Evaluation of Host miRNAs as Therapeutics against Encephalitogenic Flaviviruses

描述（由申请人提供）：嗜神经黄病毒，包括西尼罗病毒（WNV）和日本脑炎病毒（JEV）是蚊子传播的病毒，在世界范围内引起严重的发病率和死亡率。不幸的是，目前治疗与这些病毒相关的疾病的治疗方法有限。我们和其他人最近的研究表明，microRNAs （miRNAs）通过调节病毒和宿主基因表达在多种病毒的生命周期中发挥重要作用。因此，通过增强或拮抗mirna在病毒感染细胞中的功能，mirna代表了治疗干预的潜在靶点。在这个应用中，我们建议筛选miRNA类似物和反义抑制剂的文库，以鉴定代表潜在治疗靶点的单个miRNA

DESCRIPTION (provided by applicant): The neurotropic flaviviruses, including West Nile virus (WNV) and Japanese Encephalitis virus (JEV) are mosquito borne viruses that cause significant morbidity and mortality worldwide. Unfortunately, current therapeutic options for treating disease associated with these viruses are limited. Recent studies by our group and others have demonstrated that microRNAs (miRNAs) play a major role in the life cycle of multiple viruses via regulation of both viral and host gene expression. miRNAs, therefore, represent potential targets for therapeutic intervention, either through enhancing or antagonizing their functions in virally infected cells. In this application, we propose to screen a library of miRNA analogs and antisense inhibitors to identify individual miRNAs that represent potential targets for therapeutic intervention. Because miRNAs are expected to function by targeting gene expression of cellular mRNAs and host-cell pathways, we will identify these targets and pathways using immunoprecipitation of the RNA-induced silencing complex (RISC), bioinformatic analysis, and experimental verification. Therefore, at the completion of the R21 portion of this proposal, we expect to have identified multiple miRNAs whose activity can be modulated to inhibit WNV and JEV replication, as well as to have characterized their mechanism of action. In the R33 portion of the proposal, fully characterized miRNAs will be evaluated for therapeutic potential of identified miRNAs in a mouse model of WNV and JEV infection. PUBLIC HEALTH RELEVANCE: West Nile virus and Japanese encephalitis are major causes of viral encephalitis throughout the world. Because these viruses require multiple host-cell proteins and pathways to complete their replication cycle, we propose to develop cellular microRNAs, which themselves regulate expression of host-cell proteins and pathways, as potential therapeutics to combat these viruses.