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

• 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
• 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

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（由申请方提供）：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，当过表达时，介导对甲病毒（包括原型辛德毕斯病毒）以及逆转录病毒科和丝状病毒科病毒的有效抑制。最近，小RNA类似于微小或小干扰RNA，但针对基因启动子序列（反基因，或agRNA），已被发现介导转录上调和下调。该项目的目的是上调内源性ZAP的表达，并在体内模型中测试这是否改善了由于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和蛋白上调的功效和特异性及其对辛德毕斯病毒复制的影响。在目标2中，将在充分表征的鼠模型中测试活性agRNA上调ZAP表达和减少由神经毒性辛德毕斯病毒感染引起的疾病的能力。如果成功的话，这项工作将产生很大的影响，为最近发现的转录控制途径增加知识，并开辟一种治疗甲病毒感染的全新方法。这项工作将更广泛地适用于治疗逆转录病毒和丝状病毒家族成员的感染。此外，概念方法可以应用于治疗任何传染病，以及任何通过上调特定基因或基因组而受益的疾病或病症。