Modulating the post-stroke inflammatory response to improve outcome in models of cerebral ischemia

调节中风后炎症反应以改善脑缺血模型的结果

基本信息

批准号：
10055756
负责人：
Katrin I. Andreasson
金额：
$ 3.4万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10055756
关键词：
Ablation Alzheimer&apos s Disease Alzheimer&apos s disease model Amplifiers Amyloid beta-Protein Anti-Inflammatory Agents Bacteria Bioenergetics Biological Response Modifiers Blood Brain Brain Injuries Cell Lineage Cells Cellular Metabolic Process Cerebral Ischemia Cerebrum Clinical Data Development Disease Disease Outcome Disease Progression Ensure Foundations Funding Future Generations Genes Genetic Genetic study Hour Immune Immune Targeting Immune response Immune signaling Impaired cognition In Vitro Inflammation Inflammatory Inflammatory Response Injury Innate Immune Response Intestinal permeability Intestines Lamina Propria Late Onset Alzheimer Disease Lead Lipopolysaccharides Mediating Membrane Mentors Metabolic Metabolism Microglia Modeling Myelogenous Myeloid Cell Activation Myeloid Cells Nature Neuronal Injury Pathology Pathway Analysis Pathway interactions Pattern Pattern recognition receptor Peptides Peripheral Peritoneal Macrophages Pharmacology Preventive Propranolol Publishing Recovery Regulation Regulator Genes Research Risk Role Series Signal Pathway Signal Transduction Signaling Protein Spleen Sterility Stroke Surface Synapses Systems Biology TREM2 gene TYROBP gene Testing Therapeutic Time United States National Institutes of Health Variant amyloid pathology behavioral impairment brain cell career development conditional knockout experimental study genome wide association study immunoregulation improved outcome in vivo intestinal barrier macrophage metabolomics microbial monocyte motor deficit mouse model neutrophil novel post stroke pre-clinical prevent receptor response sound transcriptome transcriptomics

项目摘要

Title and Abstract The role of TREM1 signaling in the development of Alzheimer’s disease Abstract Recent systems biology studies and GWAS have confirmed a dominant role of microglial immune responses in increasing risk of late onset Alzheimer’s disease (LOAD). In parallel, studies in AD model mice demonstrate that healthy microglial function is lost with advancing amyloid pathology, and suggest that disease-modifying components of the innate immune response could be targeted to slow or halt disease progression. In recent transcriptome studies of AD model mice, we identified TREM1 as a gene highly induced in microglia and highly correlated with microglial maladaptive responses. TREM1, and its anti-inflammatory relative TREM2, both signal through DAP12, an adapter signaling protein that was recently identified in gene regulatory network analyses as a top regulator of immune genes involved in increased risk of AD. Moreover, published data in peripheral models of inflammation demonstrate a pivotal role of TREM1 in amplifying toxic aspects of the innate immune response and worsening disease progression and outcome. Recent genetic studies of the TREM1 locus demonstrate an intronic variant in TREM1 that is associated with increased CERAD pathology and cognitive decline. In this proposal, we will test the role of TREM1 in worsening microglial immune responses in models of AD. TREM1 is an inflammatory membrane receptor that is expressed on myeloid lineage cells. TREM1 is unique in its function as a potent amplifier of inflammatory responses where it generates a severe pro-inflammatory response only in association with activation of classical pattern recognition receptors. Here, we will test the hypothesis that in the development of AD, TREM1 induces a maladaptive microglial immune response to accumulating Aß peptide assemblies that accelerates synaptic and neuronal injury and behavioral impairment. We will use a combination of in vitro pharmacologic and in vivo conditional knockout strategies in AD model mice to test this hypothesis. Our studies will determine whether TREM1 amplifies the maladaptive microglial response to accumulating Aß peptides, and whether TREM1 may represent a novel immune target to slow progression to AD at pre-clinical and early clinical stages.

标题和摘要 TREM1 信号在阿尔茨海默病发展中的作用抽象的最近的系统生物学研究和 GWAS 已证实小胶质细胞免疫反应在与此同时，对 AD 模型小鼠的研究表明，晚发性阿尔茨海默病 (LOAD) 的风险增加。健康的小胶质细胞功能随着淀粉样蛋白病理的进展而丧失，并表明疾病修饰先天免疫反应的组成部分可以被靶向减缓或阻止疾病的进展。通过对 AD 模型小鼠的转录组研究，我们发现 TREM1 是小胶质细胞中高度诱导的基因，并且高度与小胶质细胞适应不良反应 TREM1 及其抗炎相关 TREM2 相关。通过 DAP12 发出信号，DAP12 是最近在基因调控网络中发现的一种接头信号蛋白分析作为参与 AD 风险增加的免疫基因的最高调节因子。炎症的外周模型证明 TREM1 在放大炎症毒性方面发挥着关键作用先天免疫反应和恶化的疾病进展和结果。 TREM1 位点显示 TREM1 中的内含子变异与 CERAD 病理增加相关在这个提案中，我们将测试 TREM1 在恶化小胶质细胞免疫中的作用。 TREM1 是一种在骨髓中表达的炎症膜受体。 TREM1 的独特之处在于其作为炎症反应的有效放大器的功能。仅与经典模式的激活相关，才会产生严重的促炎反应在这里，我们将检验以下假设：在 AD 的发展过程中，TREM1 会诱导小胶质细胞对积累的 Aß 肽组装体产生适应不良的免疫反应，加速突触和我们将结合体外药理学和体内药理学来治疗神经元损伤和行为障碍。我们的研究将确定 AD 模型小鼠的条件敲除策略是否符合这一假设。 TREM1 放大了小胶质细胞对积累的 Aß 肽的适应不良反应，以及 TREM1 是否可能一种新的免疫靶点，代表临床前和早期临床阶段 AD 的缓慢进展。