A novel regulator of extracellular nucleic acid sensing

细胞外核酸传感的新型调节剂

• 批准号: 10373106
• 负责人: Boris Reizis
• 金额: $ 21.19万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-16 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373106
• 关键词: Affect; Animal Model; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Bacterial RNA; Cells; Chemicals; Complex; DNA; Dendritic Cells; Deoxyribonucleases; Detection; Development; Digestion; Disease; Double-Stranded RNA; Enzymes; Exhibits; Genetic; Immune response; Immune system; In Vitro; Infection; Inflammation; Inflammatory; Interferon Type I; Interferons; Knockout Mice; Ligands; Lysosomes; Mediating; Molecular; Mus; Mutation; Natural Immunity; Nature; Nucleic Acids; Pancreatic ribonuclease; Pathogenicity; Pattern; Pattern Recognition; Pattern recognition receptor; Production; Proteins; RNA; RNA Viruses; Ribonucleases; Role; Signal Transduction; Systemic Lupus Erythematosus; TLR3 gene; TLR7 gene; TLR8 gene; TREX1 gene; Testing; Tissues; Toll-like receptors; antimicrobial; autoinflammatory; autoreactivity; base; cell type; cytokine; extracellular; in vivo; innate immune sensing; loss of function; novel; nuclease; pathogen; prevent; response; therapeutic protein; viral RNA

ABSTRACT Pathogen-derived RNA represents a canonical pathogen-associated molecular pattern (PAMP), and its detection by pattern recognition receptors (PRR) is a fundamental feature of innate immunity. Extracellular RNA is detected primarily via endosomal Toll-like receptors (TLRs), including those detecting single- stranded RNA (TLR7/TLR8) and double-stranded RNA (TLR3). Signaling through endosomal TLRs induces the production of cytokines including type I interferons (IFN), which elicit antiviral states and broadly activate the immune system. Sensing of both DNA and RNA is tightly regulated by nucleic acid-processing enzymes, which may be required both to generate DNA/RNA ligands for recognition by PRRs, and to prevent aberrant accumulation of nucleic acids. However, little is known about the enzymes that may control extracellular RNA and its sensing by endosomal TLRs. We have identified a candidate enzyme that may represent a negative regulator of TLR-mediated extracellular RNA sensing; as such, this protein may dampen inflammation and tissue damage during antimicrobial immune responses, as well as restrict autoreactivity in autoimmune disease. In Aim 1, we will use gain and loss-of-function approaches to test how it affects the sensing of RNA and related PAMPs by endosomal TLRs. In Aim 2, we will test its role in animal models of autoimmunity, as well as in antiviral immune responses. The proposed studies may help identify a novel regulator of innate immune sensing and provide rationale for its development as a protein therapeutic in inflammatory and/or autoimmune diseases.

摘要 病原体衍生的RNA代表典型的病原体相关分子模式（PAMP），其 模式识别受体（PRR）的检测是先天免疫的基本特征。细胞外 RNA主要通过内体Toll样受体（TLR）检测，包括检测单核苷酸的那些。 单链RNA（TLR 7/TLR 8）和双链RNA（TLR 3）。通过内体TLR的信号传导诱导 包括I型干扰素（IFN）在内的细胞因子的产生，其引起抗病毒状态并广泛激活 免疫系统. DNA和RNA的传感都受到核酸加工的严格调控 酶，其可能需要产生用于PRR识别的DNA/RNA配体，以及 防止核酸的异常积累。然而，人们对可能控制这种疾病的酶知之甚少。 细胞外RNA及其通过内体TLR的传感。我们已经确定了一种候选酶， 代表TLR介导的细胞外RNA传感的负调节因子;因此，这种蛋白质可以 抑制抗菌免疫反应期间的炎症和组织损伤，以及限制 自身免疫性疾病中的自身反应性在目标1中，我们将使用功能增益和功能损失方法来测试 它如何影响内体TLR对RNA和相关PAMP的感知。在目标2中，我们将测试其在以下方面的作用： 自身免疫的动物模型，以及抗病毒免疫应答。拟议中的研究可能会有所帮助 鉴定一种新先天免疫感应调节剂并为其作为蛋白质的开发提供理论基础 治疗炎症和/或自身免疫性疾病。