The role of STING in innate immunity

STING 在先天免疫中的作用

• 批准号: 8892552
• 负责人: Glen N. Barber
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2014-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8892552
• 关键词: Amino Acids; Apoptotic; Autophagocytosis; Autophagosome; B-Lymphocytes; Bacteria; Cells; Cessation of life; Chronic; DNA; Data; Development; Dinucleoside Phosphates; Disease; Embryonic Development; Endoplasmic Reticulum; Ensure; Etiology; Event; Exhibits; Exposure to; Gene Expression Regulation; Generations; Genes; Genetic Transcription; Genomic DNA; Health; Herpesvirus 1; Host Defense; Human; IRF3 gene; Immune; Immune response; Infection; Inflammation; Inflammatory; Integral Membrane Protein; Interferon Type I; Interferons; Laboratories; Lead; Light; Longevity; Mediating; Microbe; Mus; Mutation; Myocarditis; Natural Immunity; Necrosis; Nuclear; Parasites; Pathway interactions; Phagocytosis; Polyarthritides; Population; Post-Translational Protein Processing; Process; Production; Proteins; RNA; Regulation; Reporting; Research; Rheumatoid Arthritis; Role; Signal Pathway; Simplexvirus; Source; Syndrome; Systemic Lupus Erythematosus; TBK1 gene; TREX1 gene; Tumor Necrosis Factor-alpha; United States; Vaccination; Virus; adaptive immunity; base; cytokine; gene function; insight; microbial; novel; pathogen; plasmid DNA; prevent; response; sensor; signal processing; therapeutic target; trafficking; transcription factor; viral DNA

DESCRIPTION (provided by applicant): Our data indicates that STING (Stimulator of interferon genes) controls a key cytosolic DNA-sensing pathway and is responsible for DNaseII-deficient lethality and chronic polyarthritis (CP) as well as TREX1-mediated SLE-like disease in mice. For example, DNaseII mice die during embryonic development due to undigested DNA derived from apoptotic cells activating DNA sensors that trigger the production of type I IFN and pro- inflammatory cytokines. DNaseII-/- mice are born normally in the absence of STING, however, without any signs of inflammation-aggravated disease. Further, TREX1-/- mice which have a median lifespan of 10 weeks due to the development of inflammatory myocarditis remain viable when crossed onto a STING-/- background, and do not exhibit such disease. Mutations inTREX1 have been shown to be involved in Aicardi-Goutieres syndrome (AGS) in humans, typified by high levels of circulating type I IFN and early death. Despite this significant progress, the mechanisms that control STING function and the cytosolic DNA signaling pathway remain to be fully clarified. We thus propose two aims. The first is to further understand the mechanisms controlling STING function, such as initial activation and the triggering of cytokine production responsible for inflammatory disease. The second aim is to study the mechanisms by which Trex1 may negatively regulate STING. These objectives will shed considerable insight into mechanisms of innate immunity as well as into the causes of inflammatory disease.

描述（由申请人提供）：我们的数据表明，STING（干扰素基因刺激剂）控制着关键的胞质 DNA 传感途径，并导致 DNaseII 缺陷致死率和慢性多关节炎 (CP) 以及 TREX1 介导的 SLE 样疾病在小鼠中。例如，DNaseII 小鼠在胚胎发育过程中死亡，原因是来自凋亡细胞的未消化 DNA 激活 DNA 传感器，触发 I 型 IFN 和促炎细胞因子的产生。 DNaseII-/- 小鼠在没有 STING 的情况下正常出生，但没有任何炎症加重疾病的迹象。此外，由于发生炎症性心肌炎而具有10周中位寿命的TREX1-/-小鼠在与STING-/-背景杂交时仍能存活，并且不会表现出此类疾病。 TREX1 突变已被证明与人类 Aicardi-Goutieres 综合征 (AGS) 有关，其典型特征是循环中 I 型 IFN 水平高和过早死亡。尽管取得了这一重大进展，但控制 STING 功能和胞质 DNA 信号通路的机制仍有待完全阐明。因此，我们提出两个目标。首先是进一步了解控制 STING 功能的机制，例如初始激活和触发导致炎症疾病的细胞因子产生。第二个目的是研究 Trex1 负向调节 STING 的机制。这些目标将使人们对先天免疫机制以及炎症性疾病的原因有深入的了解。