内源性双链RNA的产生及其信号转导

项目名称： 内源性双链RNA的产生及其信号转导

项目编号： No.31471322

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 杨静华

作者单位： 山东大学

项目金额： 85万元

中文摘要： 普遍认为双链RNA是动物细胞的病原相关分子，是病毒感染动物细胞时产生的标志性产物。在此理论指导下，以双链RNA作为广谱抗病毒靶标，能有效地抑制各种病毒对人和鼠细胞的感染。近来我们研究发现，动物细胞在非病毒感染状态下，例如在炎性反应、氧化应激和化疗药物反应过程中，都可能产生内源性双链RNA。进一步研究证实，氧化应激引起的双链RNA部分由Sx-Alu RNA组成，单独表达这个Alu RNA可以激活NF-kB磷酸化和NLRP3相关的炎性反应。有理由认为，占人类基因组10% 的基因组垃圾参与了细胞应激反应。这对以双链RNA为靶点的广谱抗病毒理论形成了挑战，也对动物细胞内源性双链RNA的产生、信号转导和生物功能提出了新的问题。本项目将深入研究动物细胞内源性双链RNA的形成，阐明Alu RNA作为内源性双链RNA前体引起的细胞应激反应机制，进一步完善以双链RNA为靶点的广谱抗病毒理论。

中文关键词： 信号转导；双链RNA；氧化应激；抗病毒；转录调控

英文摘要： Long stretches of dsRNA are considered as the molecular products associated with virus infection, termed Pathogen-Associated Molecular Pattern or PAMP. Previously we have proposed a broad antiviral strategy to antagonize the countermeasures of viruses in mammanlian cells (FASEB J.25:1767, 2011).The endogeneous dsRNA-binding domains and the apoptosis signaling motif were connected to create several dsRNA-dependent caspase recruiters, termed dsCAREs, which successfully blocked a broad spectrum of pathogenic virus infections, suggesting that dsRNA is indeed a practical virus-associated molecular target for borad antiviral prophylaxis. However, in a further study we detected a large amount of non-viral dsRNA in the virus infected host cells, indicating that mammanlian cells were able to produce endogensous dsRNA with yet-unkown mechanism and biological function. Markedly, endogensous dsRNA were also detected under non-viral infection conditions, such as inflammatory stimulation by bacterial endotoxin, oxidative stresses by hydrogen peroxide. It raised the question of why and how endogensous dsRNA was formed under non-viral infection conditions. It has also challenged the dsRNA-based antiviral targeting strategies. The long term aim of this proposal is to understand the transcription of the endogeneous dsRNA precusors, and to elucidate the signal transduction mechainsms of the endogeneous dsRNA.

英文关键词： signal tranduction;dsRNA;oxidative stress;antivirus;transcription regulation