Raf激酶抑制蛋白RKIP在炎症性肠炎中的调控作用及分子机制

发布时间：2018-04-25 14:09

本文选题：炎症反应 + 肠炎　；参考：《浙江大学》2016年博士论文

【摘要】：炎症性肠炎是一类高发于人类的自身免疫性疾病,根据病理表征和发病部位不同,分为溃疡性结肠炎(ulcerative colitis,UC)和克罗恩病(Crohn's disease, CD)。多种复杂因素影响了炎症性肠炎的发生和发展。深入研究炎症性肠炎的调控机制,将为临床治疗提供新的思路和理论基础。Raf激酶抑制蛋白(Raf kinase inhibitor protein, RKIP)是调控肿瘤细胞转移,侵袭和凋亡的重要分子,并已成为肿瘤学诊断的重要分子靶标。在本研究中,我们发现RKIP在人和小鼠的炎症性肠炎的肠上皮细胞(intestinal epithelial cells,IECs)中高表达,并且RKIP表达量与炎症性肠炎的发病严重程度呈正相关。在小鼠体内敲除RKIP,导致小鼠对葡聚糖硫酸钠(dextran sulfate sodium,DSS)或2,4,6-三硝基苯磺酸(2,4,6-trinitrobenzenesulfonic acid,TNBS)敏感性降低,炎症性肠炎的发病强度明显低于野生型小鼠。RKIP缺失抑制了DSS或TNBS诱导的小鼠肠上皮细胞的凋亡,维持了肠粘膜的完整性。进一步研究发现RKIP促进TGF-β-activated kinase1(TAK1)寡聚化和自身磷酸化,进而活化NF-κB信号通路,上调P53-upregulated modulator of apoptosis (PUMA)表达,增强肠上皮细胞凋亡,最终促进肠炎症的发生和发展。本研究结果首次揭示了RKIP参与人类和小鼠炎症性肠炎的调控,为深入了解炎症性肠炎调控的分子机制提供了新的思路。RKIP的表达量与炎症性肠炎患者病程具有正向关系,提示RKIP可能作为炎症性肠炎病情的诊断依据和治疗靶点。
[Abstract]:Inflammatory enteritis is a kind of autoimmune disease with high incidence in human beings. According to the pathological features and the location of the disease, it is divided into ulcerative colitis (UCC) and Crohnen disease (CDT). A variety of complex factors affect the occurrence and development of inflammatory enteritis. Further study on the regulatory mechanism of inflammatory enteritis will provide a new idea and theoretical basis for clinical treatment. Raf kinase inhibitor protein (RKIPP) is an important molecule regulating metastasis, invasion and apoptosis of tumor cells. It has become an important molecular target for oncology diagnosis. In this study, we found that RKIP was highly expressed in intestinal epithelial cells (IECs) of human and mouse inflammatory enteritis, and the expression of RKIP was positively correlated with the severity of inflammatory enteritis. Knockout of RKIPin in vivo resulted in a decrease in the sensitivity of mice to dextran sulfate sodiumn (DSSs) or to 2DSSs, or to 2DSSs, or to 2 trinitrobenzenesulfonic acid trinitrobenzenesulfonic acid trinitrobenzenesulfonic trinitrobenzenesonic trinitrobenzene sulfonate (TNBSs). The intensity of inflammatory enteritis was significantly lower than that of wild-type mice. RKIP deletion inhibited the apoptosis of intestinal epithelial cells induced by DSS or TNBS and maintained the integrity of intestinal mucosa. Furthermore, it was found that RKIP promoted TGF- 尾 -activated kinase1 (TAK1) oligomerization and autophosphorylation, then activated NF- 魏 B signaling pathway, up-regulated the expression of P53-upregulated modulator of apoptosis, enhanced the apoptosis of intestinal epithelial cells, and promoted the occurrence and development of intestinal inflammation. The results of this study reveal for the first time that RKIP is involved in the regulation of inflammatory enteritis in human and mice, which provides a new idea for further understanding the molecular mechanism of the regulation of inflammatory enteritis. The expression of RKIP has a positive relationship with the course of inflammatory enteritis. The results suggest that RKIP may be the diagnostic basis and therapeutic target of inflammatory enteritis.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R574

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