Defining the Mechanisms by Which MS4A Genes Regulate TREM2 in Alzheimer Disease

定义 MS4A 基因在阿尔茨海默病中调节 TREM2 的机制

基本信息

批准号：
10202475
负责人：
Celeste Marie Karch
金额：
$ 56.77万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202475
关键词：
Age Alleles Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid beta-Protein Animal Model Antibodies Biochemical Biology Brain CRISPR/Cas technology Cell Nucleus Cell Survival Cells Cerebrospinal Fluid Cognitive Complex Culture Media Data Development Disease Disease model Event Exhibits Extracellular Domain Functional disorder Gene Cluster Genes Genetic Genetic Models Genomics Genotype Goals Human Human Genetics Inflammatory Response Integral Membrane Protein Knock-out Maps Mediating Membrane Proteins Meta-Analysis Metabolism Microglia Molecular Mus Myeloid Cells Needles Nerve Degeneration Neurodegenerative Disorders Orthologous Gene Pathogenesis Pathway interactions Patients Phagocytosis Pharmacology Predisposition Prevention Proteins Receptor Signaling Role Signal Transduction TREM2 gene Testing Variant brain cell cell type gene function high risk human model induced pluripotent stem cell knock-down new therapeutic target novel prevent rare variant stem cell model stem cells targeted treatment tau Proteins trafficking transcriptome sequencing uptake

项目摘要

Project Description The complex molecular events that underlie the development of Alzheimer's disease (AD) are poorly understood and are the key to developing targeted therapies. Our group and others have shown that rare variants in the triggering receptor expressed on myeloid cells 2 gene (TREM2) are associated with increased susceptibility to AD. TREM2 encodes a membrane protein that is part of a receptor-signaling complex that modulates inflammatory responses, phagocytosis and cell survival in myeloid cells, such as microglia. However, the specific role of TREM2 in AD pathogenesis remains unclear. CSF sTREM2 levels are increased in patients with symptomatic AD compared to cognitively normal controls. We have recently discovered that common variants in the MS4A locus are a major regulator of CSF sTREM2 levels. Importantly, the same allele associated with higher CSF sTREM2 levels is associated lower AD risk and delayed age at onset. We also identified a second, independent signal in the MS4A locus that encodes MS4A4A p.M159V, which has the opposite effect on CSF sTREM2 levels and AD risk. Our findings that two independent signals in the MS4A gene region have opposing effects on CSF sTREM2 levels and AD risk points to the connection between MS4A and TREM2 biology in AD pathogenesis. The goal of this project is to elucidate the mechanisms by which MS4A genes alter TREM2 function and drive AD pathogenesis. We hypothesize that MS4A4A is involved in TREM2 trafficking and cleavage and that disrupted interaction between MS4A4A and TREM2 leads to microglial dysfunction and neurodegeneration. To test this hypothesis, we will use genomic and biochemical approaches in human brains and stem cell models. The results of this project will provide the mechanistic framework needed to develop treatments that restore or enhance TREM2 functions in order to prevent neurodegenerative disease.

项目描述基于阿尔茨海默氏病（AD）发展的复杂分子事件（AD）很差理解，是开发目标疗法的关键。我们的小组和其他人表明很少见在髓样细胞2基因（Trem2）上表达的触发受体中的变体与增加有关对广告的敏感性。 TREM2编码是一种受体信号复合物的一部分的膜蛋白调节髓样细胞（例如小胶质细胞）的炎症反应，吞噬作用和细胞存活。但是，TREM2在AD发病机理中的特定作用尚不清楚。 CSF Streem2水平增加与认知正常对照相比，有症状广告的患者中。我们最近发现 MS4A基因座中的常见变体是CSF Streem2水平的主要调节剂。重要的是，同一个等位基因与较高的CSF Streem2水平相关的是较低的AD风险和发病时的延迟年龄。我们也是确定了MS4A基因座中的第二个独立信号，该信号编码MS4A4A P.M159V，该信号具有对CSF Streem2水平和AD风险的相反影响。我们的发现是MS4A中的两个独立信号基因区域对CSF Streem2水平和AD风险点具有相反的影响 AD发病机理中的MS4A和TREM2生物学。该项目的目的是通过 MS4A基因会改变TREM2功能并驱动AD发病机理。我们假设MS4A4A是参与TREM2运输和裂解，以及MS4A4A与Trem2之间的相互作用破坏了到小胶质细胞功能障碍和神经变性。为了检验这一假设，我们将使用基因组和生化在人的大脑和干细胞模型中接近。该项目的结果将提供机械需要开发恢复或增强TREM 2功能的治疗框架以防止神经退行性疾病。