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: 10333225
• 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/10333225
• 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; 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; fatty liver disease; 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.

概括 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患有代谢性疾病 患有超重或肥胖。这一趋势与2型糖尿病密切相关 和高血压，是多种慢性疾病的主要危险因素，如动脉粥样硬化、脂肪 肝脏疾病和某些类型的癌症。研究发现，无菌性炎症起着关键作用 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，例如肥胖患者，或可能导致 器官功能衰竭，例如脂肪肝患者。大多数脂肪肝患者是无症状的， 然而，炎症的发生会将脂肪肝转变为一种严重的疾病——非酒精性肝病 脂肪性肝炎 (NASH) – 可能导致肝硬化并最终导致肝衰竭（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 代谢处于反馈循环中，从而加速代谢疾病的进展。 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节的复杂过程。 在治疗之前需要仔细确定调节炎症反应的机制 可以开发出有效的疗法。我们最近发现细胞内脂质的积累会抑制 通过下调 RNA 编辑酶 ADAR1 来进行细胞 RNA 加工。我们之前 证明 ADAR1 的缺陷会激活先天性细胞质的细胞质 RNA 传感信号 免疫系统，导致严重的炎症组织损伤。新出现的证据支持这一点 RNA编辑在无菌性炎症中发挥着关键作用。然而，分子机制 该法规的基础尚未定义。在这项研究中，我们将利用我们广泛的 RNA 编辑研究、现成的动物模型以及综合专业知识方面的经验 我们的团队成员揭示细胞 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 在我们独特的细胞模型中进行了测试和比较。我们还将确定 ADAR1- 是否以及如何 介导的RNA编辑/RAN传感轴在炎症的发展中发挥着关键作用 代谢性疾病中的组织损伤。最后，我们将测试是否可以使用RNA传感信号 作为预防或减轻 NASH 小鼠炎症组织损伤的新治疗靶点 模型。