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

描述(申请人提供)：病毒性脑炎，包括由虫媒病毒西尼罗河病毒(WNV)和日本脑炎病毒(JEV)引起的脑炎，是美国和世界各地发病率和死亡率的主要来源。已证实的治疗病毒性脑炎的方法仅限于少数几种病毒，即使存在治疗方法(如治疗单纯疱疹病毒性脑炎的阿昔洛韦)，残疾和死亡仍然很严重。目前还没有有效的治疗虫媒病毒引起的脑炎的方法。迫切需要治疗嗜神经性病毒感染的新的和广泛适用的策略。我们将对从感染西尼罗河病毒或乙脑病毒的小鼠脑中提取的RNA进行微阵列分析，以寻找在病毒感染后在大脑中差异调控的新的细胞基因和途径，并可能为病毒性脑炎提供治疗靶点。在感染这两种病毒的小鼠大脑中差异调控的基因和途径将优先被用作识别的目标。然后，我们建议使用一对神经毒力和神经减毒病毒株、不同的治疗条件和额外的脑炎病毒来进行创造性的聚合酶链式反应，以识别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。 在这项建议的最后部分，我们将使用遗传学、药理学和siRNA指导的方法在体内和体外病毒致病模型中评估这些靶点。预计这些研究将确定和评估病毒性脑炎的新治疗靶点。虽然该提案的主要目标是确定西尼罗河病毒和乙脑病毒的新治疗靶点，但纳入更多的脑炎病毒可能会确定由多种不同病毒引起的脑炎的广谱治疗靶点。我们的研究也可能与中枢神经系统的其他疾病相关。

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.