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：
8298821
负责人：
MARGARET R MACDONALD
金额：
$ 25.43万
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/8298821
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. PUBLIC HEALTH RELEVANCE: Infection of humans by viruses in the Alphavirus genus of the Togaviridae family can cause fever, rash, arthritis, encephalitis and death and no specific treatments are available to combat these diseases. The studies described in this proposal will test the feasibility of an innovative therapeutic approach. Expression of the potent anti-alphavirus host factor called ZAP will be unregulated and its effect on alphavirus infection will b tested in a murine model.

描述（由申请人提供）：甲病毒（披膜病毒科）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，它会介导对甲病毒的有效抑制，包括原型辛德比斯病毒以及逆转录病毒科和丝状病毒科的病毒。最近，人们发现小RNA与微小干扰RNA类似，但针对基因启动子序列（反基因或agRNA），可介导转录上调和下调。该项目的目标是上调内源性 ZAP 的表达，并测试这是否可以改善体内模型中甲病毒感染引起的症状。这些目标将通过两个具体目标来实现。在目标 1 中，将在细胞培养物中测试针对 ZAP 启动子序列的 agRNA 的 ZAP 转录上调活性。活性序列将表征 ZAP mRNA 和蛋白质上调的功效和特异性及其对辛德比斯病毒复制的影响。在目标 2 中，活性 agRNA 将在一个良好表征的小鼠模型中测试其上调 ZAP 表达和减少由神经毒力 Sindbis 病毒感染引起的疾病的能力。如果成功，这项工作将产生巨大影响，为最近发现的转录控制途径增添知识，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，该概念方法可以应用于治疗任何传染病，以及通过上调特定基因或一组基因而受益的任何疾病或病症。公共卫生相关性：人类被披膜病毒科甲病毒属病毒感染可导致发烧、皮疹、关节炎、脑炎和死亡，并且没有特定的治疗方法可以对抗这些疾病。该提案中描述的研究将测试创新治疗方法的可行性。称为 ZAP 的有效抗甲病毒宿主因子的表达将不受调节，并将在小鼠模型中测试其对甲病毒感染的影响。