The role of cytosolic nucleotide sensors in inflammatory fibrosis

据估计，在发达国家，纤维化占所有死亡人数的45%。炎性纤维化 是慢性肾脏疾病(CKD)的组织学表现。该领域尚未解决的关键问题是 纤维化中持续低度炎症的实际触发和机制。我们认为胞质 核苷酸(RNA和DNA)感觉通路在CKD的炎性纤维化中起关键作用。胞质DNA和 双链、修饰的RNA与感染相关通过细胞质模式识别快速识别 受体(CPRR)，包括胞浆RIG-I样受体(RLR)和环状GMP-AMP合成酶(CGAS)- 干扰素基因刺激物(STING)。激活RLR和STING，通常通过TBK1(坦克结合) KK、NFkB(活化B细胞核因子轻链增强子)和IRF3/7转录因子 会触发细胞因子、趋化因子的产生，激活树突状细胞，促进T细胞的扩张，创造 肾脏中的一种纤维炎性物质。 在这个项目中，我们将探索细胞内DNA和RNA传感器过度激活的原因 炎性纤维化。系统定位胞浆DNA和RNA：A)TES和ERV的表达B)胞浆 慢性肾脏病患者和小鼠肾脏线粒体DNA与肝纤维化的关系 胞质DNA和RNA传感器。我们将定义髓系细胞和上皮细胞DNA的贡献(cGAS/STING) 以及RNA(RIG-I，MDA5)在小鼠模型中对炎性纤维化的传感途径。我们将研究是否 胞质RNA和DNA传感途径相关基因(TREX1、TRIM6和 IRF5)有助于患者肾脏疾病的发展。

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.