Oxidized RNA in SLE Pathology

项目摘要 系统性红斑狼疮是一种慢性自身免疫综合征，可累及多种器官系统， 个体已经表明，SLE患者细胞中不受控制的氧化应激有助于 许多蛋白质、脂质和DNA的功能性氧化修饰，从而引发自身免疫。 然而，RNA氧化在自身免疫性疾病如SLE的发展中所起的作用尚不清楚。 在正常和氧化应激条件下，RNA氧化水平远高于DNA氧化水平 然而，关于RNA氧化的潜在影响的可用信息很少。的一大原因 缺乏对RNA氧化的研究是一种误解，即正常的RNA周转应该减少RNA氧化的影响。 氧化RNA对细胞代谢和基因表达的影响。然而，由于核酸的氧化仅发生在 核糖体和非编码RNA在细胞中存活数天， 氧化的RNA具有有害的和长期的影响。我们的科学前提是， 细胞核、细胞质和线粒体中的RNA确保了一些RNA将更多地暴露于氧化 通过限制对氧化剂的可及性。我们在目标1中提出，MAVS介导的超极化 线粒体的分裂会使一些RNA停留在它们的表面，并促进它们的氧化。我们建议，非- 编码核糖体RNA，如5S RNA，受到很大影响。在目标2中，基于5S RNA与其自身结合的事实 转录因子，我们提出RNA氧化将导致5S RNA基因表达的变化， 核糖体基因拷贝数变异的减少。在本申请中获得的数据将提供 我们即将推出的R 01应用程序的理由，调查新的前提，自身免疫性疾病，如 SLE可能与基因组中核糖体DNA拷贝数的破坏有关，这是环境因素的结果。 exposure.

Project Summary SLE is a chronic autoimmune syndrome that can involve a variety of organ systems and frequently affects young individuals. It has been suggested that uncontrolled oxidative stress in the cells of SLE patients contributes to functional oxidative modifications of many proteins, lipids, and DNA, consequently triggering autoimmunity. However, the role RNA oxidation plays in the development of autoimmune diseases such as SLE is not known. Under both normal and oxidative stress conditions, RNA oxidation levels are much higher than DNA oxidation levels; however, available information on the potential effects of RNA oxidation is scarce. A major reason for the shortage of work on RNA oxidation is the misconception that normal RNA turnover should diminish effects of oxidized RNA on cell metabolism and gene expression. However, since oxidation of nucleic acids occurs in just a few minutes, and ribosomal and non-coding RNAs live in the cell for days, there is ample opportunity for oxidized RNA to have deleterious and long-standing effects. Our scientific premise is that spatial separation of RNA in the nucleus, cytoplasm, and mitochondria ensures that some RNAs will be more exposed to oxidation than others by restricting accessibility to oxidants. We propose in Aim 1 that MAVS-mediated hyperpolarization of mitochondria will stall some of the RNAs at their surface and promote their oxidation. We propose that non- coding ribosomal RNA, like 5S RNA, is greatly affected. In Aim 2, based on the fact that 5S RNA binds to its own transcription factor, we propose that RNA oxidation will lead to changes in 5S RNA gene expression, and also to a decrease in copy number variation of ribosomal genes. Data obtained in this application will provide the grounds for our upcoming R01 application investigating the novel premise that autoimmune diseases such as SLE can be associated with a disrupted ribosomal DNA copy number in the genome as a result of environmental exposure.