Analysis of neuronal signaling pathways following interferon stimulation

描述（由申请人提供）：尽管在免疫方面取得了进展，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群中。神经元主要是不可再生的，传统的外周病毒清除机制，如感染细胞的细胞溶解，如果针对中枢神经系统神经元，可能是有害的。虽然免疫系统可以限制病毒在大脑中的传播是显而易见的，但受感染的神经元对免疫渗入大脑所产生的炎症环境作出反应的机制在很大程度上仍未明确。考虑到炎症在病因不明的疾病（如多发性硬化症、肌萎缩性侧索硬化症、帕金森病和阿尔茨海默病）中的潜在作用，这一点尤为重要。这一建议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并最终存活病毒感染。一种转基因小鼠已经被创造出来，它在神经元中选择性地表达更高水平的STAT1。stat1和STAT2缺失小鼠也将被利用。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，以及这是否会影响病毒在中枢神经系统中的复制、传播和清除。研究神经元如何对干扰素等基本细胞因子作出反应，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清除，还可以了解神经元本身如何在这一过程中发挥作用。

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.