环状RNA分子在沙门氏菌介导肠道炎症反应的功能和分子机制

Salmonella infection is one of the leading causes of gastrointestinal diseases worldwide. Circular RNA is a new kind of RNA molecule that is different from traditional linear RNA. It is stable and hard to degrade. In recent years, studies have shown that there is a close relationship between circRNA and various human diseases. However, how circular RNA regulates the intestinal inflammatory response caused by pathogenic bacteria has not been reported. Our previous study have found that HCT116 cells with salmonella infection showed some differentially expressed circRNAs compared to that of control treatment. Through bioinformatics prediction and preliminary experimental results, we found that certain circRNAs may interact with miRNAs which have been reported to involve in inflammation. Based on this, we propose that some candidate circRNAs may participate in the regulation of Salmonella-induced host inflammatory responses through their miRNA sponge function or interaction with some proteins involved in host cell signaling. In the present application, we will use different cell lines, intestinal organs and animals as models to study the function and molecular mechanism of the circRNAs in regulating the inflammatory response caused by Salmonella infection. Since Salmonella infection is a risk factor for inflammatory bowel disease and colon cancer, we will analyze the expression of the target circRNAs in these patients in combination with clinical specimens. Our study will provide insights into mechanisms by which enteric bacteria regulate circRNA expression and potentially contribute to infection-associated diseases.

沙门氏菌感染是世界范围内胃肠道疾病的主要原因之一。环状RNA是区别于传统线性RNA的一类新型RNA分子，表达稳定，不易降解。最近的研究表明，环状 RNA 与人类多种疾病存在着密切联系，然而环状RNA如何调控病原细菌引起的肠道炎症反应的功能和机制未见报道。我们的前期研究发现，鼠伤寒沙门氏菌感染HCT116细胞后, 呈现差异表达的环状RNA分子, 通过生物信息学预测和初步实验结果发现某些环状RNA分子能与炎症反应相关的miRNAs和蛋白相互作用，调控宿主的炎症反应。根据以上的研究基础，本申请拟以细胞，肠道类器官和动物为模型，研究环状RNA分子在调控沙门氏菌感染引起宿主炎症反应的功能和分子机制。由于沙门氏菌感染是多种肠道疾病的风险因素，因此我们将结合临床标本分析目标环状RNA分子在炎症性肠病病人的表达情况，从而为预防和治疗沙门氏菌感染导致的肠道微生态失衡的肠道疾病提供研究基础，防治和治疗依据。

沙门氏菌感染是世界范围内胃肠道肠道疾病风险因素之一。环状RNA是区别于传统线性RNA的一类新型RNA分子，表达稳定，不易降解。最近的研究表明，环状 RNA 与人类多种疾病存在着密切联系，然而环状RNA如何调控病原细菌引起的肠道炎症反应的功能和机制未见报道。我们的研究结果全面揭示了鼠伤寒沙门氏菌感染肠道上皮HCT116细胞后, 呈现差异表达的环状RNA分子表达谱，发现了沙门氏菌通过调控几个候选的环状RNA分子参与炎症反应的作用。通过多种分子细胞生物学技术，我们揭示了候选的环状RNA分子Circhipk2通过调控APOBEC3G基因的表达影响沙门氏菌导致肠道炎症反应的分子机制；通过生物信息学分析和双荧光素酶报告系统等分子研究手段，揭示了Circhipk2通过海绵吸附作用影响miR-124-3p的表达从而参与结肠癌发展的作用和机制。由于沙门氏菌感染是炎症性肠病和结直肠癌的风险因素，因此我们的研究结果为进一步揭示肠道病原微生物如何和宿主互作影响肠道疾病的发生发展，提供了重要的理论基础。同时我们的研究成果也为预防和治疗沙门氏菌感染导致的肠道疾病提供了防治和治疗依据。