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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：
10409794
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/10409794
关键词：
Acute Anti-Inflammatory Agents Attenuated Automobile Driving Axon Behavior Behavioral Blood - brain barrier anatomy Bone Marrow Cells Cells Cerebrovascular Circulation Chronic Data Demyelinations Dendritic Cells Dichloromethylene Diphosphonate Disease Progression Environment EphA4 Receptor FRAP1 gene Functional disorder Health Hippocampus (Brain)Histologic Immune In Vitro Infiltration Inflammatory Inflammatory Response Injury Innate Immune Response Intervention Knock-out Knockout Mice Label Lesion Light Liposomes Mechanics Mediating Mediator of activation protein Methods Modeling Molecular Mus Natural Immunity Natural Killer Cells Neuroglia Neurologic Outcome Pathogenesis Pathway interactions Peripheral Pharmacology Phase Phenotype Phosphorylation Physiological Play Process Proteins Publishing Receptor Protein-Tyrosine Kinases 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 injury recovery innovation mRNA Expression macrophage monocyte mouse model neuroinflammation neuron loss neuroprotection neurotoxic neurovascular neurovascular injury neutrophil new therapeutic target novel preclinical study preservation repaired response transcriptomics

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.

摘要