Cytosolic DNA sensing pathway in the pathogenesis of Sjogren's Syndrome

干燥综合征(SS)是一种影响几乎所有器官的慢性自身免疫性疾病 系统，包括外分泌腺、神经系统、关节、肺和胃肠道 一条小路。人们普遍认为SS的发病与先天的过度激活有关 免疫和I型干扰素(干扰素)的产生，但启动和 在SS中维持这些反应仍然是未知的。最近的研究证实，DNA 从受损或功能障碍的线粒体中释放出来可导致I型干扰素的产生 通过激活胞浆DNA传感通路。干扰素基因刺激物 (刺蛋白)是这些途径的中心成分。我们发表的研究已经确立了 刺痛通路的全身性激活会导致小鼠出现类似SS的疾病。我们的预赛 研究表明，刺痛通路在唾液腺上皮细胞中具有功能，其 激活可诱导强健的I型干扰素反应。 目前的提议检验了线粒体DNA(MtDNA)的总体假设 唾液腺细胞中STING通路的介导激活影响SING的发病 党卫军。我们将使用培养的小鼠唾液腺细胞在体外验证这一假说。 颌下腺，我们将通过开发新的 唾液腺线粒体损伤的小鼠模型。在目标1中，我们将定义路径 参与mtDNA介导的唾液腺细胞刺激物的激活，并调查 刺激性是否会导致衰老。在目标2，我们将研究在体内的作用 唾液腺线粒体损伤和刺痛激活。为此，我们将 产生转录因子A，线粒体的唾液腺条件突变小鼠 (Tfam)和依赖锰的超氧化物歧化酶(Sod2)。 在SS的背景下，线粒体损伤和先天免疫激活 唾液腺是一个未被开发的领域。这项提案的发现将促进研究 靶向氧化应激和衰老在SS中的作用，这是线粒体损伤的已知原因 并为治疗干预提供可能的靶点。

Sjögren’s syndrome (SS) is a chronic, autoimmune disorder affecting almost all organ systems, including the exocrine glands, nervous system, joints, lungs, and the gastrointestinal tract. It is widely accepted that SS pathogenesis is associated with excessive activation of innate immunity and type I interferon (IFN) production, but the precise mechanisms for initiating and sustaining these responses in SS remain unknown. Recent studies have established that DNA released from damaged or dysfunctional mitochondria can lead to type I IFN production through the activation of cytosolic DNA sensing pathways. The stimulator of interferon gene (STING) protein is a central component of these pathways. Our published study has established that systemic activation of the STING pathway induces SS-like disease in mice. Our preliminary studies show that the STING pathway is functional in salivary gland epithelial cells, and its activation induces a robust type I IFN response. The present proposal tests the overall hypothesis that mitochondrial DNA (mtDNA) mediated activation of the STING pathway in salivary gland cells influences the pathogenesis of SS. We will test this hypothesis in vitro using salivary gland cells cultured from mouse submandibular glands, and we will complement these studies in vivo, by developing novel mouse models for mitochondrial damage in salivary glands. In Aim 1, we will define pathways involved in mtDNA mediated activation of STING in salivary gland cells, and investigate whether STING activation induces senescence. In Aim 2, we will investigate the in vivo effects of mitochondrial damage and STING activation on salivary glands. For this purpose, we will generate salivary gland conditional mutant mice for the transcription factor A, mitochondrial (Tfam), and Manganese dependent Superoxide dismutase (Sod2). In the context of SS, mitochondrial damage and innate immunity activation within the salivary glands is an underexplored area. The findings from this proposal will facilitate research targeting the role of oxidative stress and aging, known causes of mitochondrial damage, in SS pathogenesis, and provide possible targets for therapeutic interventions.