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

• 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
• 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

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(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，在全球范围内引起显著的发病率和死亡率。不幸的是，目前治疗与这些病毒相关的疾病的选择有限。我们等人最近的研究表明，microRNAs(MiRNAs)通过调节病毒和宿主基因的表达，在多种病毒的生命周期中发挥重要作用。因此，miRNAs代表了治疗干预的潜在靶点，无论是通过增强或拮抗它们在病毒感染细胞中的功能。在这项应用中，我们建议筛选miRNA类似物和反义抑制剂的文库，以确定代表潜在治疗靶点的单个miRNA 干预。由于miRNAs的功能预计是通过靶向细胞mRNAs和宿主细胞途径的基因表达来实现的，因此我们将使用RNA诱导沉默复合体(RISC)的免疫沉淀、生物信息学分析和实验验证来确定这些靶点和途径。因此，在完成该提案的R21部分后，我们预计已经确定了多个miRNAs，它们的活性可以被调节以抑制WNV和JEV的复制，并表征了它们的作用机制。在该提案的R33部分，将在WNV和JEV感染的小鼠模型中评估已识别的miRNAs的治疗潜力。