The role of cytosolic nucleotide sensors in inflammatory fibrosis

胞质核苷酸传感器在炎症纤维化中的作用

• 批准号: 10676311
• 负责人: KATALIN SUSZTAK
• 金额: $ 49.84万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676311
• 关键词: Autoimmune; B-Cell Activation; Binding; Cells; Cessation of life; Chemicals; Chronic; Chronic Kidney Failure; Clinical; Cultured Cells; Cyclic GMP; Cytosine; DNA; DNA Transposable Elements; Data; Dendritic Cells; Development; Disease; Endogenous Retroviruses; Endothelial Cells; Enhancers; Epithelial Cells; Epithelium; Extravasation; Fibrosis; Financial Hardship; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Genets; Histologic; Human; Human Genetics; IRF3 gene; In Vitro; Infection; Inflammation; Inflammatory; Injury; Injury to Kidney; Kidney; Kidney Diseases; Knowledge acquisition; Light; Lymphoid; Maps; Medicine; Methylation; Mitochondria; Mitochondrial DNA; Mus; Myelogenous; Myeloid Cells; NF-kappa B; Nuclear; Nucleotides; Pathogenesis; Pathway interactions; Patients; Pattern recognition receptor; Phosphotransferases; Play; Production; RNA; Radiation Injuries; Reaction; Renal tubule structure; Role; Sampling; Severity of illness; Signal Transduction; Stimulator of Interferon Genes; Stimulus; T-Lymphocyte; TBK1 gene; TLR3 gene; TREX1 gene; TRIM Gene; Wit; allergic response; cell type; chemokine; chronic infection; cytokine; defined contribution; genetic variant; genome wide association study; kidney cell; kidney fibrosis; mouse model; novel; pathogen; pharmacologic; receptor; receptor expression; sensor; therapeutic development; tissue injury; transcription factor

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.

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因素和机制。我们认为， 核苷酸（RNA和DNA）传感途径在CKD的炎性纤维化中起关键作用。胞质DNA和 与感染相关的双链修饰RNA被胞质模式识别快速识别 受体（cPRR），包括胞质RIG-I样受体（RLR）和环GMP-AMP合酶（cGAS）。 干扰素基因刺激因子（STING）。RLR和STING的激活，通常通过TBK 1（TANK结合） 激酶、NF κ B（活化B细胞的核因子κ-轻链增强子）和IRF 3/7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细胞扩增， 肾脏中的纤维炎性颗粒 在这个项目中，我们将探讨细胞质DNA和RNA传感器过度激活的原因， 炎症性纤维化系统地绘制细胞溶质DNA和RNA：A）TE和ERV的表达B）细胞溶质 CKD和纤维化患者和小鼠模型肾脏中的线粒体DNA及其与 胞质DNA和RNA传感器。我们将定义骨髓和上皮DNA（cGAS/STING）的贡献 和RNA（RIG-I，MDA 5）传感途径对小鼠模型中炎性纤维化的影响。我们将研究是否 在细胞溶质RNA和DNA传感途径相关基因（TREX 1、TRIM 6和 IRF 5）导致患者的肾脏疾病发展。