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

基本信息

批准号：
10552679
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10552679
关键词：
ADAR1 Acceleration 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 Macrophage 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 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 viral detection

项目摘要

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.

概括代谢疾病的患病率一直在稳步增长，超过三分之二的美国成年人遭受超重或肥胖的困扰。这种趋势与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，例如动脉粥样硬化，脂肪肝病和某些类型的癌症。研究发现，无菌感染起着关键在这些代谢疾病的病理发展过程中的作用。代谢应激会导致轻度和慢性感染，例如肥胖患者或严重感染，可能导致器官的功能衰竭，例如在脂肪肝患者中。大多数脂肪肝患者无症状，但是，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衰竭（Nash已成为在美国进行肝移植的主要原因）。此外，组织炎症可能会进一步担心反馈循环中的代谢，从而加速了代谢疾病的进展。因此，控制炎症可能是治疗这些患者的有效策略。但是，炎症是一个由许多因素和信号通路调节的复杂过程。之前需要仔细定义调节炎症反应的机制可以开发有效的疗法。我们最近发现，脂质在细胞中的积累抑制细胞RNA通过下调RNA编辑酶ADAR1的过程。我们以前证明ADAR1的缺乏激活了先天性的胞质RNA感应信号免疫系统，导致严重的炎症组织损伤。新兴证据支持 RNA编辑在无菌注射中起着至关重要的作用。但是，分子机制尚未定义此法规的基础。在这项研究中，我们将利用我们的广泛 RNA编辑研究的经验，现成的动物模型以及我们的团队成员揭示细胞RNA如何激活胞质RNA感应信号通路 RNA编辑如何调节细胞RNA的免疫原性。编辑和未经编辑的RNA将会在我们独特的细胞模型中进行了测试和比较。我们还将确定是否以及如何以及如何介导的RNA编辑/传感轴在炎症的发展中起着至关重要的作用代谢疾病的组织损伤。最后，我们将测试是否可以使用RNA敏感性信号作为预防或减弱纳什小鼠炎症组织损伤的新治疗靶点模型。