Investigation of viral ribonucleic acid recognition by human innate immune enzymes

人类先天免疫酶识别病毒核糖核酸的研究

• 批准号: RGPIN-2015-06142
• 负责人: McKenna, Sean
• 金额: $ 2.48万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=708791
• 关键词: Investigation; viral; ribonucleic; acid; recognition

A hallmark of many viral infections is the production of foreign nucleic acid molecules that are generated during the life cycle of the virus. Host cells respond to these foreign biomolecules through a variety of mechanisms, including the use of nucleic acid sensor proteins that detect and mount a defensive response against the infection. My laboratory will focus investigation on two important families of nucleic-acid binding proteins that are central to the recognition of viral infection: (i) 2'-5' oligoadenylate synthetases (OAS) and (ii) the RNA-dependent protein kinase (PKR). The interaction between these enzymes and foreign nucleic acid molecules helps to prevent viral replication by blocking necessary viral protein production. My laboratory will continue a research program to characterize the interactions between naturally occurring viral nucleic acid molecules and OAS/PKR enzymes to provide a fundamental understanding of a key mechanism used by host cells to respond to viral invasion. Biochemical characterization will identify key features of viral nucleic acid molecules, and structural biology approaches will generate three-dimensional images of complexes of interest. A novel aspect of the proposed research program is the use of naturally occurring viral nucleic acid molecules as the model systems as most studies to date have employed synthetic nucleic acid molecules that lack key characteristics typical of their viral counterparts. The results expected from the proposed research program will therefore contribute to our understanding of how these enzymes distinguish between viral and host-cell nucleic acid molecules. Trainees in my laboratory have and will continue to benefit from our expertise in the investigation of protein-nucleic acid interactions and acquire an in-demand skill set given the emerging importance of these interactions in a wide variety of biologically important systems. Highly qualified personnel trained will be well equipped for careers in basic scientific research focused on biotechnology, molecular biology, biochemistry, structural biology, and proteomics.

许多病毒感染的一个特征是在病毒的生命周期中产生外来核酸分子。宿主细胞通过多种机制对这些外来生物分子作出反应，包括使用核酸传感器蛋白检测并对感染进行防御反应。我的实验室将重点研究对识别病毒感染至关重要的两个重要的核酸结合蛋白家族：(i) 2‘-5’寡腺苷酸合成酶（OAS）和（ii） rna依赖性蛋白激酶（PKR）。这些酶和外来核酸分子之间的相互作用通过阻断必要的病毒蛋白生产来帮助阻止病毒复制。我的实验室将继续研究自然发生的病毒核酸分子与OAS/PKR酶之间的相互作用，以提供对宿主细胞响应病毒入侵的关键机制的基本理解。生化表征将确定病毒核酸分子的关键特征，结构生物学方法将产生感兴趣的复合物的三维图像。所提出的研究计划的一个新颖方面是使用天然存在的病毒核酸分子作为模型系统，因为迄今为止大多数研究都使用合成核酸分子，这些分子缺乏病毒对应物的典型关键特征。因此，拟议研究计划的预期结果将有助于我们了解这些酶如何区分病毒和宿主细胞核酸分子。我实验室的学员已经并将继续受益于我们在蛋白质-核酸相互作用研究方面的专业知识，并获得一套急需的技能，因为这些相互作用在各种生物重要系统中的重要性正在显现。训练有素的高素质人才将为从事生物技术、分子生物学、生物化学、结构生物学和蛋白质组学等基础科学研究做好充分准备。