Microglial Interferon Signaling and Ischemic Preconditioning

小胶质细胞干扰素信号转导和缺血预处理

基本信息

批准号：
8332299
负责人：
JONATHAN R WEINSTEIN
金额：
$ 33.56万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8332299
关键词：
Agonist Area Binding Brain Brain Injuries Cause of Death Cells Complex DNA Sequence Data Set Experimental Models Exposure to Family Feedback Functional disorder Gene Expression Genes Genetic Transcription Genomics Goals Hypoglycemia Hypoxia IFNAR1 gene IFNAR2 gene IL10RB gene ISGF3G protein Immune Immune response In Vitro Infarction Infection Injection of therapeutic agent Interferons Investigation Ischemia Ischemic Preconditioning Luc Gene Mediating Microglia Middle Cerebral Artery Occlusion Molecular Molecular Profiling Molecular Target Mus Myelogenous Myeloid Cells Neurons Outcome Pharmacotherapy Phenotype Play Proteins Regulatory Element Relative (related person)Reperfusion Therapy Reporter Research Research Project Grants Resistance Role Signal Pathway Signal Transduction Signal Transduction Pathway Sorting - Cell Movement Source Stroke TLR4 gene Therapeutic Intervention Tissues Toll-like receptors Transcription Factor 3 Tyrosine Phosphorylation United States Wild Type Mouse Work acute stroke autocrine cellular targeting cytokine disability in vivo interferon-stimulated gene factor 3 macrophage nervous system disorder nestin protein neurobehavioral neuroprotection neutralizing antibody novel paracrine receptor relating to nervous system response response to injury

项目摘要

DESCRIPTION (provided by applicant): Ischemic preconditioning (IPC) in the brain is a robust neuroprotective phenomenon in which a brief ischemic exposure increases resistance to the injurious effects of subsequent prolonged ischemia. Characterizing the cellular and molecular mechanisms of IPC is an active area of investigation in stroke research. Microglia, the brain's specialized tissue macrophages, play a major role in the neuroinflammatory response and in many neurological diseases including stroke. Several lines of evidence support a role for microglia in IPC. Microglia express Toll-like receptors (TLRs) that mediate powerful immune responses to exogenous and endogenous agonists. TLR4 is required for IPC-induced neuroprotection. In order to elucidate the mechanisms by which microglial TLR4 contributes to IPC, we carried out cell-targeted genomic analyses specifically on microglia exposed to either ischemic conditions in vitro or IPC in vivo. Results from both datasets identified robust expression of type 1 and/or type 3 interferon (IFN)-stimulated genes (ISGs) as the predominant transcriptomal feature of ischemia-exposed WT, but not TLR4-/-, microglia. The IFN family of cytokines is recognized as a key component of the innate immune response to infection. Recent work has implicated microglial IFN signaling as an important regulator of the injury response induced by non-infectious mechanisms. The focus of this proposal is to characterize the role of type 1 & 3 IFNs in mediating the IPC phenomenon and the microglial response to ischemia using both in vitro (hypoxia/hypoglycemia treatment of primary microglia) and in vivo (middle cerebral artery occlusion/reperfusion) experimental models.

描述（由申请人提供）：大脑中的缺血预适应（IPC）是一种强大的神经保护现象，其中短暂的缺血暴露增加了对随后长期缺血的伤害作用的抵抗力。表征 IPC 的细胞和分子机制是中风研究的一个活跃研究领域。小胶质细胞是大脑的特殊组织巨噬细胞，在神经炎症反应和包括中风在内的许多神经系统疾病中发挥着重要作用。多项证据支持小胶质细胞在 IPC 中的作用。小胶质细胞表达 Toll 样受体 (TLR)，可介导对外源性和内源性激动剂的强大免疫反应。 TLR4 是 IPC 诱导的神经保护所必需的。为了阐明小胶质细胞 TLR4 促进 IPC 的机制，我们专门针对暴露于体外缺血条件或体内 IPC 的小胶质细胞进行了细胞靶向基因组分析。两个数据集的结果均表明 1 型和/或 3 型干扰素 (IFN) 刺激基因 (ISG) 的强劲表达是缺血暴露 WT 的主要转录特征，但 TLR4-/-、小胶质细胞则不然。细胞因子 IFN 家族被认为是针对感染的先天免疫反应的关键组成部分。最近的研究表明小胶质细胞干扰素信号传导是非感染机制诱导的损伤反应的重要调节因子。本提案的重点是通过体外（原代小胶质细胞的缺氧/低血糖治疗）和体内（大脑中动脉闭塞/再灌注）来表征 1 型和 3 型干扰素在介导 IPC 现象和小胶质细胞对缺血的反应中的作用。）实验模型。