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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）：甲病毒（托加病毒科）引起相当大的人类和动物发病率和死亡率。目前还没有针对这些病毒引起的疾病的特异性治疗方法。锌指抗病毒蛋白（ZAP）是一种宿主蛋白，当过表达时介导对甲型病毒（包括原型Sindbis病毒）以及逆转录病毒科和丝状病毒科病毒的有效抑制。最近，类似于微干扰rna或小干扰rna，但指向基因启动子序列（抗基因，或agnas）的小rna被发现介导转录的上下调节。本项目的目的是在体内模型中上调内源性ZAP的表达，并测试其是否能改善甲病毒感染引起的症状。这些目标将在两个具体目标中实现。在Aim 1中，针对ZAP启动子序列的agnas将在细胞培养中测试ZAP转录上调活性。活性序列将被表征为ZAP mRNA和蛋白上调的有效性和特异性及其对Sindbis病毒复制的影响。在Aim 2中，活性agrna将在一个特征良好的小鼠模型中进行测试，以确定它们上调ZAP表达和减少神经毒性Sindbis病毒感染引起的疾病的能力。如果成功，这项工作将具有很高的影响，为最近发现的转录控制途径增加知识，并开辟治疗甲病毒感染的全新方法。这项工作将更广泛地适用于逆转录病毒和丝状病毒家族成员感染的治疗。此外，概念方法可用于治疗任何传染病，以及通过上调某一特定基因或一组基因而受益的任何疾病或病症。