Mechanisms of Apoptosis in the central nervous system

描述（由申请人提供）：病毒性脑炎仍然是全世界发病率和死亡率的主要原因。只有少数嗜神经病毒可获得有效治疗，即使这些感染得到最佳治疗，残余死亡率和神经系统后遗症仍然相当可观。目前尚无针对黄病毒的既定治疗方法，包括西尼罗河病毒（WNV）（美国流行性脑炎的最常见原因）和日本脑炎病毒（JEV）（世界范围内病毒性脑炎的最常见原因）。同样，尽管阿昔洛韦治疗改善了1型单纯疱疹（HSV-1）脑炎（西方世界最常见的急性散发性脑炎）的预后，但残留的发病率和死亡率仍然很高。此外，在所有新出现的病毒性疾病中，近一半与脑炎或严重的神经临床症状有关。因此，迫切需要识别和治疗病毒性中枢神经系统（CNS）感染的新策略。目的1。鉴定在病毒性脑炎期间受差异调控的特定细胞基因，并有可能作为这些疾病的新治疗靶点。现有数据表明，由多种病毒引起的脑炎与类似细胞信号通路的激活有关。我们之前进行了微阵列分析，以确定呼肠孤病毒诱导脑炎期间差异调节的基因。我们现在建议对单纯疱疹病毒1型和西尼罗河病毒引起的脑炎期间从小鼠大脑中提取的mRNA进行微阵列分析，并确定这三种病毒共同存在的细胞基因表达和细胞信号通路的改变。这些基因很有可能为多种病毒引起的脑炎提供治疗靶点。在感染其他脑炎病毒（包括乙脑病毒、辛德比斯病毒（SINV）和委内瑞拉马脑炎病毒（VEEV））后，将通过确定这些基因的表达和这些途径的激活，进一步评估使用这些基因表达改变或这些途径的激活作为病毒诱导脑炎治疗靶点的适用性。目标2。病毒性脑炎新治疗靶点的评价。在特定目标1中提出的实验将确定细胞基因和信号通路，这些基因和信号通路有可能作为病毒诱导脑炎的治疗靶点。我们建议通过阻断这些基因和途径的表达来确定病毒诱导的发病机制，从而评估这些潜在的治疗靶点。

DESCRIPTION (provided by applicant): Viral-induced encephalitis remains a major cause of morbidity and mortality throughout the world. Effective therapies are available for only a few neurotropic viruses, and even when these infections are optimally treated, residual mortality and neurological sequelae remain considerable. No established treatment exists for flaviviruses, including West Nile virus, (WNV) the most common cause of epidemic encephalitis in the United States and Japanese encephalitis virus (JEV), the most common cause of viral encephalitis worldwide. Similarly, although treatment with acyclovir improves the outcome of herpes simplex type-1 (HSV-1) encephalitis, the most common acute sporadic encephalitis in the Western world, residual morbidity and mortality remain significant. Further, nearly half of all emerging viral diseases are associated with encephalitis or serious neurological clinical symptoms. Novel strategies for identifying and treating viral central nervous system (CNS) infections are thus urgently needed. OBJECTIVE 1. To identify specific cellular genes that are differentially regulated during virus-induced encephalitis and have potential as novel therapeutic targets for these diseases. Available data suggests that encephalitis induced by a variety of viruses is associated with the activation of similar cellular signaling pathways. We have previously performed microarray analysis to determine genes that are differentially regulated during reovirus-induced encephalitis. We now propose to perform microarray analysis of mRNA extracted from the brains of mice during HSV-1- and WNV-induced encephalitis and to identify alterations in cellular gene expression and cellular signaling pathways that are common all 3 viruses. These genes are expected to have a high likelihood of providing therapeutic targets for encephalitis induced by a variety of viruses. The applicability of using altered expression of these genes or activation of these pathways as therapeutic targets for virus-induced encephalitis will be further assessed by determining the expression of these genes and activation of these pathways in the brain following infection with other encephalitic viruses, including JEV, Sindbis virus (SINV), and Venezualen equine encephalitis virus (VEEV). OBJECTIVE 2. Evaluation of novel therapeutic targets for virus-induced encephalitis. The experiments proposed in specific aim 1 will identify cellular genes and signaling pathways that have potential as therapeutic targets for virus-induced encephalitis. We propose to evaluate these potential therapeutic targets by determining virus-induced pathogenesis using treatments designed to block expression of these genes and pathways. PUBLIC HEALTH RELEVANCE: Viral-induced encephalitis remains a major cause of morbidity and mortality throughout the world. The proposed studies will identify cellular genes and signaling pathways that are activated during virus-induced encephalitis. In addition, the proposed studies will evaluate the role of these genes and pathways as novel therapeutic targets for these diseases.