Role of the ADAR1-mediated RNA editing ∕ RNA sensing axis in sterile inflammation

ADAR1 介导的 RNA 编辑 – RNA 传感轴在无菌炎症中的作用

• 批准号: 10092918
• 负责人: Qingde Wang
• 金额: $ 38.98万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092918
• 关键词: ADAR1; Adaptor Signaling Protein; Adult; Animal Model; Antiviral Response; Atherosclerosis; Attenuated; Autoimmune; Biological Models; Cell model; Cells; Cellular Stress; Cessation of life; Chronic; Chronic Disease; Cirrhosis; Cytoplasm; Data; Development; Disease; Down-Regulation; Endothelial Cells; Enzymes; Experimental Animal Model; Failure; Fatty Liver; Feedback; Genes; Hepatocyte; Homeostasis; Hypertension; Immune; Immune response; Inflammation; Inflammatory; Injury; Innate Immune Response; Innate Immune System; Interferons; Invaded; Knock-out; Knockout Mice; Lead; Length; Lipids; Liver; Liver Failure; Liver diseases; Mediating; Metabolic Diseases; Metabolic stress; Metabolism; Molecular; Molecular Structure; Mus; Mutation; Natural Immunity; Non-Insulin-Dependent Diabetes Mellitus; Normal Cell; Obesity; Organ; Overweight; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Phenotype; Play; Positioning Attribute; Prevalence; Process; Public Health; RNA; RNA Editing; Reaction; Regulation; Research; Risk Factors; Role; Signal Pathway; Signal Transduction; Sterility; Testing; Tissues; Transcript; cancer type; cell type; effective therapy; experience; genome-wide; immune activation; immune system function; immunogenic; immunogenicity; immunological status; immunoregulation; insight; lipid metabolism; liver injury; liver transplantation; macrophage; member; mouse model; new therapeutic target; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; obese patients; prevent; pseudotoxoplasmosis syndrome; receptor; response; screening; tissue injury; treatment strategy; trend; viral RNA

Summary The prevalence of metabolic disease has been steadily increasing, and over two-thirds of US adults suffer from being either overweight or obese. This trend is closely associated with type 2 diabetes mellitus and hypertension, and is a major risk factor for multiple chronic diseases, such as atherosclerosis, fatty liver disease, and certain types of cancers. Studies have found that sterile inflammation plays a critical role during the pathologic development of these metabolic diseases. Metabolic stress causes either mild and chronic inflammation, such as in obese patients, or severe inflammation that may lead to an organ’s functional failure, such as in fatty liver patients. Most fatty liver patients are asymptomatic, however, the occurrence of inflammation converts fatty liver to a severe condition – non-alcoholic steatohepatitis (NASH) – which may lead to cirrhosis and eventually liver failure, (NASH has become the primary cause of liver transplantation in US). In addition, tissue inflammation can further worsen the metabolism in a feedback loop, thereby accelerating the progress of metabolic diseases. Therefore, controlling inflammation may potentially be an effective strategy for treating these patients. However, inflammation is a complicated process regulated by many factors and signaling pathways. The mechanisms that regulate the inflammatory reactions need to be carefully defined before effective therapies can be developed. We recently found that accumulation of lipid in cells suppresses cellular RNA processes through downregulation of the RNA editing enzyme ADAR1. We previously demonstrated that deficiency of ADAR1 activates the cytosolic RNA sensing signaling of the innate immune system, which leads to severe inflammatory tissue injuries. Emerging evidence supports that RNA editing plays a critical role in sterile inflammation. However, the molecular mechanism underlying this regulation has not been defined. In this study, we will take advantage of our extensive experience in RNA editing studies, ready-to-be-used animal models, and the combined expertise of our team members to reveal how cellular RNA activates the cytosolic RNA sensing signaling pathway and how RNA editing regulates the cellular RNA’s immunogenicity. Edited and unedited RNAs will be tested and compared in our unique cell models. We will also determine whether and how the ADAR1- mediated RNA editing/RAN sensing axis plays its critical role in the development of inflammatory tissue injury in metabolic disease. Finally, we will test whether RNA sensing signaling can be used as a new therapeutic target to prevent or attenuate inflammatory tissue injuries in a NASH mouse model.

总结 代谢性疾病的患病率一直在稳步上升，超过三分之二的美国成年人 要么超重要么肥胖。这种趋势与2型糖尿病密切相关 和高血压，并且是多种慢性疾病的主要危险因素，如动脉粥样硬化，脂肪肝， 肝脏疾病和某些癌症。研究发现，无菌性炎症在 在这些代谢性疾病的病理发展过程中的作用。代谢压力会导致 轻度和慢性炎症，如肥胖患者，或严重炎症，可能导致 器官功能衰竭，如脂肪肝患者。大多数脂肪肝患者无症状， 然而，炎症的发生将脂肪肝转化为严重的疾病-非酒精性 脂肪性肝炎（NASH）-可能导致肝硬化并最终导致肝功能衰竭，（NASH已成为 美国肝移植的主要原因）。此外，组织炎症会进一步恶化 新陈代谢处于反馈循环中，从而加速代谢性疾病的进展。 因此，控制炎症可能是治疗这些患者的有效策略。 然而，炎症是一个受多种因素和信号通路调控的复杂过程。 调节炎症反应的机制需要仔细定义， 可以开发有效的治疗方法。我们最近发现细胞中脂质的积累抑制了 通过下调RNA编辑酶ADAR 1进行细胞RNA加工。我们之前 表明ADAR 1的缺乏激活了先天性巨噬细胞的胞质RNA传感信号传导， 免疫系统，导致严重的炎性组织损伤。新出现的证据表明， RNA编辑在无菌炎症中起着关键作用。然而，分子机制 这一规定的依据尚未确定。在这项研究中，我们将利用我们广泛的 在RNA编辑研究方面的经验，现成的动物模型，以及 我们的团队成员揭示了细胞RNA如何激活胞质RNA传感信号通路 以及RNA编辑如何调节细胞RNA的免疫原性。编辑和未编辑的RNA将被 在我们独特的细胞模型中进行测试和比较。我们还将确定ADAR 1是否以及如何- 介导的RNA编辑/RAN传感轴在炎症的发展中起着关键作用。 代谢性疾病中的组织损伤。最后，我们将测试RNA传感信号是否可以用于 作为预防或减轻NASH小鼠中炎性组织损伤的新治疗靶点 模型