Analysis of neuronal signaling pathways following interferon stimulation

描述（由申请方提供）：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者中。神经元主要是不可再生的，并且在外周中采用的病毒清除的传统机制，例如感染细胞的细胞溶解，如果靶向CNS神经元，则可能证明是有害的。虽然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的反应机制在很大程度上仍然不确定。鉴于炎症在不明病因的疾病中的潜在作用，如多发性硬化症、肌萎缩侧索硬化症、帕金森病和阿尔茨海默病，这一点尤其重要。这项提议将确定神经元中独特的干扰素诱导的信号传导如何帮助这些细胞控制并最终存活病毒感染。已经创建了一种转基因小鼠，其在神经元中选择性地表达更高水平的STAT 1。也将使用STAT-1和STAT 2缺陷型小鼠。这些模型将用于确定STAT表达的改变是否对干扰素的神经元反应性有影响，以及这是否可能对CNS中的病毒复制、传播和清除有影响。研究神经元如何对干扰素等基本细胞因子做出反应，不仅可以使我们更好地了解病毒是如何从CNS中清除而不牺牲神经元活力的，而且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.