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

病毒引起的神经元疾病新治疗靶点的鉴定和评估

• 批准号: 8867128
• 负责人: Kenneth L. Tyler
• 金额: $ 46.61万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8867128
• 关键词: Acyclovir; Animals; Arboviruses; Biological Assay; Brain; Brain Diseases; Cell Death; Central Nervous System Diseases; Cessation of life; Data; Didelphidae; Disease; Disease Outcome; Encephalitis; Encephalitis Viruses; Equus caballus; Evaluation; Family; Gene Deletion; Gene Expression; Gene Targeting; Genes; Genetic; Genomic approach; Goals; Herpes encephalitis; Hospitalization; Human; Individual; Infection; Japanese encephalitis virus; Methods; Microarray Analysis; Modeling; Morbidity - disease rate; Mus; Neurons; Pathogenesis; Pathway Analysis; Pathway interactions; Pattern; Phase; RNA; RNA Interference; Regulation; Reovirus; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Pathway Gene; Small Interfering RNA; Source; System; Treatment Efficacy; Viral; Viral Encephalitis; Viral Pathogenesis; Virus; Virus Diseases; West Nile virus; cell growth regulation; differential expression; disability; effective therapy; human disease; improved; in vivo; inhibitor/antagonist; innovation; mortality; neurotropic; new therapeutic target; novel; novel strategies; protein expression; research study; therapeutic evaluation; therapeutic target; transcription factor; treatment strategy

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 will 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.

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）是美国和全世界发病率和死亡率的主要来源。 世界病毒性脑炎的快速治疗仅限于少数病毒，即使治疗 存在（例如，阿昔洛韦治疗单纯疱疹病毒性脑炎），残疾和死亡仍然很严重。目前有 对虫媒病毒引起的脑炎没有有效的治疗方法。新的和广泛适用的战略， 迫切需要嗜神经性病毒感染的治疗。 我们将对从感染西尼罗河病毒的小鼠大脑中提取的RNA进行微阵列分析， JEV，以确定新的细胞基因和途径，在大脑中的差异调节， 病毒感染，并可提供病毒性脑炎的治疗靶点。基因和途径， 在用两种病毒感染的小鼠的脑中差异调节的蛋白质将被优先使用， 目标的然后，我们提出使用神经毒性和神经毒性对进行本发明的PCR方法。 神经减毒病毒株，不同的治疗条件和其他脑炎病毒，以确定 致病基因和信号传导途径，这些基因和信号传导途径最有可能提供治疗靶点， 病毒性脑炎在本提案的最后部分，我们将在体内和体外模型中评估这些靶点， 使用遗传学、药理学和siRNA定向方法的病毒发病机制。 预计这些研究将确定和评估新的病毒治疗靶点， 脑炎虽然该提案的主要目标是确定WNV和JEV的新治疗靶点， 包括其他脑炎病毒可以确定脑炎的广谱治疗靶点 由各种不同的病毒引起。我们的研究也可能与其他疾病有关， 中枢神经系统