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

基本信息

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
项目类别：
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

项目摘要

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，纤维化占发达国家所有死亡人数的45％。炎症纤维化是慢性肾脏疾病（CKD）的组织学表现。该领域的关键尚未解决的问题是纤维化中持续的低级注射的实际触发器和机制。我们提出了胞质核苷酸（RNA和DNA）感应途径在CKD中的炎症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，通过胞质模式识别迅速识别受体（CPRR），包括胞质RIG-I样受体（RLR）和环状GMP-AMP合酶（CGAS） - 干扰素基因的刺激剂（STING）。 RLR和Sting的激活通常通过TBK1（储罐结合）激酶，NFKB（活化B细胞的核因子Kappa-Light-light-right-chain-Emhancer）和IRF3/7转录因子将触发生产细胞因子，趋化因子，激活树突细胞并促进T细胞膨胀，从而产生肾脏中的纤维炎症米尔。在这个项目中；我们将探讨胞质DNA和RNA传感器过量激活的原因炎症纤维化。系统地绘制胞质DNA和RNA：a）TE和ERV的表达b）胞质 CKD和纤维化的患者和小鼠模型的儿童的线粒体DNA及其与他们与胞质DNA和RNA传感器。我们将定义髓样和上皮的DNA（CGA/STING）的贡献和RNA（RIG-I，MDA5）在小鼠模型中炎症性纤维化的敏感性途径。我们将检查是否在胞质RNA和DNA传感途径相关基因中观察到的遗传变异体（TREX1，TRIM6和 IRF5）有助于患者的肾脏疾病发展。