Oxidized RNA in SLE Pathology

SLE 病理学中的氧化 RNA

• 批准号: 9535082
• 负责人: Andreas Koenig
• 金额: $ 10.17万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-27 至 2019-03-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9535082
• 关键词: 8-hydroxyguanosine; Affect; Antiviral Agents; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Back; Binding; Cell Nucleus; Cells; Cellular Metabolic Process; Chronic; Collaborations; Copy Number Polymorphism; Cytoplasm; DNA; DNA copy number; Data; Development; Disease; Ensure; Environmental Exposure; Etiology; Exposure to; Feedback; Gene Expression; Genes; Genetic Transcription; Genome; Guanosine; Individual; Interferons; Lead; Lipids; Lupus; Mediating; Mitochondria; Modification; Molecular Conformation; Nucleic Acids; Oxidants; Oxidative Stress; Oxides; Pathogenesis; Pathologic; Pathology; Patients; Play; Proteins; RNA; RNA Binding; RNA Sequences; RNA Transport; RNA, Ribosomal, 5S; Reactive Oxygen Species; Ribosomal DNA; Ribosomal RNA; Ribosomes; Role; SS-A antigen; Signaling Protein; Site; Structure; Surface; Symptoms; Syndrome; Systemic Lupus Erythematosus; T-Lymphocyte; Transcription Factor TFIIIA; Travel; Untranslated RNA; Virus Diseases; Work; analog; base; bisphenol A; body system; dosage; helicase; mitochondrial dysfunction; novel; oxidation; protein complex; stressor; transcription factor

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.

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，常见于年轻人。 个人。已有研究表明，系统性红斑狼疮患者细胞中不受控制的氧化应激有助于 许多蛋白质、脂类和DNA的功能性氧化修饰，从而触发自身免疫。 然而，RNA氧化在系统性红斑狼疮等自身免疫性疾病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的氧化水平都远远高于dna的氧化水平。 然而，关于RNA氧化的潜在影响的现有信息很少。一个主要原因是 缺乏关于RNA氧化的工作是一种误解，认为正常的RNA周转应该会减弱 氧化RNA对细胞代谢和基因表达的影响。然而，由于核酸的氧化只发生在 几分钟后，核糖体和非编码RNA在细胞中存活数天，就有足够的机会 氧化的RNA具有有害和长期的影响。我们的科学前提是空间分离 细胞核、细胞质和线粒体中的rna确保了某些rna更容易被氧化。 通过限制氧化剂的可及性而不是其他方法。我们在目标1中提出，MAVS介导的超极化 线粒体的缺失会使表面的一些RNA停滞，并促进它们的氧化。我们建议非- 编码核糖体RNA，就像5S RNA一样，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，我们认为RNA氧化会导致5S RNA基因表达的变化，而且 导致核糖体基因拷贝数变异减少。在此应用程序中获得的数据将提供 我们即将推出的R01应用程序调查的新前提是自身免疫性疾病 系统性红斑狼疮可能与基因组中核糖体DNA拷贝数的中断有关，这是环境因素的结果 曝光。