PDF(Pubmed)
Abstract：
The glucocorticoid receptor (GR) and ten-eleven translocation 2 (TET2), respectively, play a crucial role in regulating immunity and inflammation, and GR interacts with TET2. However, their synergetic roles in inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn\'s disease (CD), remain unclear. This study aimed to investigate the co-target gene signatures of GR and TET2 in IBD and provide potential therapeutic interventions for IBD. By integrating public data, we identified 179 GR- and TET2-targeted differentially expressed genes (DEGs) in CD and 401 in UC. These genes were found to be closely associated with immunometabolism, inflammatory responses, and cell stress pathways. In vitro inflammatory cellular models were constructed using LPS-treated HT29 and HCT116 cells, respectively. Drug repositioning based on the co-target gene signatures of GR and TET2 derived from transcriptomic data of UC, CD, and the in vitro model was performed using the Connectivity Map (CMap). BMS-536924 emerged as a top therapeutic candidate, and its validation experiment within the in vitro inflammatory model confirmed its efficacy in mitigating the LPS-induced inflammatory response. This study sheds light on the pathogenesis of IBD from a new perspective and may accelerate the development of novel therapeutic agents for inflammatory diseases including IBD.
摘要：
糖皮质激素受体（GR）和十11易位2（TET2），分别,在调节免疫和炎症中起着至关重要的作用，和GR与TET2相互作用。然而,它们在炎症性肠病（IBD）中的协同作用，包括溃疡性结肠炎（UC）和克罗恩病（CD），仍然不清楚。本研究旨在研究IBD中GR和TET2的共同靶基因特征，并为IBD提供潜在的治疗干预措施。通过整合公共数据，我们在CD中鉴定了179个GR和TET2靶向差异表达基因(DEGs),在UC中鉴定了401个。发现这些基因与免疫代谢密切相关，炎症反应，和细胞应激途径。使用LPS处理的HT29和HCT116细胞构建体外炎症细胞模型，分别。基于来自UC转录组数据的GR和TET2的共同靶基因特征的药物重新定位，CD,并使用连接性图(CMap)进行体外模型。BMS-536924成为顶级治疗候选药物，其在体外炎症模型中的验证实验证实了其在减轻LPS诱导的炎症反应中的功效。这项研究从一个新的角度揭示了IBD的发病机制，并可能加速开发包括IBD在内的炎症性疾病的新型治疗剂。
