Dissecting the differential role of TREM2 and TYROBP in microglial homeostasis, activation, and disease

剖析 TREM2 和 TYROBP 在小胶质细胞稳态、激活和疾病中的不同作用

基本信息

批准号：
10640102
负责人：
Gabriela Farias Quipildor
金额：
$ 7.59万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2022-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10640102
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease pathology Amyloid beta-Protein Amyloidosis Anti-Inflammatory Agents Apolipoprotein E Binding Proteins Biological Assay Brain Cause of Death Cell Survival Cells Complex Coupling Cytoplasmic Tail Data Dementia Disease Disease associated microglia Evaluation Event Exhibits Exposure to Gene Expression Regulation Global Change Goals Homeostasis Human ITAM Immune Immunologic Surveillance Individual Inflammation Inflammatory Inflammatory Response Knock-in Knockout Mice Late Onset Alzheimer Disease Ligand Binding Lipids Lipopolysaccharides Mass Spectrum Analysis Memory Loss Microglia Missense Mutation Mitogen-Activated Protein Kinases Modeling Molecular Molecular Profiling Morphology Mutation Natural regeneration Nerve Degeneration Neurodegenerative Disorders Neurons PIK3CG gene Pathogenesis Pathway interactions Peptides Phagocytes Phagocytosis Phase Phenotype Phosphopeptides Phosphoric Monoester Hydrolases Phosphorylation Phosphoserine Phosphotyrosine Physiological Point Mutation Proliferating Proline Protein Isoforms Protein Kinase Protein Phosphatase 2A Regulatory Subunit PR53 Protein phosphatase Proteins Proto-Oncogene Proteins c-akt Receptor Protein-Tyrosine Kinases Research Rest Risk Role SYK gene Senile Plaques Signal Pathway Signal Transduction Signaling Protein Stimulus Synaptic plasticity TREM2 gene TYROBP gene Testing Threonine United States Up-Regulation Variant abeta oligomer aged chemokine cognitive skill cytokine effective therapy extracellular glial activation immunoregulation inhibitor insight loss of function migration neuroprotection neurotoxicity normal aging pathogen pharmacologic phosphatase inhibitor phosphoproteomics protein aggregation recruit repaired response stoichiometry synaptic pruning tau aggregation therapeutic target

项目摘要

PROJECT SUMMARY/ABSTRACT The Alzheimer’s Association describes Alzheimer’s disease (AD) as “the most common type of dementia”, a term that generally describes the loss of memory and some forms of cognitive skills that interfere with everyday activities. AD is one of the top three causes of death in aged individuals in the United States. It was first described by Alois Alzheimer in 1906 as an accumulation of extracellular amyloid plaques and intracellular neurofibrillary tau tangles; yet, more than a century later, there is still no effective treatment or cure to the disease. Although an abundance of research has focused on understanding AD, there are still many unknowns to the mechanisms of disease pathogenesis. Microglia, the primary immune cell in the brain, have multiple activation phenotypes that are involved in broad and complex functions in the brain, including in neurotoxicity and release of inflammatory cytokines, in repair and regeneration, in immune regulation, in neuroprotection and release of anti-inflammatory cytokines, in cell survival/proliferation/migration, and in phagocytosis. TREM2 and TYROBP are known to form a complex in microglia that can lead to complex intracellular signaling networks, and these proteins have recently emerged as important regulators of the transition between resting (homeostatic) microglia and its activation states. Recent findings from our group and others have shown a TYROBP-dependent and TREM2-independent molecular signature that exhibits involvement in the early transition step from homeostatic microglia to disease-associated microglia (DAM). Interestingly, the sequential step of DAM activation is TREM2-dependent. However, the underlying mechanisms of how TREM2 or TYROBP regulate these downstream cellular phenotypes are largely unknown. In this proposal, we aim to systematically test whether, and to what extent, AD-relevant stimuli, such as amyloid beta (A) oligomers or physiological Apolipoprotein E 3 or 4 isoforms are able to activate microglia, in the absence of TYROBP or TREM2 or in the presence of the AD-associated Trem2 R47H knockin mutation. Here, we will utilize a thorough approach to investigate not only signal transduction and various cellular activation pathways, but also we will use state-of-the-art mass spectrometry-based phosphoproteomics to unbiasedly examine global changes in phosphopeptides, in order to specifically elucidate differences in microglial homeostasis and activation states in our models. The overall goal of the study is to understand the differential roles of TREM2 and TYROBP in the mechanisms underlying microglial activation in the context of disease-like stimuli, and to ultimately identify potential therapeutic targets that specifically focus on microglia activation phenotypes, and that could contribute to the delay or treatment of AD pathology.

项目摘要/摘要阿尔茨海默氏症协会将阿尔茨海默氏病（AD）描述为“最常见的类型痴呆”，这个术语通常描述了记忆的丧失和某些形式的认知技能每天的活动。广告是美国老年人死亡原因之一。它 1906年，Alois Alzheimer首先将其描述为细胞外淀粉样斑块的积累和细胞内神经原纤维tau缠结；然而，一个多世纪后，仍然没有有效的治疗或治愈疾病。尽管大量的研究集中在理解广告上，但仍然有很多疾病发病机理机制未知。小胶质细胞是大脑中的主要免疫细胞，具有多种激活表型大脑中广泛而复杂的功能，包括神经毒性和炎症细胞因子的释放，修复和再生，在免疫调节中，在神经保护和抗炎细胞因子的神经保护和释放中细胞存活/增殖/迁移以及吞噬作用。已知TREM2和Tyrobp在可导致复杂细胞内信号网络的小胶质细胞，这些蛋白质最近出现了作为静止（稳态）小胶质细胞及其激活状态之间过渡的重要调节因子。最近的我们小组和其他人的发现表现出依赖Tyrobp和TREM2的分子从稳态小胶质细胞到疾病相关的早期过渡步骤表现出参与的签名小胶质细胞（大坝）。有趣的是，大坝激活的顺序步骤依赖于TREM2。但是， Trem2或Tyrobp如何调节这些下游蜂窝表型的基本机制在很大程度上是未知。在此提案中，我们旨在系统地测试是否以及在何种程度上与广告相关的刺激，例如淀粉样蛋白β（A）低聚物或物理载脂蛋白E3或4同工型能够激活小胶质细胞，在不存在TyroBP或Trem2，或在存在AD相关的TREM2 R47H敲击蛋白突变的情况下。在这里，我们将采用彻底的方法来研究信号转导和各种细胞激活途径，但我们也将使用最先进的基于质谱的磷光蛋白质组学来公正检查磷酸肽的全球变化，以特别阐明小胶质细胞的差异我们的模型中的稳态和激活状态。该研究的总体目标是了解差异 Trem2和Tyrobp在疾病样的小胶质细胞激活的机制中的作用刺激，并最终识别出特别关注小胶质细胞激活的潜在治疗靶标表型，这可能有助于AD病理的延迟或治疗。