本文選題：炎癥反應(yīng) + 腸炎　； 參考：《浙江大學(xué)》2016年博士論文

【摘要】：炎癥性腸炎是一類高發(fā)于人類的自身免疫性疾病,根據(jù)病理表征和發(fā)病部位不同,分為潰瘍性結(jié)腸炎(ulcerative colitis,UC)和克羅恩病(Crohn's disease, CD)。多種復(fù)雜因素影響了炎癥性腸炎的發(fā)生和發(fā)展。深入研究炎癥性腸炎的調(diào)控機(jī)制,將為臨床治療提供新的思路和理論基礎(chǔ)。Raf激酶抑制蛋白(Raf kinase inhibitor protein, RKIP)是調(diào)控腫瘤細(xì)胞轉(zhuǎn)移,侵襲和凋亡的重要分子,并已成為腫瘤學(xué)診斷的重要分子靶標(biāo)。在本研究中,我們發(fā)現(xiàn)RKIP在人和小鼠的炎癥性腸炎的腸上皮細(xì)胞(intestinal epithelial cells,IECs)中高表達(dá),并且RKIP表達(dá)量與炎癥性腸炎的發(fā)病嚴(yán)重程度呈正相關(guān)。在小鼠體內(nèi)敲除RKIP,導(dǎo)致小鼠對(duì)葡聚糖硫酸鈉(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,炎癥性腸炎的發(fā)病強(qiáng)度明顯低于野生型小鼠。RKIP缺失抑制了DSS或TNBS誘導(dǎo)的小鼠腸上皮細(xì)胞的凋亡,維持了腸粘膜的完整性。進(jìn)一步研究發(fā)現(xiàn)RKIP促進(jìn)TGF-β-activated kinase1(TAK1)寡聚化和自身磷酸化,進(jìn)而活化NF-κB信號(hào)通路,上調(diào)P53-upregulated modulator of apoptosis (PUMA)表達(dá),增強(qiáng)腸上皮細(xì)胞凋亡,最終促進(jìn)腸炎癥的發(fā)生和發(fā)展。本研究結(jié)果首次揭示了RKIP參與人類和小鼠炎癥性腸炎的調(diào)控,為深入了解炎癥性腸炎調(diào)控的分子機(jī)制提供了新的思路。RKIP的表達(dá)量與炎癥性腸炎患者病程具有正向關(guān)系,提示RKIP可能作為炎癥性腸炎病情的診斷依據(jù)和治療靶點(diǎn)。
[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.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R574

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