Analysis of neuronal signaling pathways following interferon stimulation

描述(申请人提供)：尽管免疫接种取得了进展，但中枢神经系统(CNS)的病毒感染仍然是脑炎和神经退化的毁灭性原因，特别是在年轻人、老年人和免疫功能受损的人中。神经元主要是不可再生的，在外围使用的传统病毒清除机制，如感染细胞的细胞溶解，如果针对中枢神经系统神经元，可能被证明是有害的。虽然免疫系统显然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、帕金森氏症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。这一提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病毒感染并最终存活下来。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。STAT-1和STAT2基因缺陷的小鼠也将被利用。这些模型将被用来确定STAT表达的改变是否会影响神经元对干扰素的反应，以及这是否会对病毒在中枢神经系统的复制、传播和清除产生影响。研究神经元对干扰素等基本细胞因子的反应可能会使我们更好地理解病毒是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出来的，而且神经元本身也会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.