Identification and evaluation of novel therapeutic targets for virus-induced neuronal disease

描述（由申请人提供）：病毒性脑炎，包括由虫媒病毒西尼罗病毒（WNV）和日本脑炎病毒（JEV）引起的脑炎，是美国和全世界发病率和死亡率的主要来源。病毒性脑炎已证实的治疗方法仅限于几种病毒，即使存在治疗方法（例如治疗单纯疱疹脑炎的无环鸟苷），残疾和死亡仍然很严重。目前对虫媒病毒引起的脑炎没有有效的治疗方法。迫切需要新的和广泛适用的治疗嗜神经病毒感染的策略。我们将对从感染西尼罗河病毒或乙脑病毒的小鼠大脑中提取的RNA进行微阵列分析，以确定病毒感染后大脑中差异调节的新细胞基因和途径，并可能为病毒性脑炎提供治疗靶点。在感染两种病毒的小鼠大脑中受到不同调节的基因和途径将被优先用作确定的目标。然后，我们建议采用一种创造性的PCR方法，使用神经毒性和神经减毒病毒株，不同的治疗条件和其他脑炎病毒，以确定最有可能为病毒性脑炎提供治疗靶点的致病基因和信号通路。

DESCRIPTION (provided by applicant): Viral encephalitis, including encephalitis induced by the arboviruses West Nile virus (WNV) and Japanese encephalitis virus (JEV), is a major source of morbidity and mortality both in the U.S. and throughout the world. Proven treatments for viral encephalitis are limited to only a few viruses and even when treatments exist (e.g. acyclovir for herpes simplex encephalitis) disability and death remain significant. There are currently no effective treatments for arbovirus-induced encephalitis. Novel and broadly applicable strategies for the treatment of neurotropic viral infections are desperately needed. We will perform microarray analysis on RNA extracted from the brains of mice infected with WNV or JEV in order to identify novel cellular genes and pathways that are differentially regulated in the brain following virus infection and which may provide therapeutic targets for viral encephalitis. Genes and pathways that are differentially regulated in the brains of mice infected with both viruses wil be preferentially used as identified targets. We then propose to perform an inventive PCR approach using pairs of neurovirulent and neuroattenuated viral strains, different treatment conditions and additional encephalitis viruses to identify pathogenic genes and signaling pathways which have the highest likelihood of providing therapeutic targets for viral encephalitis. In the final part of this proposal we will evaluate these targets in in vivo and ex vivo models of viral pathogenesis using genetic, pharmacologic and siRNA directed approaches. It is expected that these studies will identify and evaluate novel therapeutic targets for virus encephalitis. Although the main goal of the proposal to identify novel therapeutic targets for WNV and JEV the inclusion of additional encephalitic viruses may identify broad spectrum therapeutic targets for encephalitis induced by a wide variety of different viruses. Our studies may also have relevance for other diseases of the central nervous system.