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: 8471054
• 负责人: Kenneth L. Tyler
• 金额: $ 19.62万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8471054
• 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; Genomics; 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; Venezuelan Equine Encephalitis Virus; Viral; Viral Encephalitis; Viral Pathogenesis; Virus; Virus Diseases; West Nile virus; cell growth regulation; 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

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.

描述（由申请人提供）：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，是美国和全世界发病率和死亡率的主要来源。经证实的病毒性脑炎治疗方法仅限于少数病毒，即使存在治疗方法（例如用于治疗单纯疱疹脑炎的阿昔洛韦），残疾和死亡仍然很严重。目前尚无针对虫媒病毒引起的脑炎的有效治疗方法。迫切需要治疗嗜神经病毒感染的新颖且广泛适用的策略。 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通路，并可能为病毒性脑炎提供治疗靶点。感染这两种病毒的小鼠大脑中受到差异调节的基因和通路将优先用作已确定的目标。然后，我们建议使用成对的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进行创造性的PCR方法，以鉴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传导途径。 在本提案的最后部分，我们将使用遗传、药理学和 siRNA 指导方法在病毒发病机制的体内和离体模型中评估这些靶标。 预计这些研究将确定和评估病毒脑炎的新治疗靶点。尽管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，但纳入其他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。