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

基本信息

批准号：
8841447
负责人：
Kenneth L. Tyler
金额：
$ 46.46万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/8841447
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 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

项目摘要

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.

病毒脑炎，包括西尼罗河病毒（WNV）诱导的脑炎和日本脑炎病毒（JEV）是美国乃至整个整个地区发病率和死亡率的主要来源世界。经过验证的病毒脑炎治疗仅限于几种病毒，即使治疗存在（例如，用于单纯疱疹脑炎的阿西洛韦）残疾和死亡仍然很大。目前有没有有效治疗弧菌病毒诱发的脑炎。新颖且广泛适用的策略迫切需要对神经性病毒感染的治疗。我们将对从感染了WNV或感染的小鼠的大脑中提取的RNA进行微阵列分析 JEV是为了鉴定新的细胞基因和途径在大脑中受到差异调节的途径病毒感染，可能为病毒脑炎提供治疗靶标。基因和途径在被两种病毒感染的小鼠的大脑中受到差异调节，将优先使用如确定的目标。然后，我们建议使用成对的神经性肺部和神经肌抑制病毒菌株，不同的治疗条件和其他脑炎病毒，以鉴定致病基因和信号通路，其可能是提供治疗靶标的最高可能性病毒脑炎。在本提案的最后一部分中，我们将在体内和离体模型中评估这些目标使用遗传学，药理和siRNA定向方法的病毒发病机理。预计这些研究将识别并评估病毒的新型治疗靶标脑炎。尽管该提案的主要目标是确定WNV和JEV的新型治疗靶标纳入其他脑炎病毒可能会鉴定出广泛的脑炎治疗靶标由多种不同的病毒诱导。我们的研究也可能与其他疾病有关中枢神经系统。