Mechanisms of type I interferon neuropathology following traumatic brain injury

摘要 这项建议旨在确定创伤性脑损伤后小胶质细胞I型干扰素信号转导的调节。 脑损伤（TBI），并确定这是如何影响神经炎症，神经变性，和 脑外伤后的神经认知后遗症TBI是一个主要的公共卫生问题，代表了一个主要的原因， 从童年到中年的死亡和残疾。不幸的是，创伤性脑损伤的药物治疗 不存在。针对特定继发性损伤级联的治疗策略， 神经炎症是非常必要的。小胶质细胞，中枢神经系统的主要免疫细胞，在激活的免疫系统中持续存在。 在单次TBI后数月和数年的状态，并与神经变性有关。机制 导致持续的、破坏性的神经炎症与炎症的消退还不清楚。我们最近 然而，已发表的工作表明，TBI后亚急性时间点的小胶质细胞转录组 高度富集I型干扰素刺激基因，这提出了I型干扰素是否是关键的问题。 信号分子导致持续的、失调的小胶质细胞活化。的类型和细胞来源 TBI后激活小胶质细胞的I型干扰素是未知的。同样，I型的具体影响 干扰素对持续小胶质细胞反应性的影响以及小胶质细胞介导的 TBI后的神经变性和神经功能障碍仍然未知。使用横向液压冲击 结合复杂的小鼠遗传学，我们的数据将揭示细胞特异性 I型干扰素信号传导对继发性损伤的影响。该提案的假设是，多个I型 干扰素驱动调节失调的小胶质细胞亚群的发育、免疫细胞募集以及随后的 TBI后发生的神经变性和神经行为障碍。在第一个目标中，我们将确定 驱动持续性小胶质细胞和CNS干扰素刺激基因的I型IFN的类型和细胞来源 TBI后的表达。在第二个目标中，我们将确定I型IFN信号对小胶质细胞的影响。 亚群及其在TBI后的转录激活。最后，在第三个目标中，我们将确定 I型干扰素激活的小胶质细胞影响神经病理学和神经认知的机制 TBI后的功能障碍，包括通过募集CD8+ T细胞。由于创伤性脑损伤是一种无法治愈的 在美国，死亡和残疾的原因，有必要进一步研究的具体机制， 继发性损伤，最终可能会发现新的治疗方法。

Abstract This proposal seeks to determine the regulation of microglial type I interferon signaling following traumatic brain injury (TBI) and to identify how this affects neuroinflammation, neurodegeneration, and the neurocognitive sequelae following TBI. TBI is a major public health problem, representing a leading cause of death and disability from childhood through middle adulthood. Unfortunately, pharmacologic therapies for TBI are non-existant. Treatment strategies that target specific secondary injury cascades like dysregulated neuroinflammation are critically needed. Microglia, the primary immune cells of the CNS, persist in an activated state for months and years following a single TBI and are associated with neurodegeneration. Mechanisms that result in sustained, damaging neuroinflammation vs resolution of inflammation are unclear. Our recently published work, however, demonstrated that the microglial transcriptome at a subacute time point following TBI was highly enriched for type I interferon stimulated genes raising the question of if type I interferons are key signaling molecules resulting in sustained, dysregulated microglial activation. The types and cell sources of type I interferons activating microglia following TBI are unknown. Similarly, the specific effects of type I interferons on sustained microglial reactivity and the subsequent mechanisms of microglial mediated neurodegeneration and neurologic dysfunction following TBI remain unknown. Using a lateral fluid percussion injury model of TBI in mice, combined with sophisticated mouse genetics, our data will uncover cell-specific effects of type I interferon signaling on secondary injury. The hypothesis of this proposal is that multiple type I IFNs drive development of dysregulated microglia subsets, immune cell recruitment, and the subsequent neurodegeneration and neurobehavioral impairments that occur after TBI. In the first aim, we will identify the types and cell-sources of type I IFNs driving persistent microglial and CNS interferon stimulated gene expression following TBI. In the second aim, we will determine the impact of type I IFN signaling on microglial subsets and their transcriptional activation following TBI. Finally, in the third aim, we will determine the mechanisms by which type I interferon activated microglial impact neuropathology and neurocognitive dysfunction following TBI, including through their recruitment of CD8+ T cells. As TBI is a leading, untreatable cause of death and disability in the US, there is a critical need for further study of the specific mechanisms of secondary injury so that ultimately, new therapies may be discovered.