Divergent age-dependent peripheral innate immune response following 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。最近的前- 临床研究揭示了外周血单核/巨噬细胞(PDM)的神经毒性作用。 我们的初步发现表明，这种反应可能在幼年来源的小鼠存在的情况下受到抑制 然而，这种神经保护反应的原因仍不清楚。这项研究的目的是 应用于表征分化的、年龄相关的细胞和分子机制(S) 颅脑损伤后的PDM反应及其在调节神经血管功能障碍中的作用。我们的建议是建立在 大量的初步和已发表的数据显示了脑外伤后不同的受伤年龄反应。少年儿童- 衍生的PDMS表现出减少的促炎表型，成人的PDM耗竭和替代 来自幼年老鼠的那些具有神经保护作用。此外，我们还发现，Pdm特异性的Tie2/EphA4 受体串扰调节其在整个年龄段的促炎状态。我们假设年龄是- 颅脑损伤后不同的预后是由于对产品数据管理反应的相关差异所致。我们将使用特定于细胞的 耗竭、pdm替代以及新的转基因小鼠模型。这些方法将包括 严格的行为、组织学和创新的低投入全基因组组学相关性评估和 胎膜老化对损伤转归的影响机制(S)。我们还将提供一个框架，用于重新装备 神经炎症反应，以加速脑外伤后的恢复和抑制促炎过程。

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.