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: 10642677
• 负责人: Jie Gao
• 金额: $ 23.63万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642677
• 关键词: Affinity; Affinity Chromatography; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Apolipoprotein E; Biochemical; Biological Process; Biotin; Brain; Cell Line; Cell physiology; Cells; Co-Immunoprecipitations; Dementia; Development; Disease associated microglia; Engineering; Enzymes; Etiology; Genetic Diseases; Genetic study; Genotype; Goals; Human Genetics; Immune response; Immune signaling; Immune system; Impaired cognition; Impairment; Kinetics; Knowledge; Label; Late Onset Alzheimer Disease; Ligand Binding; Ligands; Ligase; Link; Lipoprotein (a); Maps; Mediating; Membrane; Membrane Proteins; Microglia; Molecular; Mus; Neurodegenerative Disorders; Orphan; Pathway interactions; Pattern; Phagocytes; Phenotype; Procedures; Process; Proteins; Proteomics; Reporting; Risk; Role; Sampling; Signal Transduction; System; TREM2 gene; Variant; design; experimental study; insight; loss of function; neurotransmission; novel; novel therapeutic intervention; protein complex; protein protein interaction; rare variant; receptor; response; scaffold; stable cell line; temporal measurement; trafficking

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.

项目摘要 髓样细胞表达触发受体2（TREM 2）最近成为髓样细胞表达的主要调控因子。 免疫信号传导枢纽，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。罕见变体R47 H TREM 2中的R62和R62 H显著增加晚发性阿尔茨海默病（AD）的风险， 表明改变的TREM 2信号传导足以驱动AD病理。 尽管令人兴奋的遗传学研究将TREM 2变体与AD病因联系起来，但分子生物学研究表明， 这种基因型-表型关系的潜在机制仅得到部分解释。 蛋白质-蛋白质相互作用（PPI）是细胞信号传导正常功能的核心， 经常观察到PPI的正常模式的调节过程和中断， 与人类遗传疾病有关因此，将与TREM 2相互作用的蛋白质定位在一个 全系统水平是理解TREM 2通路分子机制的基础 以及剖析在AD相关TREM 2变体中改变的特定小胶质细胞信号传导。在 在本申请中，我们提出使用TurboID在小胶质细胞中绘制TREM 2蛋白相互作用组， 基于邻近标记的方法（目的1），并分析TREM 2相互作用组的变化 由AD相关变异R47 H和R62 H引起（目的2）。研究完成后， 识别TREM 2信号传导的新型调节剂，并深入了解TREM 2信号传导的因果机制。 AD中的TREM 2变体。从这个项目中产生的知识也将有助于设计新颖的 靶向TREM 2治疗AD的治疗策略。