RSKs对炎症性肠病CD4+T细胞的免疫调控和机制研究

炎症性肠病（IBD）是一类慢性、复发性的肠道非特异炎症性疾病，CD4+T细胞介导的免疫应答异常激活是其发病的关键因素。90kDa核糖体S6激酶（RSKs）是一类位于Ras-MAPK级联反应下游的丝氨酸/苏氨酸激酶，主要通过磷酸化下游底物参与细胞增殖、存活等生理过程，在肿瘤等疾病的发生发展中起了重要作用。我们前期研究发现，RSKs抑制剂能显著抑制IBD患者外周血CD4+T细胞增殖和向Th1/Th17细胞分化，提示RSKs可能通过调控CD4+T细胞的增殖分化参与IBD患者肠黏膜炎症的发生。因此，本课题拟运用qRT-PCR、WB、流式细胞术等细胞分子生物学技术，分析RSKs在IBD患者中的表达与激活情况，探索其对IBD患者CD4+T细胞的免疫调节作用并阐明其潜在的机制；通过构建结肠炎动物模型并进行药物干预，明确RSKs抑制剂对小鼠结肠炎的治疗作用，以期为IBD患者提供新的免疫治疗靶点。

Inflammatory bowel diseases (IBD), comprised of Crohn’s disease (CD) and ulcerative colitis (UC), are chronic and remittent-relapsing inflammatory diseases affecting all or part of the gastrointestinal tract. Aberrant intestinal mucosal immune responses mediated by CD4+ T cells are considered to be the crucial factor in the pathogenesis of IBD. 90-kDa ribosomal S6 kinases (RSKs) are a group of highly conserved Ser/Thr protein kinases that act as downstream effectors of the Ras-MAPK signaling pathway. RSKs have been found to be involved in numerous cellular processes, such as cell proliferation and survival, through phosphorylation of a range of substrates, thus participating in the development of tumors and immune diseases. However, the exact role of RSKs in regulating mucosal immune responses of IBD is still unclear. In our preliminary experiments, we found that RSK inhibitor could significantly inhibit IBD CD4+ T cell proliferation and differentiation into Th1/Th17 cells, indicating that RSKs may be involved in the CD4+ T cell-mediated intestinal mucosal immune responses in the development of IBD. In this study，we will analyze the expression and activation of RSKs in IBD patients, and explore the potential role of RSKs in regulating CD4+ T cell immune responses of IBD. Furthermore, experimental colitis models in mice will be established to explore whether RSK inhibitor can alleviate intestinal mucosal inflammation. In summary, this work will clarify the potential role of RSKs in the pathogenesis of IBD, and may provide a novel therapeutic target for IBD treatment.