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

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Sj?gren?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.
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