Evaluation of Host miRNAs as Therapeutics against Encephalitogenic Flaviviruses

宿主 miRNA 作为抗脑炎黄病毒治疗药物的评价

基本信息

批准号：
8471055
负责人：
ALEC J HIRSCH
金额：
$ 21.15万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
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 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8471055
关键词：
Affect Alphavirus Antiviral Agents Bioinformatics Cells Complex Culicidae Data Disease Evaluation Flavivirus Gene Expression Growth Herpesviridae Immunoprecipitation In Vitro Indirect Immunofluorescence Individual Infection Japanese Encephalitis Japanese encephalitis virus Libraries Life Cycle Stages Messenger RNA Methods MicroRNAs Mitogen-Activated Protein Kinases Morbidity - disease rate Mus Myeloid Cells Neurons Organ Pathway interactions Peptides Play Positioning Attribute Proteins RNA-Induced Silencing Complex Regulation Relative (related person)Role Staging Testing Therapeutic Therapeutic Intervention Time Treatment Efficacy Viral Viral Encephalitis Viral Physiology Virus Virus Diseases Virus Replication West Nile virus analog cellular targeting combat experimental analysis high throughput screening in vivo inhibitor/antagonist mortality mouse model neurotropic screening

项目摘要

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.

描述（由申请人提供）：嗜神经性黄病毒，包括西尼罗河病毒（WNV）和日本脑炎病毒（JEV），是蚊媒病毒，在世界范围内引起显着的发病率和死亡率。不幸的是，目前治疗与这些病毒相关的疾病的治疗选择是有限的。我们小组和其他人最近的研究表明，microRNA (miRNA) 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着重要作用。因此，miRNA 代表了治疗干预的潜在靶点，可以通过增强或拮抗其在病毒感染细胞中的功能来实现。在此应用中，我们建议筛选 miRNA 类似物和反义抑制剂文库，以鉴定代表潜在治疗靶点的单个 miRNA 干涉。由于 miRNA 预计通过靶向细胞 mRNA 的基因表达和宿主细胞通路发挥作用，因此我们将使用 RNA 诱导沉默复合物 (RISC) 的免疫沉淀、生物信息学分析和实验验证来识别这些靶标和通路。因此，在完成该提案的 R21 部分后，我们期望能够鉴定出多种 miRNA，其活性可以通过调节来抑制 WNV 和 JEV 复制，并确定其作用机制。在该提案的 R33 部分中，将评估完全表征的 miRNA 在 WNV 和 JEV 感染小鼠模型中的治疗潜力。