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

干燥综合征发病机制中的细胞质 DNA 传感途径

基本信息

批准号：
10265571
负责人：
Umesh S Deshmukh
金额：
$ 21.85万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-17 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265571
关键词：
Address Adult Adverse effects Affect Age Aging Area Autoimmune Diseases Binding Cannulations Cell Aging Cell Nucleus Cells Characteristics Chronic Clinical Complement Cultured Cells Cyclic GMP Cytosol DNA Data Development Diagnosis Disease Drug Targeting Enterobacteria phage P1 Cre recombinase Epithelial Cells Exocrine Glands Extravasation Fatigue Gastrointestinal tract structure Gene Activation Gene Expression Gene Proteins Genes Genetic Transcription Goals Golgi Apparatus IL6 gene IRF3 gene Immune Targeting Immune response In Vitro Inflammatory Inflammatory Response Innate Immune Response Interferon Type I Interferons Joints Knockout Mice Lead Link Literature LoxP-flanked allele Lung Manganese Mediating Mitochondria Mitochondrial DNA Modeling Monitor Mus Mutant Strains Mice NF-kappa B Natural Immunity Nervous system structure Nucleotides Oxidative Stress Pathogenesis Pathogenicity Pathway interactions Patients Play Process Production Protein-Serine-Threonine Kinases Proteins Publishing Research Role Salivary Salivary Glands Severity of illness Sjogren&apos s Syndrome Stimulator of Interferon Genes Submandibular gland Superoxide Dismutase TBK1 gene TNF gene Tamoxifen Targeted Research Testing Therapeutic Therapeutic Intervention Xerostomia adeno-associated viral vector base body system chemokine conditional knockout conditional mutant cytokine drug testing eye dryness factor A human old age (65+)in vivo lacrimal mitochondrial dysfunction mouse model novel protein expression response senescence sensor stressor targeted treatment transcription factor

项目摘要

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.

Sjögren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