本文選題：實驗性腸炎 + 炎癥相關(guān)的結(jié)腸癌　； 參考：《華東師范大學》2016年博士論文

【摘要】：炎性腸病病程延綿反復,尚無根治方法并且發(fā)生率逐年上升,這嚴重影響患者生活質(zhì)量,耗費大量醫(yī)療資源,阻礙社會經(jīng)濟發(fā)展。因此,亟需對其病因和發(fā)病機制進行深入研究。REGγ是蛋白酶體激活因子的成員之一,它能夠與20S蛋白酶體結(jié)合促進一系列蛋白以泛素和能量(ATP)非依賴的方式降解。在研究葡聚糖硫酸鈉(DSS)誘導的實驗性腸炎小鼠模型中,我們發(fā)現(xiàn)REGγ缺陷型小鼠較野生型小鼠而言病情明顯緩和。另外,骨髓移植實驗暗示REGγ主要是在非造血細胞中發(fā)揮作用,影響腸炎的發(fā)生發(fā)展。一系列的分子生物學實驗證明在腸炎組織上皮細胞里REGγ和NFκB信號通路形成一個互相正調(diào)控的環(huán)路。REGy能夠通過非泛素和非ATP依賴的方式降解IκBε (NFκB信號通路中一個重要的負調(diào)控因子)增強NFκB信號通路的活性。而REGy作為NFκB信號下游的一個靶基因,它的表達在轉(zhuǎn)錄水平受NFκB的直接調(diào)節(jié)。營救實驗(Rescue assay)的結(jié)果顯示REGγ/IκBs雙敲小鼠能夠基本重現(xiàn)野生型小鼠的腸炎表型,這些證據(jù)表明REGγ可以通過特異性調(diào)控IκBε來影響腸炎。在進一步研究AOM/DSS誘導炎癥相關(guān)的結(jié)腸癌模型時我們發(fā)現(xiàn),REGy敲除之后結(jié)腸腫瘤的數(shù)目顯著下降,腫瘤的直徑也顯著變小,而REGy/IκBε雙敲小鼠的結(jié)腸癌表型與野生型小鼠的表型相似,這些結(jié)果證明IκBε在REGγ缺陷小鼠抵制炎癥相關(guān)的結(jié)腸癌的發(fā)生中也發(fā)揮著重要作用。通過生物信息學以及免疫組織化學染色分析我們發(fā)現(xiàn),REGγ的表達與人類潰瘍性結(jié)腸炎存在正相關(guān)性,REGγ與IκBε的表達在潰瘍性結(jié)腸炎組織中存在負相關(guān)性�？偟膩碚f,我們的研究結(jié)果闡明了REGγ對IκBε的負調(diào)控機制,為研究NFκB信號通路和炎性腸病以及炎癥相關(guān)的結(jié)腸癌的發(fā)生發(fā)展提供了一個新的分子機制,為防御和治療相關(guān)疾病提供了一個潛在的藥物靶點。
[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 緯 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 緯 deficient mice were more relaxed than the wild-type mice. In addition, bone marrow transplantation experiments suggested that REG 緯 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 緯 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 緯 / I 魏 Bs double knockout mice could basically reproduce the enteritis phenotype of wild type mice, which suggested that REG 緯 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 緯 deficient mice. By bioinformatics and immunohistochemical staining, we found that there is a positive correlation between the expression of REG 緯 and the expression of I 魏 B 蔚 in human ulcerative colitis. There is a negative correlation between the expression of REG 緯 and I 魏 B 蔚 in ulcerative colitis. In general, our results illustrate the negative regulation mechanism of REG 緯 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.
【學位授予單位】：華東師范大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R574;R735.35

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