Regulation of the Microglial Neuroimmune Response by Long Non-Coding RNAs

项目摘要/摘要 病毒或细菌感染引起的全身炎症是神经免疫失调的直接原因 并与多种神经退行性病变有关，如多发性硬化症(MS)。小胶质细胞 参与病原体清除的先天免疫过程，有助于神经康复和 神经毒性。适当的小胶质细胞免疫功能支持神经发生和突触发育，调节 动态平衡的神经元和神经胶质活性，并提供宿主防御病原体和损伤。调控失调 小胶质细胞的免疫功能可能参与导致神经毒性的神经炎性过程。这个 小胶质细胞功能可塑性的机制以及小胶质细胞免疫反应是否 神经保护或神经毒性还不是很清楚。长的基因间非编码RNA(LincRNAs)是 调节小胶质细胞可塑性的首选候选基因，因为许多lincRNAs是早期初级反应 其表达受环境信号刺激的基因。LincRNAs与人类 炎症性疾病和神经病理，如MS我们的合作工作已经确定了lincRNAs TLR4对巨噬细胞和小胶质细胞促炎基因表达的调节作用 染色质重塑的调节。基于这些研究，我们假设基因的差异表达 LincRNAs作为基因转录调节因子调控神经保护性或小胶质细胞的表达 神经毒性表型。此外，我们认为lincRNAs的差异表达将有助于 小胶质细胞反应在清除病原体和促进正常功能或引起 神经毒性和促进神经退行性变。为了解决这一假设，我们挖掘了整个转录组 数据，并使用体外模型系统鉴定在小胶质细胞前体中反向表达的lincRNAs。 炎性神经毒性(TLR4刺激)和抗炎性神经营养(IL-4刺激)功能 各州。我们最近发表的工作表明，lincRNAs在小胶质细胞中差异表达 神经炎性和神经营养状态以及沉默神经炎性lincRNAs可以减少 神经毒性。初步证据表明，特定的lincRNAs在退行性变的皮质中过度表达 进行性、慢性多发性硬化症的小鼠组织模型本方案的目的是研究 LincRNAs介导小胶质细胞致炎状态的机制(目标1)和确定 病毒诱导的急性和慢性多发性硬化症小鼠模型是否存在lincRNA的差异表达(目的 2)。这项提议在概念上是创新的，因为它将提供有关lincRNA调节机制的信息 神经免疫和神经毒性。这些研究直接适用于新技术的开发。 限制与炎性神经病理相关的神经变性的治疗策略。

PROJECT SUMMARY/ABSTRACT Systemic inflammation due to viral or bacterial infection is a direct cause of dysregulated neuroimmune responses and is linked to several neurodegenerative pathologies such as multiple sclerosis (MS). Microglia participate in innate immune processes of pathogen clearance contributing to both neurorecovery and neurotoxicity. Proper microglial immune function supports neurogenesis and synapse development, regulates homeostatic neuronal and glial activity, and provides host defense against pathogens and injury. Dysregulation microglial immune function is likely to contribute to neuroinflammatory processes that cause neurotoxicity. The mechanisms governing microglial functional plasticity and whether microglial immune responses are neuroprotective or neurotoxic are not well understood. Long intergenic non-coding RNAs (lincRNAs) are prime candidates for regulating microglial plasticity because many lincRNAs are early-primary response genes whose expression is stimulated by environmental signals. LincRNAs are associated with human inflammatory disease and neuropathologies such as MS. Our collaborative work has identified lincRNAs that regulate pro-inflammatory gene expression in TLR4-stimulated macrophages and microglia through modulation of chromatin remodeling. Based on these studies, we hypothesize that differential expression of lincRNAs act as regulators of gene transcription to control microglial expression of neuroprotective or neurotoxic phenotypes. Further, we propose that differential expression of lincRNAs will contribute to whether microglial responses are effective in clearing pathogens and promoting normal function or causing neurotoxicity and promoting neurodegeneration. To address this hypothesis, we mined whole-transcriptome data and used an in vitro model system to identify lincRNAs that are inversely expressed in microglial pro- inflammatory neurotoxic (TLR4-stimulated) and anti-inflammatory neurotrophic (IL-4-stimulated) functional states. Our recently published work shows that lincRNAs are differentially expressed in microglial neuroinflammatory and neurotrophic states and that silencing neuroinflammatory lincRNAs can reduce neurotoxicity. Preliminary evidence shows that specific lincRNAs are overexpressed in degenerating cortical tissue of a mouse model for progressive, chronic MS. The objectives of this proposal are to investigate the mechanisms by which lincRNAs mediate a proinflammatory state in microglia (Aim 1) and to determine whether differential lincRNA expression underlies viral-induced acute and chronic mouse models of MS (Aim 2). This proposal is conceptually innovative as it will provide information about lincRNA-regulated mechanisms of neuroimmunity and neurotoxicity. These studies are directly applicable to the development of new therapeutic strategies for limiting the neurodegeneration associated with inflammatory neuropathologies.