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: 9888928
• 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 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888928
• 关键词: Alzheimer' s Disease; Animal Model; Antiviral Agents; Autoimmune Process; 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; 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; Maintenance; Mediating; Microglia; Mitochondria; Modeling; Molecular; Multiple Sclerosis; Mus; Myeloid Cells; Neurologic; Neurons; Nuclear; Outcome; Pathway interactions; Patients; Pattern Recognition; Pharmaceutical Preparations; Predisposition; Prevention; Production; Protein phosphatase; Proteins; Publishing; RNA Processing; RNA Splicing; Race; 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; induced pluripotent stem cell; innate immune mechanisms; interdisciplinary approach; macrophage; mouse model; multiple sclerosis patient; nervous system disorder; novel; novel therapeutics; prevent; protein expression; 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.

炎症反应的个体变化调节多发性硬化症（MS）和其他的严重程度 脑损伤的类型。这些炎症反应的引发，放大和解决部分发生 通过巨噬细胞和相关免疫细胞介导的先天免疫信号传导。这个实验室有 在人类巨噬细胞中发现了新型的先天免疫信号通路，这些信号通路受细胞内调节 电压门控钠通道的剪接变体。这些通道调节dsRNA的模式识别， 抗病毒基因的细胞内信号传导，囊泡运输和转录。在MS的鼠标模型中 这些通道之一的表达，人类巨噬细胞SCN5A，在小鼠巨噬细胞中降低了疾病 严重程度并增强组织修复。最近发表的工作表明，新发现的频道 人类巨噬细胞SCN10A的变体以SCN5A协同的方式起作用，以调节RNA处理 编码DNA修复蛋白PPP1R10的转录本。新的初步数据证明了个人 PPP1R10表达调节的变化。新数据还表明，SCN10A本地化为线粒体 在细胞损伤期间，调节​​ATP的产生。该修订的建议的目的是表征 这些先天的免疫信号传导机制和动物模型。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 细胞生物能的维修和维护。该假设将以三个目的进行评估：1）分析 人类巨噬细胞通道如何调节PPP1R10蛋白表达，2）确定人如何 巨噬细胞通道变体调节线粒体功能，3）表征巨噬细胞SN10A的方式 SCN5A预防组织损伤。对于AIM 1，提出的模型是细胞损伤的内源性信号 激活人巨噬细胞SCN10A和SCN5A以启动依赖钙的核信号通路 调节DNA修复蛋白PPP1R10的表达。假设这是个人变化 途径增加了炎症性疾病（如MS）的组织损伤风险。对于AIM 2，建议 人类巨噬细胞SCN10A在细胞损伤期间定位于线粒体，以暂时增加 线粒体ATP产生。还假设SCN10A和SCN5A调节线粒体，一种细胞 保护机制。对于AIM 3，据推测，表达SCN5A人类变体的巨噬细胞 SCN10A通过增强DNA修复和 维护生物能学。这些假设将使用主要学科方法进行测试 人类巨噬细胞的文化；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；在多发性硬化症的小鼠模型中，实验自身免疫 脑脊髓炎。期望我们将确定生物能学和 与MS和相关疾病有关的组织修复。长期目标是开发新的生物标志物 疾病的敏感性和严重程度，并确定预防和减少长期的新型治疗策略 MS退伍军人的期限残疾。