年份:
    2021
  • 负责人:
    Jie Gao
  • 依托单位:
The Idol-ApoE receptor pathway in Alzheimer's disease
  • 批准号:
    9923900
  • 项目类别:
  • 资助金额:
    $24.9万
  • 财政年份:
    2017
  • 负责人:
    Jie Gao
  • 依托单位:
海外基金