Analysis of a Type I Interferon Responsive Microglia Subset in Traumatic Brain Injury

创伤性脑损伤中 I 型干扰素反应性小胶质细胞亚群的分析

• 批准号: 10514571
• 负责人: CHRISTINE LINDA HSIEH
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10514571
• 关键词: Acute; Acute Brain Injuries; Affect; Age; Alzheimer' s disease model; Animal Model; Anti-Inflammatory Agents; Antisense Oligonucleotide Therapy; Antisense Oligonucleotides; Apoptotic; Applications Grants; Automobile Driving; Behavior; Behavioral; Biological Markers; Brain; Brain Injuries; Cells; Chronic; Clinic; Collaborations; Communication; Cues; Dangerousness; Data; Development; Disease; Disease associated microglia; Environment; Evaluation; Experimental Models; Gene Expression; Gene Expression Profile; Genes; Genetic; Genomics; Goals; Government; Growth Factor; Health Care Costs; Heterogeneity; Histology; Histopathology; Homeostasis; Hour; Human; IFNAR1 gene; Immune; Immune response; Incidence; Infection; Infiltration; Inflammation; Inflammatory; Injury; Interferon Receptor; Interferon Type I; Interferons; Knowledge; Lesion; Leukocytes; Link; Macrophage; Mediating; Methods; Microglia; Military Personnel; Molecular; Multiple Sclerosis; Mus; Natural Immunity; Nerve Degeneration; Neurons; Neurosciences Research; Outcome; Pathology; Pathway interactions; Patients; Persons; Phagocytosis; Pharmacologic Substance; Pharmacological Treatment; Plasma; Production; Proliferating; Publishing; RNA; Recovery of Function; Role; STING1 gene; Sentinel; Sex Differences; Signal Transduction; Site; Soldier; Specificity; Surveys; Synaptophysin; TBI treatment; Testing; Therapeutic; Time; Traumatic Brain Injury; Treatment Efficacy; Veterans; Vision; behavioral outcome; biomarker identification; cell injury; cell type; chemokine; conditional knockout; cytokine; design; disability; effective therapy; efficacy testing; functional improvement; functional outcomes; improved; improved outcome; innate immune pathways; interferon alpha receptor; knock-down; mRNA Expression; mouse model; neuroinflammation; neuroprotection; neurotoxic; novel; novel therapeutic intervention; pathogen; pharmacologic; preclinical study; preservation; receptor; recruit; repaired; response; single-cell RNA sequencing; synaptic pruning; therapeutic target; tissue repair; transcription factor; wound healing

TBI is a major cause of disability and a significant burden to health care costs in the US. TBI management lacks effective pharmacological treatment. Neuroinflammation is a component of secondary injury that can worsen brain injury, and it progresses over time, thus allowing opportunities to pharmacologically intervene. The goal of this project is to better understand a novel microglia subset in TBI, and determine whether it is a cellular mechanism driving pathology in TBI. We hope that knowledge of microglia heterogeneity will lead to more effective and precise therapeutic approaches or help identify biomarkers for TBI. Our vision is to target inflammatory microglia subsets to block harmful responses, while allowing neuroprotective microglia to promote wound repair. We used the unbiased approach of single-cell RNA sequencing to identify several microglia subsets induced by acute, sub-acute, and chronic TBI in mice. The gene expression profile Irf7hi microglia significantly express RNA of several interferon-stimulated genes (ISGs) indicating that they are responding to type I IFNs, such as IFN. It has been shown the type I IFN pathway is harmful in TBI. However, the mechanisms, cells, or subsets of cells mediating this pathway have not been elucidated. We hypothesize that the Irf7hi microglia subset worsens TBI, and that dampening of IFNAR1 in microglia by genetic and pharmacological targeting will reduce the activation of this microglia subset and improve TBI. The type I IFN response is relevant to civilian TBI as IFN is significantly upregulated in the plasma of human patients within 6 hours post-TBI. We will test whether the mechanism of the type I IFN-mediated pathway mediating detrimental effects in mice is due to Irf7hi microglia. In our first aim, we propose to investigate the temporal dynamics and spatial localization of Irf7hi microglia to determine its persistence and progression during acute, sub-acute, and chronic TBI by histology and single-cell RNA seq. Sex differences in the response to TBI will be examined by high-throughput multiplexing approaches. In our second aim, we will test the impact of conditionally targeting IFNAR1 and possibly STING in microglia. Inflammation, histopathology, and behavior post-TBI will be evaluated. Our third aim will employ a new approach of therapy for TBI by using antisense oligonucleotides (ASOs) designed to knock down IFNAR1 or IRF7 gene expression. We will test the capacity of these ASOs to improve TBI in a preclinical study. Studies of microglia subsets will be reciprocally informative across neuroinflammatory diseases. This proposal is mechanistic, and translationally relevant to the clinic. Elucidation of critical innate immune cell subsets during neuroinflammation will advance TBI and neuroscience research.

TBI是残疾的主要原因，也是美国医疗保健费用的重大负担。TBI管理 缺乏有效的药物治疗。神经炎症是继发性损伤的组成部分， 恶化脑损伤，随着时间的推移，它的进展，从而允许机会，以避免干预。的 该项目的目标是更好地了解TBI中的一种新的小胶质细胞亚群，并确定它是否是一种细胞 TBI病理学驱动机制我们希望对小胶质细胞异质性的了解将导致更多的研究。 有效和精确的治疗方法或帮助识别TBI的生物标志物。我们的目标是 炎症性小胶质细胞亚群阻断有害反应，同时允许神经保护性小胶质细胞促进 伤口修复 我们使用单细胞RNA测序的无偏方法来鉴定几个小胶质细胞亚群 在小鼠中由急性、亚急性和慢性TBI诱导。Irf7hi小胶质细胞的基因表达谱显著高于对照组， 表达几种干扰素刺激基因（ISG）的RNA，表明它们对I型IFN有应答， 如IFN γ。已经显示I型IFN途径在TBI中是有害的。然而，这些机制、细胞或 介导该途径的细胞亚群尚未阐明。我们假设Irf7hi小胶质细胞亚群 通过遗传和药理学靶向抑制小胶质细胞中的IFNAR1， 激活小胶质细胞亚群并改善TBI。 I型IFN应答与平民TBI相关，因为IFN γ在TBI患者的血浆中显著上调。 TBI后6小时内的人类患者。我们将测试I型干扰素介导的途径的机制是否 介导小鼠中的有害作用是由于Irf7hi小胶质细胞。在我们的第一个目标中，我们建议调查 Irf7hi小胶质细胞的时间动态和空间定位，以确定其在 急性、亚急性和慢性TBI的组织学和单细胞RNA测序。TBI反应的性别差异 将通过高通量多路复用方法进行检查。在我们的第二个目标中，我们将测试 有条件地靶向小胶质细胞中的IFNAR 1并可能靶向STING。炎症、组织病理学和行为 将对TBI后进行评估。我们的第三个目标将采用一种新的方法治疗创伤性脑损伤， 设计用于敲低IFNAR 1或IRF 7基因表达的寡核苷酸（ASO）。我们将测试 这些ASO在临床前研究中改善TBI。 小胶质细胞亚群的研究将在神经炎性疾病中提供大量信息。这 建议是机械的，并且与临床相关。关键先天免疫细胞的阐明 神经炎症过程中的亚群将推进TBI和神经科学研究。