Regulation and Relevance of Neuron-Specific Interferon Signaling Pathways

神经元特异性干扰素信号通路的调节和相关性

• 批准号: 9291695
• 负责人: GLENN F RALL
• 金额: $ 44.28万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9291695
• 关键词: Ablation; Accounting; Affect; Antiviral Agents; Astrocytes; Autoimmunity; Binding; Biological Availability; Biology; Brain; Brain Diseases; Brain Neoplasms; Cells; Central Nervous System Diseases; Clinical Research; Color; Complex; Data; Disease; Event; Exposure to; Fibroblasts; Flow Cytometry; Foundations; Genes; Hippocampus (Brain); Human; Infection; Inflammation; Inflammatory; Interferon Type II; Interferons; Laboratories; Lasers; Life; Ligands; Link; Literature; Location; MAPK3 gene; Measles virus; Mediating; Mediator of activation protein; Microdissection; Mus; Neuraxis; Neuroglia; Neurons; Outcome; Pathogenesis; Pathway interactions; Physiology; Population; Prevalence; Regulation; Resolution; Role; STAT protein; STAT1 gene; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Testing; Textbooks; Transducers; Traumatic Brain Injury; Variant; Viral; Viral Load result; Virus; Virus Diseases; Work; abstracting; base; cell type; cytokine; cytotoxicity; in vivo; insight; nervous system disorder; neuroinflammation; neuronal survival; neurotropic; outcome forecast; pathogen; population based; prevent; programs; protein function; receptor; response; viral RNA

Project Summary/Abstract Neuroinflammation can occur as a consequence of neurotropic viral infection, brain tumor, traumatic brain injury, or autoimmunity, and the prognoses pursuant to these events are often poor. Despite the prevalence of diseases in which neuroinflammation may be a key component of damage, little is known about how cytokines, including interferons (IFNs), affect neuronal physiology. Moreover, virtually nothing is known about the IFN response in distinct neuronal sub-populations (based on either location or function). In preliminary studies, we showed that primary hippocampal neurons express less of the key IFN signal transducer, STAT1, than do non-neuronal cells, including primary fibroblasts and astrocytes. In fact, while interferon-gamma (IFNγ) is necessary for protection from an otherwise lethal neurotropic measles virus infection, STAT1 is not required for mouse survival or viral clearance. These data, the first to decouple STAT1 from IFNγ signaling, imply that alternative signaling pathways are utilized in neurons. Our recent work indicates that other signal transducers are disproportionately induced in neurons, which we speculate results in the activation of a pro-survival program that braces the neuron from neuroinflammatory cytotoxicity. This proposal pursues two complementary aims to test the hypothesis that cell- intrinsic differences in the expression levels of signal transducers can diversify the cellular response to a given cytokine ligand. Our objective is to characterize the IFNγ signaling pathways in neurons, to show how use of alternative (non-STAT1-mediated) pathways affects viral clearance and neuronal biology, and to identify how differences in neuronal subtype may contribute to a more sophisticated understanding of inflammation in the brain. Ultimately, these studies will provide a foundation upon which to build rational strategies to prevent or treat life-threatening brain disorders.

项目概要/摘要 神经炎症可能是由于嗜神经病毒感染、脑肿瘤、创伤性脑损伤、 或自身免疫，这些事件的预后往往很差。尽管疾病流行 其中神经炎症可能是损伤的关键组成部分，但人们对细胞因子（包括细胞因子）如何作用知之甚少。 干扰素（IFN）影响神经元生理学。此外，实际上对 IFN 反应一无所知。 不同的神经元亚群（基于位置或功能）。在初步研究中，我们表明 原代海马神经元比非神经元细胞表达更少的关键 IFN 信号转导器 STAT1， 包括原代成纤维细胞和星形胶质细胞。事实上，虽然干扰素γ (IFNγ) 对于保护是必需的 对于致命的嗜神经性麻疹病毒感染，STAT1 不是小鼠生存或病毒感染所必需的 清除。这些数据是第一个将 STAT1 与 IFNγ 信号传导分离的数据，这意味着替代信号传导途径 被用于神经元。我们最近的工作表明，其他信号传感器在 神经元，我们推测这会导致促生存程序的激活，从而使神经元免受 神经炎症细胞毒性。该提案追求两个互补的目标来检验细胞的假设 信号转导器表达水平的内在差异可以使细胞对给定的反应多样化 细胞因子配体。我们的目标是表征神经元中的 IFNγ 信号通路，以展示如何使用 替代（非 STAT1 介导的）途径影响病毒清除和神经元生物学，并确定如何影响病毒清除和神经元生物学 神经元亚型的差异可能有助于更深入地了解炎症 脑。最终，这些研究将为制定合理的预防或治疗策略提供基础 危及生命的脑部疾病。