Upregulation of ZAP expression as a novel approach for anti-alphavirus therapy

ZAP 表达上调作为抗甲病毒治疗的新方法

基本信息

批准号：
8420421
负责人：
MARGARET R MACDONALD
金额：
$ 19.92万
依托单位：
ROCKEFELLER 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：
2012-02-15 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8420421
关键词：
Alphavirus Alphavirus Infections Antiviral Agents Arginine Arthritis Bioterrorism Categories Cell Culture Techniques Cell Line Cell physiology Cells Cessation of life Communicable Diseases Complex Disease Double-Stranded RNA Down-Regulation Encephalitis Ensure Exanthema Family Fever Filoviridae Filovirus Functional RNA Future Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Guidelines Human Virus In Vitro Infection Injection of therapeutic agent Integration Host Factors Interferons Knowledge Mediating Messenger RNA MicroRNAs Modeling Mus Neurons Outcome Pathway interactions Peptides Prevention Promoter Regions Proteins RNA RNA Interference Regulation Retroviridae Sindbis Virus Site Small Interfering RNA Small RNA Specificity Structure Symptoms System Tail Testing Therapeutic Time Togaviridae Toxic effect Transcript Transcriptional Regulation Translational Repression Up-Regulation Veins Virus Virus Diseases Virus Replication Work Zinc Fingers animal morbidity combat design gene discovery human morbidity in vitro testing in vivo in vivo Model infancy innovation macrophage member mortality novel novel strategies promoter protein expression prototype rabies virus glycoprotein G virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): Alphaviruses (Togaviridae family) cause considerable human and animal morbidity and mortality. There are currently no specific treatments for diseases caused by these viruses. The zinc-finger antiviral protein (ZAP) is a host protein that when over expressed mediates potent inhibition of alphaviruses, including the prototype Sindbis virus, as well as viruses in the Retroviridae and Filoviridae families. Recently, small RNAs similar to micro or small interfering RNAs, but directed to gene promoter sequences (anti-gene, or agRNAs), have been found to mediate transcriptional up- and down regulation. The objectives of this project are to up regulate expression of endogenous ZAP and test whether this ameliorates symptoms due to alphavirus infection in an in vivo model. The objectives will be accomplished in two specific aims. In Aim 1, agRNAs directed to ZAP promoter sequences will be tested in cell culture for ZAP transcriptional up regulation activity. Active sequences will be characterized for efficacy and specificity of the ZAP mRNA and protein up regulation and their effect on Sindbis virus replication. In Aim 2, the active agRNAs will tested in a well characterize murine model for their ability to up regulate ZAP expression and reduce disease caused by neurovirulent Sindbis virus infection. If successful, the work will be of high impact, adding knowledge to this recently discovered transcriptional control pathway, and opening up a whole new approach to the treatment of alphavirus infection. The work will be more broadly applicable to the treatment of infection by members of the Retrovirus and Filovirus families. Moreover, the conceptual approach could be applied to treat any infectious disease, as well as any disease or condition that would benefit by up regulation of a specific gene or set of genes.

描述（由申请人提供）：α病毒（Togaviridae家族）引起了相当大的人类和动物的发病率和死亡率。目前尚无针对这些病毒引起的疾病的具体治疗方法。锌指抗病毒蛋白（ZAP）是一种宿主蛋白，当过度表达时，它介导了包括原型的αIndbis病毒在内的α病毒的有效抑制作用，以及逆转录病毒和Filoviridae家族中的病毒。最近，发现与微型或小干扰RNA相似的小RNA，但已发现针对基因启动子序列（抗基因或AgrNA），可介导转录的上下调节。该项目的目标是提高内源性ZAP的表达，并测试这是否可以改善体内模型中α病毒感染引起的症状。目标将以两个具体的目标来实现。在AIM 1中，将针对ZAP启动子序列的AGRNA在细胞培养中测试ZAP转录调节活性。活跃序列将以ZAP mRNA和蛋白质调节的功效和特异性以及对信德比斯病毒复制的影响的特异性进行特征。在AIM 2中，活跃的AGRNA将在鼠模型中测试，以表征其调节ZAP表达并减少神经脊髓性的Sindbis病毒感染引起的疾病的能力。如果成功的话，这项工作将具有很高的影响，从而为最近发现的转录控制途径增加了知识，并为α病毒感染的治疗打开了全新的方法。这项工作将更广泛地适用于逆转录病毒和filevirus家族成员对感染的治疗。此外，概念方法可以应用于治疗任何传染病，以及通过调节特定基因或一组基因受益的任何疾病或状况。