RNA氧化损伤是RNA最常见的损伤方式，在多种疾病中具有重要作用，但在急性肾损伤（AKI）中的研究仍是空白。本课题将首次表征AKI中氧化RNA水平变化，探索RNA氧化损伤与AKI的相关性。RNA降解是清除氧化RNA的主要途径，但机制未明。通过前期筛选发现ISG20是AKI小鼠肾组织中表达升高最显著的外切核糖核酸酶；在缺氧-复氧压力下，沉默ISG20可加剧RNA氧化损伤和肾小管上皮细胞死亡，而高表达ISG20则具有明显改善作用；ISG20清除氧化RNA的作用依赖于其酶活性，并可能需要RNA外切体辅助。本课题将运用肾小管特异性基因敲除小鼠，形态学、细胞和分子生物学、RNA氧化分析等方法，明确ISG20在AKI中通过介导氧化RNA降解缓解肾脏损伤的功能，并以ISG20-RNA外切体途径为核心探讨ISG20降解氧化RNA的分子机制。此研究将鉴定新型氧化RNA降解机制，为AKI防治提供新靶点和思路。

Oxidation is the most common type of damage that occurs in cellular RNA. RNA oxidative damage is implicated in the pathogenesis of many types of human diseases, however the study of RNA oxidative damage in acute kidney injury (AKI) remains a blank space. For the first time we will investigate the level change of oxidized RNA in AKI, and explore the correlation between RNA oxidative damage and AKI. The major approach by which cells eliminate the oxidized RNA seems to be by degradation, but the detailed mechanisms remain largely unexplored. Our preliminary screening study showed that ISG20 was the exoribonuclease with the most significantly upregulated expression in kidney from AKI mice. Under hypoxia/reoxygenation condition, inhibition of ISG20 expression exacerbated RNA oxidative damage and death of renal tubular epithelial cell. Consistently, overexpression of ISG20 ameliorated hypoxia/reoxygenation-induced RNA oxidative damage and cell injury. The role of ISG20 in the elimination of oxidized RNA was dependent on it's exoribonuclease activity and may require the assistance of RNA exosome complex. Therefore, the present study is designed to explore the role of ISG20-mediated degradation of oxidized RNA in AKI using renal tubular specific knockout mice, various methods of morphology, cellular and molecular biology, and RNA oxidation analysis. We will further investigate the molecular mechanism of ISG20-mediated degradation of oxidized RNA focusing on the ISG20-RNA exosome complex pathway. This study will identify a completely new degradation mechanism of oxidized RNA and provide new target and idea for the prevention and treatment of AKI.