The role of cytosolic nucleotide sensors in inflammatory fibrosis

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It is estimated that fibrosis contributes to 45 percent of all deaths in the developed world. Inflammatory fibrosis is the histological manifestation of chronic kidney disease (CKD). The critical unresolved question in the field is the actual trigger and mechanism for the persistent low-grade inflammation in fibrosis. We propose that cytosolic nucleotide (RNA and DNA) sensing pathways plays key role in inflammatory fibrosis in CKD. Cytosolic DNA and double stranded, modified RNA is associated with infections is rapidly recognized by cytosolic pattern recognition receptors (cPRR) including the cytosolic RIG-I-like receptors (RLR), and the cyclic GMP-AMP synthase (cGAS)– stimulator of interferon genes (STING). Activation of RLR and STING, usually via the TBK1 (TANK-binding) kinase, NFkB (nuclear factor kappa-light-chain-enhancer of activated B cells) and IRF3/7 transcription factors will trigger the production cytokines, chemokines, activate dendritic cells, and promote T cell expansion, creating a fibroinflammatory milleu in the kidney. In this project; We will explore the cause of excessive activation of cytosolic DNA and RNA sensors in inflammatory fibrosis. Systematically map cytosolic DNA and RNA: A) expression of TEs and ERVs B) cytosolic mitochondrial DNA in kidneys of patients and mouse models of CKD and fibrosis and their correlation with cytosolic DNA and RNA sensors. We will define the contribution of myeloid and epithelial, DNA (cGAS/STING) and RNA (RIG-I, MDA5) sensing pathways to inflammatory fibrosis in mouse models. We will examine whether genetic variants observed in cytosolic RNA and DNA sensing pathway associated genes (TREX1, TRIM6 and IRF5) contribute to kidney disease development in patients.