Divergent age-dependent peripheral innate immune response following TBI

TBI 后不同年龄依赖性外周先天免疫反应

• 批准号: 10295232
• 负责人: Michelle Lee Theus
• 金额: $ 41.17万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10295232
• 关键词: Acute; Adolescent; Adult; Affect; Age; Attenuated; Behavior; Behavioral; Biochemical; Blood - brain barrier anatomy; Blood Vessels; Cells; Cerebrovascular Circulation; Chronic; Data; Endothelial Cells; EphA4 Receptor; Female; Functional disorder; Goals; Health; Hippocampus (Brain); Histologic; IL4 gene; Immune; Immunologics; In Vitro; Infiltration; Inflammation; Inflammatory; Injury; Innate Immune Response; Intervention; Lesion; Light; Mediating; Microglia; Molecular; Mus; Neutrophil Activation; Outcome; Pathogenesis; Pathogenicity; Patients; Peripheral; Phagocytes; Pharmacology; Phenotype; Physiological; Process; Publishing; Recovery; Recovery of Function; Reporter; Research; Rodent Model; Role; Technology; Testing; Time; Tissues; Transgenic Mice; Transgenic Organisms; Traumatic Brain Injury; Traumatic Brain Injury recovery; age related; aged; behavioral phenotyping; central nervous system injury; disability; drug discovery; epigenomics; functional outcomes; genome-wide; genome-wide analysis; immunoregulation; improved; in vivo; inflammatory milieu; innovation; macrophage; male; monocyte; mouse model; neuroinflammation; neuron loss; neuroprotection; neurotoxic; neurovascular; neurovascular injury; neutrophil; new therapeutic target; novel; novel strategies; porcine model; pre-clinical; preclinical study; protective effect; repaired; response; response to injury; restoration; transcriptomics

ABSTRACT Neuroinflammation has emerged as a critical component of secondary injury following brain trauma. Recent pre- clinical studies have shed light on the neurotoxic effects of peripheral-derived monocyte/macrophages (PDM). Our preliminary findings suggest this response may be dampened in the presence of juvenile-derived murine PDMs, however the cause of this neuroprotective response remains unknown. The research objective of this application is to characterize the cellular and molecular mechanism(s) underlying the divergent, age-dependent PDM response and their role in mediating neurovascular dysfunction following TBI. Our proposal builds upon extensive preliminary and published data demonstrating a distinct age-at-injury response following TBI. Juvenile- derived PDMs display reduced pro-inflammatory phenotype, and adult PDM depletion and replacement with those from juvenile mice confer neuroprotection. Moreover, we discovered that PDM-specific Tie2/EphA4 receptor crosstalk regulates their pro-inflammatory state across the age spectrum. We hypothesize that age- related differences in the PDM response underlie divergent outcomes 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 omics assessment of the relevance and mechanism(s) of PDM age on injury outcomes. We will also provide a framework for retooling the neuroinflammatory response to accelerate pro-recovery and dampen pro-inflammatory processes after TBI.

摘要 神经炎症已成为脑外伤后继发性损伤的重要组成部分。近期预- 临床研究揭示了外周来源的单核细胞/巨噬细胞（PDM）的神经毒性作用。 我们的初步研究结果表明，这种反应可能会受到抑制，在青少年来源的小鼠， 然而，这种神经保护反应的原因仍然未知。本研究的目的是 应用是表征细胞和分子机制（S）的分歧，年龄依赖性 PDM反应及其在介导TBI后神经血管功能障碍中的作用。我们的建议建立在 广泛的初步和已发表的数据表明，TBI后有明显的损伤年龄反应。青少年─ 衍生的PDM显示出降低的促炎表型，并且成人PDM消耗和替换为 来自幼年小鼠的那些赋予神经保护作用。此外，我们发现PDM特异性Tie 2/EphA 4 受体相互作用在年龄范围内调节它们的促炎状态。我们假设这个年龄- PDM反应的相关差异是TBI后不同结果的基础。我们将使用细胞特异性 消耗和PDM替代以及新型转基因小鼠模型。这些方法将包括 严格的行为，组织学和创新的低输入全基因组组学评估的相关性， PDM年龄对损伤结局的影响机制。我们还将提供一个框架， 在TBI后，神经炎性反应加速促恢复和抑制促炎过程。