Novel mechanisms suppressing the pro-resolving phenotype of peripheral innate immunity following traumatic brain injury

抑制创伤性脑损伤后外周先天免疫的促解决表型的新机制

基本信息

批准号：
10607999
负责人：
Michelle Lee Theus
金额：
$ 40万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607999
关键词：
Acceleration Acute Anti-Inflammatory Agents Attenuated Automobile Driving Axon Behavior Behavioral Blood - brain barrier anatomy Blood Vessels Bone Marrow Cells Cd68 Cells Cerebrovascular Circulation Chronic Data Demyelinations Dendritic Cells Dichloromethylene Diphosphonate Disease Progression Environment EphA4 Receptor FRAP1 gene Functional disorder Health Hippocampus Histologic Immune In Vitro Infiltration Inflammatory Inflammatory Response Injury Innate Immune Response Intervention Knock-out Knockout Mice Label Lesion Liposomes Macrophage Mechanics Mediating Mediator Methods Modeling Molecular Mus Natural Immunity Natural Killer Cells Neuroglia Neurologic Outcome Pathogenesis Pathway interactions Peripheral Phase Phenotype Phosphorylation Physiological Play Process Proteins Publishing Recovery Recovery of Function Regulation Reporter Research Role Signal Transduction Testing Time Tissues Transgenic Organisms Trauma Traumatic Brain Injury Traumatic Brain Injury recovery Up-Regulation axon growth axon guidance behavioral phenotyping chemokine controlled cortical impact cytokine cytotoxic drug discovery epigenomics genome-wide glial activation immune activation immunoregulation improved in vivo injured innovation mRNA Expression monocyte mouse model neuroinflammation neuron loss neuroprotection neurotoxic neurovascular neurovascular injury neutrophil new therapeutic target novel pharmacologic preclinical study preservation repaired response tool transcriptomics

Acceleration Acute Anti-Inflammatory Agents Attenuated Automobile Driving Axon Behavior Behavioral Blood - brain barrier anatomy Blood Vessels Bone Marrow Cells Cd68 Cells Cerebrovascular Circulation Chronic Data Demyelinations Dendritic Cells Dichloromethylene Diphosphonate Disease Progression Environment EphA4 Receptor FRAP1 gene Functional disorder Health Hippocampus Histologic Immune In Vitro Infiltration Inflammatory Inflammatory Response Injury Innate Immune Response Intervention Knock-out Knockout Mice Label Lesion Liposomes Macrophage Mechanics Mediating Mediator Methods Modeling Molecular Mus Natural Immunity Natural Killer Cells Neuroglia Neurologic Outcome Pathogenesis Pathway interactions Peripheral Phase Phenotype Phosphorylation Physiological Play Process Proteins Publishing Recovery Recovery of Function Regulation Reporter Research Role Signal Transduction Testing Time Tissues Transgenic Organisms Trauma Traumatic Brain Injury Traumatic Brain Injury recovery Up-Regulation axon growth axon guidance behavioral phenotyping chemokine controlled cortical impact cytokine cytotoxic drug discovery epigenomics genome-wide glial activation immune activation immunoregulation improved in vivo injured innovation mRNA Expression monocyte mouse model neuroinflammation neuron loss neuroprotection neurotoxic neurovascular neurovascular injury neutrophil new therapeutic target novel pharmacologic preclinical study preservation repaired response tool transcriptomics

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项目摘要

ABSTRACT Neuroinflammation has emerged as a critical component of secondary injury and disease progression following brain trauma. Recent pre-clinical studies have shed light on the neurotoxic effects of peripheral innate immunity. Our preliminary findings suggest this overzealous response may be mediated by EphA4/mTOR signaling which negatively regulates the anti-inflammatory state of peripheral-derived monocyte/macrophages (PDMs). The research objective of this application is to characterize the cellular and molecular mechanism(s) underlying innate immunity and PDM polarization status in the regulation of tissue damage and functional recovery following TBI. Our proposal builds upon extensive preliminary and published data demonstrating a distinct protective and reduced pro-inflammatory response in the absence of peripheral EphA4 using chimeric mice following controlled cortical impact (CCI) injury. Interestingly, PDMs-derived from EphA4null mice directly confer neuroprotection and blood brain-barrier preservation in a model of monocyte depletion and replacement. Moreover, we discovered that PDM-specific EphA4 suppresses phosphorylation of key proteins involved in the mTOR pathway, a novel mediator of the pro-resolving state of PDMs. We hypothesize that EphA4 mediates the pro-inflammatory innate immune response by suppressing mTOR signaling, which induces PDM infiltration, polarization and phenotypic behaviors that drive neurovascular dysfunction following TBI. We will employ cell-specific depletions, and PDM replacement as well as novel transgenic murine models. These approaches will include rigorous behavioral, histological and innovative low-input genome-wide epigenomic and transcriptomic assessment of the relevance and mechanism(s) of PDM behaviors. We will also provide a framework for retooling the neuroinflammatory response to accelerate recovery and dampen pro-inflammatory processes after TBI.

抽象的神经炎症已成为继发性损伤和疾病进展的关键组成部分脑创伤。最近的临床前研究阐明了周围先天免疫的神经毒性作用。我们的初步发现表明，这种过度狂热的反应可能是由epha4/mtor信号传导介导的负调节外周衍生的单核细胞/巨噬细胞（PDMS）的抗炎状态。这该应用的研究目标是表征基础的细胞和分子机制在调节组织损伤和功能恢复后，先天免疫和PDM极化状态之后 TBI。我们的建议建立在广泛的初步和发布的数据的基础上，证明了独特的保护性和在控制后使用嵌合小鼠在没有外周以Epha4的情况下减少促炎反应皮质冲击（CCI）损伤。有趣的是，从Epha4null小鼠衍生的PDMS直接赋予神经保护和单核细胞耗竭和替代模型中的血液脑性保存。而且，我们发现了 PDM特异性EPHA4抑制了与MTOR途径有关的关键蛋白的磷酸化，这是一种新型 PDMS的支持状态的调解人。我们假设Epha4介导了促炎的先天性免疫反应通过抑制MTOR信号传导，从而诱导PDM浸润，极化和表型 TBI后驱动神经血管功能障碍的行为。我们将采用特定细胞的耗竭和PDM 替代品以及新型的转基因鼠模型。这些方法将包括严格的行为，相关性的组织学和创新的低输入基因组的表观基因组和转录组评估和PDM行为的机制。我们还将提供一个框架来改造神经炎症性对TBI后加速恢复和抑制促炎过程的反应。