Mechanisms of type I interferon neuropathology following traumatic brain injury

创伤性脑损伤后 I 型干扰素神经病理学机制

• 批准号: 10735072
• 负责人: Elizabeth Newell
• 金额: $ 52.33万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735072
• 关键词: Acute; Adult; Affect; Antigen Presentation; Automobile Driving; Brain; Brain Injuries; Brain region; CD8-Positive T-Lymphocytes; CXCL10 gene; Cause of Death; Cells; Childhood; Chronic; Chronic Phase; Data; Dendritic Cells; Detection; Development; Disease; Flow Cytometry; Functional disorder; Gene Expression; Genes; Goals; Histocompatibility Antigens Class I; Histologic; Hour; IFNAR1 gene; Immune; Impaired cognition; Impairment; In Situ; Individual; Inflammation; Inflammatory; Injury; Interferon Type I; Interferon alpha; Interferons; Invaded; Knockout Mice; Lateral; Leukocytes; Measures; Mediating; Messenger RNA; Microglia; Modeling; Molecular; Mus; Myelogenous; Nerve Degeneration; Nervous System Physiology; Nervous System Trauma; Neurocognitive; Neurologic Dysfunctions; Neuronal Injury; Neurons; PTPRC gene; Pathway interactions; Pharmacological Treatment; Phenotype; Population; Public Health; Publishing; Quantitative Reverse Transcriptase PCR; Regulation; Research; Resolution; Signal Transduction; Signaling Molecule; Source; Supporting Cell; T-Lymphocyte; TBI Patients; TBI treatment; Testing; Therapeutic; Time; Tissues; Transcriptional Activation; Trauma; Traumatic Brain Injury; Work; brain tissue; burden of illness; chemokine; cognitive function; cytotoxic CD8 T cells; disability; effective therapy; experimental study; fluid percussion injury; glial activation; improved; interest; interferon alpha receptor; middle age; mouse genetics; neurobehavioral; neurobehavioral test; neuroimaging; neuroinflammation; neuron loss; neuropathology; neuroprotection; neurotoxicity; new therapeutic target; novel therapeutics; pharmacologic; receptor; recruit; repaired; response; single-cell RNA sequencing; therapeutic target; transcriptome; translational barrier; treatment strategy; white matter

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.

摘要 这项建议试图确定创伤后小胶质细胞I型干扰素信号的调节。 脑损伤(TBI)，并确定这如何影响神经炎症、神经变性和 脑外伤后的神经认知后遗症。创伤性脑损伤是一个主要的公共卫生问题，是 从儿童时期到成年中期的死亡和残疾。不幸的是，脑损伤的药物治疗 是不存在的。针对特定继发性损伤的治疗策略，如失调 神经炎症性疾病是迫切需要的。小胶质细胞是中枢神经系统的主要免疫细胞，它持续存在于激活的 单次脑损伤后的几个月和几年的状态，并与神经退化有关。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，已发表的研究表明，脑外伤后亚急性时间点的小胶质细胞转录组 高度富含I型干扰素刺激基因，这引发了I型干扰素是否是关键的问题 信号分子导致持续的、失调的小胶质细胞激活。细胞类型和细胞来源 脑外伤后激活小胶质细胞的I型干扰素尚不清楚。同样，第一类病毒的具体影响 干扰素对小胶质细胞持续反应性的影响及其机制 脑外伤后的神经退行性变和神经功能障碍仍不清楚。使用侧向流体敲击 脑外伤小鼠的损伤模型，结合复杂的小鼠遗传学，我们的数据将揭示细胞特异性 I型干扰素信号在继发性损伤中的作用。这一提议的假设是多个类型I 干扰素驱动失调的小胶质细胞亚群的发展、免疫细胞的募集，以及随后的 脑外伤后发生的神经退行性变和神经行为损害。在第一个目标中，我们将确定 驱动持续性小胶质细胞和中枢神经系统干扰素刺激基因的I型干扰素的类型和细胞来源 在TBI之后的表达式。在第二个目标中，我们将确定I型干扰素信号对小胶质细胞的影响 脑损伤后亚群及其转录激活。最后，在第三个目标中，我们将确定 I型干扰素激活小胶质细胞影响神经病理和神经认知的机制 脑外伤后的功能障碍，包括通过CD8+T细胞的募集。因为TBI是一种领先的，无法治疗的 在美国，死亡和残疾的原因，迫切需要进一步研究的具体机制 因此，最终可能会发现新的治疗方法。