8-羟基鸟苷（8-oxoG）是最常见的核酸氧化修饰形式之一，许多老年神经退行性病变患者体内均发现有含8-oxoG氧化RNA的大量蓄积。我们的最新研究发现，8-oxoG在mRNA中的大量累积，是淀粉样蛋白（Aβ）体内蓄积和产生的重要机制之一。目前已知共有7种蛋白参与RNA中8-oxoG的清除和修复，除MTH1外，其他蛋白的研究目前仅处于起步阶段。本研究利用CRISPR/CAS9文库筛选方法，结合前期构建的药物抗性基因表达系统，拟在全基因水平上寻找参与8-oxoG及变异蛋白质清除的全新基因，结合LC-MS/MS技术、Gluc报告基因系统、蛋白体外重组技术、8-oxoG结合活性检测、TurboID、基因敲除小鼠等多种技术手段，在分子、细胞及动物整体水平等多个层次研究新基因的生物学功能。本课题可有效拓展人们对氧化RNA及变异蛋白质清除机制的了解，并为研究其与老化及老化相关疾病提供新的研究思路。

It is well known that 8-oxo-7,8-dihydroguanine (8-oxoG) is one of the most abundant forms of oxidized nucleotides and oxidized RNAs with 8-oxoG have been reported to be accumulated in patients with neurodegenerative diseases. Our recent study revealed that the incorporation of 8-oxoG into mRNA strand could induce translation errors, thus accelerating the production of the pathogenic amyloid β peptides in mammalian cells. To date, totally 7 key enzymes have been reported to be involved in the clearance of 8-oxoG from RNAs. However, little is known about their exact roles, except for MTH1. In this project, we plan to find out some new key defense factors for the clearance of oxidized RNA or their translated abnormal proteins, by combine the widely used genome-wide CRISPR/CAS9 library screening technique and our abnormal protein detection system with drug-resistance gene. Following by LC-MS/MS, Gluc reporter system, recombinant expression system, 8-oxoG binding technology, TurboID and gene-knock-out mice model, we plan to systematically explore the biological functions of newly screened genes at molecular, cellular and animal levels. This project can expand and enrich current insights into the clearance mechanism for 8-oxoG or translated abnormal proteins. Thus, provides new perspective to understand their relationship with aging and aging-related diseases.