Analysis of neuronal signaling pathways following interferon stimulation

干扰素刺激后的神经信号通路分析

• 批准号: 8435071
• 负责人: Sarah Elizabeth Cavanaugh
• 金额: $ 0.96万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435071
• 关键词: Acute; Address; Alzheimer' s Disease; Antiviral Agents; Antiviral Response; Attenuated; Brain; CD46 Antigen; Cell Survival; Cells; Central Nervous System Diseases; Central Nervous System Viral Diseases; Cytolysis; Data; Disease; Elderly; Encephalitis; Environment; Etiology; Gene Expression; Goals; Herpesviridae; Immune; Immune response; Immune system; Immunization; Immunocompromised Host; Infection; Infiltration; Inflammation; Inflammatory; Injury; Interferon Type I; Interferon Type II; Interferon-beta; Interferons; Kinetics; Laboratories; Lead; Measles virus; Modeling; Morbidity - disease rate; Multiple Sclerosis; Mus; Nerve Degeneration; Neuraxis; Neuron-Specific Enolase; Neurons; Parkinson Disease; Pattern; Phosphorylation; Play; Population; Primary Lateral Sclerosis; Process; RNA; Role; Rosa; STAT1 gene; STAT2 gene; Shapes; Signal Pathway; Signal Transduction; Stroke; System; Testing; Transgenic Mice; Transgenic Organisms; Vaccines; Viral; Virus; Virus Diseases; West Nile virus; cell type; clinically relevant; cytokine; effective therapy; human trophoblast leucocyte common antigen; improved; mortality; mouse model; novel therapeutics; overexpression; promoter; protein expression; response; therapeutic development; treatment strategy

DESCRIPTION (provided by applicant): Despite advances in immunization, viral infections of the central nervous system (CNS) remain a devastating cause of encephalitis and neurodegeneration, particularly in the young, elderly, and immunocompromised. Neurons are principally non-renewable and traditional mechanisms of viral clearance that are employed in the periphery, such as cytolysis of infected cells, could prove detrimental if targeted towards CNS neurons. While it is clear that the immune system can limit viral spread in the brain, the mechanisms by which infected neurons respond to the inflammatory environment created by immune infiltration into the brain remain largely undefined. This is especially important given the potential role of inflammation in diseases of unknown etiology, such as multiple sclerosis, amyotropic lateral sclerosis, Parkinson's and Alzheimer's disease. This proposal will determine how unique interferon-induced signaling in neurons may help these cells control and ultimately survive viral infection. A transgenic mouse has been created that expresses higher levels of STAT1 selectively in neurons. STAT-1 and STAT2- deficient mice will be utilized as well. These models will be used to determine whether altered STAT expression has an effect on neuronal responsiveness to interferons, as well as whether this may have an effect on viral replication, spread, and clearance in the CNS. Studying how neurons respond to essential cytokines such as interferons can potentially lead us to a greater understanding of not only how virus is cleared from the CNS without sacrificing neuronal viability, but also how neurons themselves play a role in this process.

描述（由申请人提供）：尽管免疫接种取得了进步，但中枢神经系统（CNS）的病毒感染仍然是脑炎和神经变性的破坏性原因，特别是在年轻人、老年人和免疫功能低下的人中。神经元主要是不可再生的，在外周使用的传统病毒清除机制（例如受感染细胞的细胞溶解）如果针对中枢神经系统神经元，可能会产生有害影响。虽然很明显免疫系统可以限制病毒在大脑中的传播，但受感染的神经元对免疫渗透到大脑中所产生的炎症环境做出反应的机制在很大程度上仍不清楚。考虑到炎症在多发性硬化症、肌萎缩侧索硬化症、帕金森病和阿尔茨海默病等不明原因疾病中的潜在作用，这一点尤其重要。该提案将确定神经元中独特的干扰素诱导信号如何帮助这些细胞控制病毒感染并最终存活下来。一种转基因小鼠能够在神经元中选择性表达更高水平的 STAT1。 STAT-1 和 STAT2 缺陷小鼠也将被使用。这些模型将用于确定 STAT 表达的改变是否会影响神经元对干扰素的反应性，以及这是否会影响中枢神经系统中的病毒复制、传播和清除。研究神经元如何对干扰素等重要细胞因子做出反应，不仅可以使我们更好地了解病毒如何在不牺牲神经元活力的情况下从中枢神经系统中清除，而且可以更好地了解神经元本身如何在此过程中发挥作用。