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）和其他疾病的发病和严重程度