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

> **NIH NIH R21** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2020 · $262,200

## Abstract

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.

## Key facts

- **NIH application ID:** 10143574
- **Project number:** 1R21DE029707-01A1
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Umesh S Deshmukh
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $262,200
- **Award type:** 1
- **Project period:** 2020-09-17 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143574

## Citation

> US National Institutes of Health, RePORTER application 10143574, Cytosolic DNA sensing pathway in the pathogenesis of Sjogren's Syndrome (1R21DE029707-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10143574. Licensed CC0.

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