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：
8712571
负责人：
JONATHAN R WEINSTEIN
金额：
$ 33.46万
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/8712571
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）：大脑中的缺血性预处理（IPC）是一种强大的神经保护现象，其中短暂的缺血性暴露会增加对随后延长缺血的有害影响的抵抗力。表征IPC的细胞和分子机制是中风研究中的一个活跃研究领域。小胶质细胞是大脑的专门组织巨噬细胞，在神经炎症反应以及包括中风在内的许多神经系统疾病中起着重要作用。几条证据支持小胶质细胞在IPC中的作用。小胶质细胞表达收费受体（TLR），可介导对外源和内源性激动剂的强大免疫反应。 IPC诱导的神经保护需要TLR4。为了阐明小胶质细胞TLR4有助于IPC的机制，我们在体外对小胶质细胞进行了针对细胞靶向的基因组分析。两个数据集的结果都鉴定出类型1和/或类型3个干扰素（IFN）刺激的基因（ISGS）的鲁棒表达是缺血暴露的WT的主要转录术特征，但不是TLR4 - / - ，微og。 IFN细胞因子家族被认为是对感染的先天免疫反应的关键组成部分。最近的工作已将小胶质IFN信号传导作为非感染机制引起的损伤反应的重要调节剂。该提案的重点是表征1型和3型IFN在介导IPC现象中的作用，以及使用体外（低氧/低血糖治疗原发性小胶质细胞）和体内（中大脑动脉/再生/再生促进/再生）实验模型的体外（低氧/低血糖治疗）实验模型。