The role of STING in innate immunity

描述（由申请人提供）：我们的数据表明，STING（干扰素基因刺激因子）控制一个关键的细胞质dna传感通路，并负责小鼠dna ii缺陷致死性和慢性多关节炎（CP）以及trex1介导的slea样疾病。例如，DNaseII小鼠在胚胎发育期间死亡，原因是来自凋亡细胞的未消化DNA激活DNA传感器，从而触发I型IFN和促炎细胞因子的产生。然而，在没有STING的情况下，DNaseII-/-小鼠正常出生，没有任何炎症加重疾病的迹象。此外，由于炎症性心肌炎的发展，TREX1-/-小鼠的中位寿命为10周，当交叉到STING-/-背景时，TREX1-/-小鼠仍然存活，并且不会表现出这种疾病。inTREX1突变已被证明与人类aicardii - goutieres综合征（AGS）有关，其典型特征是高水平的循环I型IFN和早期死亡。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充分阐明。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，如初始激活和触发炎症性疾病的细胞因子生产。第二个目的是研究Trex1负调控STING的机制。这些目标将对先天免疫的机制以及炎症性疾病的原因有相当大的了解。

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.