Regulation of susceptibility and severity of inflammatory diseases of the central nervous system by novel innate immune signaling pathways in human myeloid cells

通过人骨髓细胞中新型先天免疫信号通路调节中枢神经系统炎症性疾病的易感性和严重程度

• 批准号: 10516089
• 负责人: MICHAEL D CARRITHERS
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10516089
• 关键词: Alzheimer' s Disease; Animal Model; Autoimmune; Bioenergetics; Biological Markers; Brain; Brain Diseases; Brain Injuries; Calcium; Calcium Signaling; Caring; Cell Death; Cell Survival; Cells; Cellular Stress; Central Nervous System Diseases; Chromosome 6; Clinical; DNA Maintenance; DNA Repair; DNA Repair Gene; DNA Repair Inhibition; Data; Development; Disease; Disease susceptibility; Double-Stranded RNA; Drug Targeting; Experimental Autoimmune Encephalomyelitis; Genes; Genetic Transcription; Goals; Health; Human; Immune; Immune signaling; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Interferon Type I; Introns; Laboratories; Lesion; Link; MHC Class I Genes; Macrophage; Maintenance; Mediating; Microglia; Mitochondria; Modeling; Molecular; Multiple Sclerosis; Mus; Myeloid Cells; Neurologic; Neurons; Nuclear; Outcome; Pathway interactions; Patients; Pattern Recognition; Pharmaceutical Preparations; Pluripotent Stem Cells; Predisposition; Prevention; Production; Protein phosphatase; Proteins; Publishing; RNA Processing; RNA Splicing; Recovery; Regulation; Research; Resolution; Risk; Sampling; Services; Severities; Severity of illness; Signal Pathway; Signal Transduction; Sodium Channel; Spinal Cord; Stimulus; Stroke; Testing; Transcript; Translations; Traumatic Brain Injury; Variant; Veterans; Viral Genes; Work; care costs; cell injury; cost; disability; ds-DNA; expectation; immune activation; individual variation; innate immune mechanisms; interdisciplinary approach; mouse model; multiple sclerosis patient; nervous system disorder; novel; novel therapeutic intervention; prevent; protein expression; racial population; response; tissue injury; tissue repair; trafficking; treatment strategy; voltage; young adult

Individual variation in inflammatory responses regulates onset and severity of multiple sclerosis (MS) and other types of brain injury. Initiation, amplification, and resolution of these inflammatory responses occur in part through innate immune signaling mediated by macrophages and related immune cells. This laboratory has discovered novel innate immune signaling pathways in human macrophages that are regulated by intracellular splice variants of voltage-gated sodium channels. These channels regulate pattern recognition of dsRNA, intracellular signaling, vesicular trafficking, and transcription of anti-viral genes. In a mouse model of MS, expression of one of these channels, human macrophage SCN5A, in mouse macrophages reduced disease severity and enhanced tissue repair. Recently published work demonstrates that a newly discovered channel variant, human macrophage SCN10A, acts in a synergistic manner with SCN5A to regulate RNA processing of a transcript that encodes a DNA repair protein, PPP1R10. New preliminary data demonstrate individual variation in regulation of PPP1R10 expression. New data also reveal that SCN10A localizes to mitochondria during cellular injury and regulates ATP production. The objective of this revised proposal is to characterize these innate immune signaling mechanisms in human cells and an animal model. The central hypothesis is that human macrophage SCN10A and SCN5A prevent cell and tissue injury through enhancement of DNA repair and maintenance of cellular bioenergetics. This hypothesis will be assessed in three aims: 1) Analyze how human macrophage channel variants regulate PPP1R10 protein expression, 2) Determine how the human macrophage channel variants regulate mitochondrial function, and 3) Characterize how macrophage SN10A and SCN5A prevent tissue injury. For Aim 1, the proposed model is that endogenous signals of cellular injury activate human macrophage SCN10A and SCN5A to initiate a calcium-dependent nuclear signaling pathway that regulates expression of the DNA repair protein PPP1R10. It is hypothesized that individual variation in this pathway increases the risk of tissue injury in inflammatory diseases such as MS. For Aim 2, it is proposed that human macrophage SCN10A localizes to mitochondria during cellular injury to transiently increase mitochondrial ATP production. It is also hypothesized that SCN10A and SCN5A regulate mitophagy, a cellular protective mechanism. For Aim 3, it is postulated that macrophages that express human variants of SCN5A and SCN10A prevent tissue injury in inflammatory lesions through enhancement of DNA repair and maintenance of bioenergetics. These hypotheses will be tested using multidisciplinary approaches in primary cultures of human macrophages; macrophages, microglia, and neurons derived from human induced- pluripotent stem cells; and in the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis. The expectations are that we will identify novel regulatory mechanisms of bioenergetics and tissue repair that are relevant to MS and related diseases. The long-term goals are to develop new biomarkers of disease susceptibility and severity and identify novel therapeutic strategies that prevent and reduce long- term disability of Veterans with MS.

炎症反应的个体差异调节多发性硬化症（MS）和其他疾病的发作和严重程度 脑损伤的类型。这些炎症反应的启动、放大和消退部分发生 通过巨噬细胞和相关免疫细胞介导的先天免疫信号。这个实验室有 发现了人类巨噬细胞中受细胞内调节的新型先天免疫信号传导途径 电压门控钠通道的剪接变体。这些通道调节 dsRNA 的模式识别， 细胞内信号传导、囊泡运输和抗病毒基因的转录。在 MS 小鼠模型中， 这些通道之一（人巨噬细胞 SCN5A）在小鼠巨噬细胞中的表达可减少疾病 严重程度和增强的组织修复。最近发表的工作表明，一个新发现的通道 变体，人巨噬细胞 SCN10A，与 SCN5A 协同作用，调节 RNA 加工 编码 DNA 修复蛋白 PPP1R10 的转录本。新的初步数据表明个人 PPP1R10 表达调节的变化。新数据还表明 SCN10A 定位于线粒体 在细胞损伤期间调节 ATP 的产生。本修订提案的目标是描述 人类细胞和动物模型中的这些先天免疫信号机制。中心假设是 人类巨噬细胞 SCN10A 和 SCN5A 通过增强 DNA 来防止细胞和组织损伤 修复和维持细胞生物能量。该假设将从三个目标进行评估：1）分析 人类巨噬细胞通道变体如何调节 PPP1R10 蛋白表达，2) 确定人类如何 巨噬细胞通道变体调节线粒体功能，以及 3) 描述巨噬细胞 SN10A 如何调节 SCN5A 可以防止组织损伤。对于目标 1，提出的模型是细胞损伤的内源信号 激活人巨噬细胞 SCN10A 和 SCN5A 启动钙依赖性核信号通路 调节 DNA 修复蛋白 PPP1R10 的表达。据推测，这方面的个体差异 途径会增加多发性硬化症等炎症性疾病中组织损伤的风险。对于目标 2，建议 人巨噬细胞 SCN10A 在细胞损伤期间定位于线粒体，短暂增加 线粒体 ATP 产生。还假设 SCN10A 和 SCN5A 调节线粒体自噬，这是一种细胞 保护机制。对于目标 3，假设表达人类 SCN5A 变体的巨噬细胞 SCN10A 通过增强 DNA 修复和预防炎症病变中的组织损伤 维持生物能量学。这些假设将在小学阶段使用多学科方法进行检验 人类巨噬细胞培养物；源自人类诱导的巨噬细胞、小胶质细胞和神经元 多能干细胞；在多发性硬化症小鼠模型中，实验性自身免疫 脑脊髓炎。我们的期望是我们将确定生物能量学的新调控机制和 与多发性硬化症及相关疾病相关的组织修复。长期目标是开发新的生物标志物 疾病易感性和严重程度，并确定预防和减少长期疾病的新治疗策略 患有多发性硬化症的退伍军人的长期残疾。