蛋白酶体激活因子REGγ在实验性肠炎及炎症相关的结肠癌中的作用与机制

发布时间：2018-06-15 14:54

本文选题：实验性肠炎 + 炎症相关的结肠癌　；参考：《华东师范大学》2016年博士论文

【摘要】：炎性肠病病程延绵反复,尚无根治方法并且发生率逐年上升,这严重影响患者生活质量,耗费大量医疗资源,阻碍社会经济发展。因此,亟需对其病因和发病机制进行深入研究。REGγ是蛋白酶体激活因子的成员之一,它能够与20S蛋白酶体结合促进一系列蛋白以泛素和能量(ATP)非依赖的方式降解。在研究葡聚糖硫酸钠(DSS)诱导的实验性肠炎小鼠模型中,我们发现REGγ缺陷型小鼠较野生型小鼠而言病情明显缓和。另外,骨髓移植实验暗示REGγ主要是在非造血细胞中发挥作用,影响肠炎的发生发展。一系列的分子生物学实验证明在肠炎组织上皮细胞里REGγ和NFκB信号通路形成一个互相正调控的环路。REGy能够通过非泛素和非ATP依赖的方式降解IκBε (NFκB信号通路中一个重要的负调控因子)增强NFκB信号通路的活性。而REGy作为NFκB信号下游的一个靶基因,它的表达在转录水平受NFκB的直接调节。营救实验(Rescue assay)的结果显示REGγ/IκBs双敲小鼠能够基本重现野生型小鼠的肠炎表型,这些证据表明REGγ可以通过特异性调控IκBε来影响肠炎。在进一步研究AOM/DSS诱导炎症相关的结肠癌模型时我们发现,REGy敲除之后结肠肿瘤的数目显著下降,肿瘤的直径也显著变小,而REGy/IκBε双敲小鼠的结肠癌表型与野生型小鼠的表型相似,这些结果证明IκBε在REGγ缺陷小鼠抵制炎症相关的结肠癌的发生中也发挥着重要作用。通过生物信息学以及免疫组织化学染色分析我们发现,REGγ的表达与人类溃疡性结肠炎存在正相关性,REGγ与IκBε的表达在溃疡性结肠炎组织中存在负相关性。总的来说,我们的研究结果阐明了REGγ对IκBε的负调控机制,为研究NFκB信号通路和炎性肠病以及炎症相关的结肠癌的发生发展提供了一个新的分子机制,为防御和治疗相关疾病提供了一个潜在的药物靶点。
[Abstract]:The course of inflammatory bowel disease is repeated, there is no radical cure and the incidence rate is rising year by year, which seriously affects the quality of life of patients, consumes a lot of medical resources and hinders the development of social economy. Therefore, it is urgent to study the etiology and pathogenesis of proteasome activator. REG 纬 is a member of proteasome activator, which can bind with 20s proteasome to promote the degradation of a series of proteins in ubiquitin and energy-dependent manner. In order to study the experimental enteritis mice induced by dextran sodium sulfate (DSS), we found that the REG 纬 deficient mice were more relaxed than the wild-type mice. In addition, bone marrow transplantation experiments suggested that REG 纬 mainly played a role in non-hematopoietic cells and affected the occurrence and development of enteritis. A series of molecular biological experiments have shown that REG 纬 and NF 魏 B signaling pathway form a positive regulation loop. REGy can degrade I 魏 B 蔚 -NF 魏 B signal pathway in a non-ubiquitin and ATP-dependent manner. The desired negative regulatory factor) enhances the activity of NF-魏 B signaling pathway. As a target gene downstream of NF 魏 B signal, the expression of REGy is directly regulated by NF 魏 B at the transcriptional level. Rescue assay showed that REG 纬 / I 魏 Bs double knockout mice could basically reproduce the enteritis phenotype of wild type mice, which suggested that REG 纬 could affect enteritis by regulating I 魏 B 蔚 specifically. In the further study of the inflammatory related colon cancer model induced by AOM / DSS, we found that the number of colon tumors and the diameter of tumor decreased significantly after REGy knockout, while the phenotype of REGyR / I 魏 B 蔚 double knockout mice was similar to that of wild type mice. These results suggest that I 魏 B 蔚 also plays an important role in the development of anti-inflammatory colon cancer in REG 纬 deficient mice. By bioinformatics and immunohistochemical staining, we found that there is a positive correlation between the expression of REG 纬 and the expression of I 魏 B 蔚 in human ulcerative colitis. There is a negative correlation between the expression of REG 纬 and I 魏 B 蔚 in ulcerative colitis. In general, our results illustrate the negative regulation mechanism of REG 纬 on I 魏 B 蔚, and provide a new molecular mechanism for the study of NF 魏 B signaling pathway and inflammatory bowel disease, as well as the pathogenesis and development of inflammatory colon cancer. It provides a potential drug target for the defense and treatment of related diseases.
【学位授予单位】：华东师范大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R574;R735.35

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