發(fā)布時間：2018-06-07 09:14

  本文選題：大鼠 + 類風(fēng)濕性關(guān)節(jié)炎　； 參考：《揚(yáng)州大學(xué)》2017年碩士論文

【摘要】：類風(fēng)濕性關(guān)節(jié)炎(RA)是一種系統(tǒng)性的自身免疫性疾病,關(guān)節(jié)炎發(fā)病在家禽家畜中均有存在,尤其對雞、豬、牛的危害較為嚴(yán)重。該病雖然致死率不高,但其一旦發(fā)病便難以痊愈,導(dǎo)致畜禽行動不便,出現(xiàn)發(fā)育遲緩,經(jīng)濟(jì)價值降低甚至淘汰,由此給養(yǎng)殖場帶來嚴(yán)重?fù)p失。已有研究發(fā)現(xiàn)將白細(xì)胞介素1受體(IL-1R)基因轉(zhuǎn)染進(jìn)大鼠,抑制了白細(xì)胞介素β(IL-1β)的作用,大鼠RA癥狀可得到明顯改善。骨髓間充質(zhì)干細(xì)胞(BMSCs)生物學(xué)特性獨(dú)特并且參與多環(huán)節(jié)的免疫調(diào)節(jié),具有促進(jìn)損傷的修復(fù)的作用,因而被廣泛應(yīng)用于免疫性疾病的細(xì)胞治療。本實(shí)驗(yàn)利用Ⅱ型膠原蛋白誘導(dǎo)方法制備RA模型大鼠,初步探討RA發(fā)病的免疫機(jī)制。研究RA的發(fā)病與IL-1β表達(dá)量變化的關(guān)系,并用IL-1β小干擾RNA(SiRNA)體內(nèi)轉(zhuǎn)染結(jié)合BMSCs移植治療RA模型大鼠,研究BMSCs聯(lián)合基因治療對RA的治療效果。1關(guān)節(jié)炎大鼠模型的制備及部分機(jī)制的研究采用尾根部散點(diǎn)注射雞Ⅱ型膠原和完全復(fù)氏佐劑乳化液的方法制備類風(fēng)濕性關(guān)節(jié)炎大鼠模型,實(shí)驗(yàn)組分為CIA、AA和正常組,造模后以大鼠足趾腫脹、強(qiáng)迫游泳、DR-X線成像、臟器指數(shù)、關(guān)節(jié)病理切片等進(jìn)行檢測,篩選出成功RA大鼠模型。通過對成功大鼠模型的血清中IL-1β、脾臟組織Treg的特異性標(biāo)志物Foxp3及Treg細(xì)胞表面的TGF-β1以及凋亡相關(guān)分子PD-1的研究,探討調(diào)節(jié)性T細(xì)胞在RA發(fā)生發(fā)展中的意義。結(jié)果顯示,AA模型組和CIA模型組的大鼠體重增長速度下降,CIA模型鼠減緩更明顯,CIA造模組14天內(nèi)關(guān)節(jié)腫脹明顯,21天后大鼠左右關(guān)節(jié)腫脹達(dá)到病程的最高峰,30天后部分大鼠關(guān)節(jié)僵直、畸形、表面出現(xiàn)皮膚出現(xiàn)結(jié)節(jié)。CIA組和AA組大鼠脾臟、胸腺占體重指數(shù)極顯著高于正常對照組(p0.01);兩模型組大鼠強(qiáng)迫游泳不動時間從造模后1周、2周、3周、4周均極顯著高于正常組(p0.01),掙扎時間均極顯著低于正常對照組(p0.01);關(guān)節(jié)滑膜組織切片顯示,大鼠模型關(guān)節(jié)軟骨有明顯的糜爛或潰瘍,滑膜、關(guān)節(jié)軟骨及關(guān)節(jié)腔內(nèi)有重度的混合型炎性細(xì)胞浸潤,另外還可見有多核巨細(xì)胞即肉芽腫的形成。AA模型組和CIA模型組大鼠造模后2周血清中IL-1β含量極顯著高于正常對照組(18.49±1.70pg/mL、36.98±0.97pg/mLvs16.23±0.44pg/mL;p0.01),兩模型大鼠 PD-1、TGF-β1、Foxp3的相對表達(dá)量極顯著低于對照組(p0.01),同時CIA模型大鼠脾臟中PD-1、TGF-β1、Foxp3的表達(dá)量極顯著低于AA模型大鼠(p0.01)。提示采用尾根部散點(diǎn)注射雞Ⅱ型膠原和完全復(fù)氏佐劑乳化液成功建立RA大鼠模型,且模型大鼠血清內(nèi)IL-1β的表達(dá)量隨RA病程而上升。RA的發(fā)生可能與調(diào)節(jié)性T細(xì)胞數(shù)量的減少或者功能缺陷有關(guān)。2 IL-1β-siRNA干擾BMSCs中IL-1β表達(dá)的實(shí)驗(yàn)研究針對RA模型大鼠血清中IL-1β的含量顯著高于正常大鼠的實(shí)驗(yàn)結(jié)果,利用降低動物機(jī)體IL-1β分泌技術(shù),阻止炎癥反應(yīng)進(jìn)程,本實(shí)驗(yàn)利用LPS體外刺激BMSCs高表達(dá)IL-1β,模擬RA體內(nèi)炎癥反應(yīng),采用siRNA干擾技術(shù)體外干擾BMSCs表達(dá)IL-1β,通過ELISA法和Westernblot對IL-1β蛋白水平表達(dá)變化進(jìn)行檢測,Q-PCR對IL-1β基因水平的表達(dá)變化進(jìn)行檢測,篩選出最佳IL-1β SiRNA抑制基因。LPS刺激后,LPS-BMSCs組與BMSCs組細(xì)胞上清以和裂解物中的IL-1β量存在極顯著差異(p0.01),通過熒光強(qiáng)度篩選siRNA的最佳轉(zhuǎn)染條件為1OOnMsiRNA與0.5ul轉(zhuǎn)染試劑的組合;siRNA干擾后,BMSCs培養(yǎng)上清中LPS-BMSCs組的IL-1β表達(dá)量極顯著高于對照組(347.84±6.17pg/mL vs 119.38±2.92pg/mL;p0.01);LPS+SiRNA157、LPS+SiRNA238、LPS+SiRNA788 的表達(dá)量分別為 126.21±2.25pg/mL、52.66±1.72pg/mL、101.83±3.65 pg/mL均極顯著低于LPS-BMSCs組(p0.01)。三條siRNA序列均可沉默IL-1β的蛋白表達(dá),其中SiRNA238組的IL-1β表達(dá)極顯著低于對照組(P0.01)。LPS+BMSCs+siRNA157、LPS+BMSCs+siRNA238、LPS+BMSCs+siRNA788 的 mRNA 相對表達(dá)量極顯著低于 LPS+BMSCs(0.92±0.079、0.28±0.015、0.97±0.174vs2.74±0.15;p0.01),LPS+BMSCs+siRNA238同時也極顯著低于正常對照組(p0.01)。提示LPS刺激BMSCs后成功模擬了體內(nèi)炎性反應(yīng)促進(jìn)了 IL-β在胞內(nèi)外的過表達(dá),蛋白水平、基因水平檢測篩選出IL-1β最佳干擾siRNA238。3.IL-1β-siRNA聯(lián)合BMSCs對類風(fēng)濕關(guān)節(jié)炎模型大鼠的治療研究本實(shí)驗(yàn)通過IL-1β小干擾RNA體內(nèi)轉(zhuǎn)染結(jié)合BMSCs移植治療RA模型大鼠,以大鼠生長情況、足趾腫脹、強(qiáng)迫游泳、關(guān)節(jié)病理切片、血清中IL-1β的含量等進(jìn)行檢測,研究BMSCs聯(lián)合基因治療對RA的治療效果。對治療后老鼠脾臟組織Treg的特異性標(biāo)志物Foxp3及Treg細(xì)胞表面的TGF-β1以及凋亡相關(guān)分子PD-1進(jìn)行檢測,繼續(xù)探討調(diào)節(jié)性T細(xì)胞在RA發(fā)生發(fā)展中的意義。IL-1β SiRNA238治療組和IL-1βSiRNA238+BMSCs治療組大鼠的體重增長、足趾腫脹較PBS治療組都極顯著升高(p0.01),IL-1βSiRNA+BMSCs治療組升高更明顯。IL-1β SiRNA治療組和IL-1β SiRNA+BMSCs治療組大鼠強(qiáng)迫游泳不動時間在治療后1周、2周極顯著低于治療對照組(p0.01)。治療后1周、2周、3周IL-1β SiRNA238+BMSCs治療組大鼠掙扎時間都極顯著高于IL-1βSiRNA238治療組(p0.01)。治療后1周、2周IL-1β SiRNA治療組大鼠和IL-1β SiRNA+BMSCs治療組大鼠血清中IL-1β的濃度極顯著低于PBS治療對照組(p0.01),且治療后1周、2周IL-1β SiRNA238+BMSCs治療組大鼠血清中IL-1β的濃度都極顯著高于IL-1β SiRNA238治療組(p0.01)。IL-1β SiRNA238治療組PD-1、TGF-β1、Foxp3的相對表達(dá)量極顯著高于治療對照組(p0.01),IL-1βSiRNA+BMSCs治療組PD-1、TGF-β1、Foxp3的相對表達(dá)量極顯著高于治療對照組(p0.01),IL-1βSiRNA+BMSCs治療組大鼠脾臟中PD-1、TGF-β1、Foxp3的表達(dá)量極顯著高于IL-1β SiRNA治療組(p0.01)。本實(shí)驗(yàn)結(jié)果提示,BMSCs協(xié)同治療可以增強(qiáng)IL-1βSiRNA體內(nèi)轉(zhuǎn)染治療RA的效果,該實(shí)驗(yàn)為基因聯(lián)合細(xì)胞治療RA開辟了新思路。
[Abstract]:Rheumatoid arthritis (RA) is a systematic autoimmune disease. Arthritis is found in poultry and domestic animals, especially in chickens, pigs and cattle. Although the mortality rate is not high, it is difficult to recover once the disease is fatal, which leads to the slow development of livestock and poultry, the decrease of economic value and even elimination of economic value. It has caused serious loss to the farm. It has been found that the gene of interleukin 1 receptor (IL-1R) is transfected into rats and the effect of IL-1 beta (IL-1 beta) is inhibited. The symptoms of RA in rats can be significantly improved. The biological characteristics of bone marrow mesenchymal stem cells (BMSCs) are unique and participate in multiple link immunomodulating, which can promote the repair of injury. It is widely used in the cell therapy of immune diseases. In this experiment, RA model rats were prepared by using type II collagen induction method. The immune mechanism of RA was preliminarily discussed. The relationship between the pathogenesis of RA and the changes of IL-1 beta expression was studied, and the IL-1 beta small interference RNA (SiRNA) in vivo transfection and BMSCs transplantation were used to treat the rat model of RA. Study on the effect of BMSCs combined gene therapy on RA, the preparation and part of the mechanism of.1 arthritis rat model, the rat model of rheumatoid arthritis was prepared by injection of chicken type II collagen and complete compound's adjuvant emulsification in the tail root. The experimental group was divided into CIA, AA and normal group. After the model, the rat toe was swelled and forced to be forced. Swimming, DR- X ray imaging, Viscera index, joint pathological section were detected, and a successful RA rat model was screened. Through the study of IL-1 beta in the serum of successful rat model, the specific marker of Treg in the spleen tissue, TGF- beta 1 on the surface of Treg cell and apoptosis related molecule PD-1, the development of regulatory T cells in the development of RA was discussed. The results showed that the weight growth rate of rats in the AA model group and the CIA model group decreased, the CIA model rat slowed down more obviously, the joint swelling in the CIA model group was obvious within 14 days, and the swelling of the left and right joints reached the peak in the course of the disease in 21 days. After 30 days, the joints of the rats were stiff and deformed, and the surface of the skin appeared in the.CIA group and the AA group of the spleen of the.CIA group. The body mass index of the thymus was significantly higher than that of the normal control group (P0.01), and the time of forced swimming in the two model group was significantly higher than that of the normal group (P0.01) at 1 weeks, 2 weeks, 3 weeks, and 4 weeks, and the struggle time was significantly lower than that of the normal control group (P0.01). There was a severe mixed inflammatory cell infiltration in the synovial membrane, articular cartilage and articular cavity, and the content of IL-1 beta in the serum of the.AA model group and the CIA model group was significantly higher than that of the normal control group (18.49 + 1.70pg/mL, 36.98 + 0.97pg/mLvs16.23 + 0.44pg/mL; P0.01), two in the 2 weeks. The relative expression of PD-1, TGF- beta 1 and Foxp3 in the model rats was significantly lower than that in the control group (P0.01), and the expression of PD-1, TGF- beta 1, Foxp3 in the CIA model rats was significantly lower than that of the AA model rats (P0.01). The expression of IL-1 beta in serum increases with the course of RA disease and the occurrence of.RA may be associated with the decrease in the number of regulatory T cells or functional defects related to the interference of.2 IL-1 beta -siRNA in BMSCs IL-1 beta expression in BMSCs, the content of IL-1 beta in serum of RA model rats is significantly higher than that of normal rats, and the secretion of IL-1 beta secretion in animal body is reduced. Technology, to prevent the process of inflammatory reaction, this experiment uses LPS to stimulate BMSCs high expression of IL-1 beta in vitro, to simulate the inflammatory reaction in RA, and to use siRNA interference technique to interfere with BMSCs to express IL-1 beta in vitro, to detect the expression of IL-1 beta protein by ELISA and Westernblot, and to detect the expression changes of the IL-1 beta gene level, screening and screening the expression of the IL-1 beta gene. After the best IL-1 beta SiRNA inhibitory gene.LPS stimulation, there was a very significant difference between the cell supernatant of the LPS-BMSCs group and the BMSCs group and the IL-1 beta in the lysate (P0.01). The optimum transfection condition of siRNA by fluorescence intensity was the combination of 1OOnMsiRNA and 0.5ul transfection reagents; siRNA interference, the expression of the beta expression in the BMSCs culture supernatant It was significantly higher than the control group (347.84 + 6.17pg/mL vs 119.38 + 2.92pg/mL; P0.01); LPS+SiRNA157, LPS+SiRNA238, LPS+SiRNA788, respectively, were 126.21 + 2.25pg/mL, 52.66 + 1.72pg/mL, and 101.83 + 3.65 pg/mL were significantly lower than LPS-BMSCs group (P0.01). The expression of beta was significantly lower than that of the control group (P0.01).LPS+BMSCs+siRNA157, and the relative expression of mRNA in LPS+BMSCs+siRNA238 and LPS+BMSCs+siRNA788 was significantly lower than that of LPS+BMSCs (0.92 + 0.079,0.28 + 0.015,0.97 + 0.174vs2.74 + 0.15; P0.01), and LPS+BMSCs+siRNA238 was also significantly lower than that of the normal control group (P0.01). The inflammatory response in vivo promotes the over expression of IL- beta in and out of the cell, protein level, and gene level detection and screening of the best interference of IL-1 beta siRNA238.3.IL-1 beta -siRNA combined with BMSCs in the treatment of rheumatoid arthritis rats. The experiment is carried out by IL-1 beta small interference RNA transfection in vivo and BMSCs transplantation for the treatment of RA model rats, and the rat is born in rats. Long condition, toes swollen, forced swimming, joint pathological section and the content of IL-1 beta in serum were detected, and the therapeutic effect of BMSCs combined gene therapy on RA was studied. The specific markers of Treg in the spleen tissue of mice after treatment, TGF- beta 1 and Treg cell PD-1 were detected, and the regulatory T continued to be explored. The significance of cells in the development of RA in the.IL-1 beta SiRNA238 treatment group and the IL-1 beta SiRNA238+BMSCs group was significantly higher than that of the PBS group (P0.01). The increase of the IL-1 beta SiRNA+BMSCs treatment group was more obvious in the.IL-1 beta SiRNA treatment group and the IL-1 beta group. After 1 weeks, 2 weeks was significantly lower than the treatment control group (P0.01). The struggle time of the rats in the IL-1 beta SiRNA238+BMSCs treatment group after 1 weeks, 2 weeks and 3 weeks was significantly higher than the IL-1 beta SiRNA238 treatment group (P0.01). The concentration of IL-1 beta in the serum of the IL-1 beta SiRNA treatment group and the IL-1 beta SiRNA+BMSCs treatment group of the IL-1 beta SiRNA treatment group was significantly lower than that of the PBS treatment for the 1 weeks after treatment. In the control group (P0.01), and 1 weeks after treatment, the concentration of IL-1 beta in the serum of IL-1 beta SiRNA238+BMSCs group was significantly higher than that of the IL-1 beta SiRNA238 treatment group (P0.01).IL-1 beta SiRNA238 treatment group PD-1, TGF- beta 1, and the relative expression of Foxp3 was significantly higher than that of the treatment control group. The expression level was significantly higher than that in the treatment control group (P0.01). The expression of PD-1, TGF- beta 1, Foxp3 in the IL-1 beta SiRNA+BMSCs group was significantly higher than that in the IL-1 beta SiRNA treatment group (P0.01). The results of this experiment suggest that the synergistic therapy of BMSCs can enhance the effect of IL-1 beta transfection in vivo. This experiment opens up a combination of gene combined cell therapy. A new way of thinking.
【學(xué)位授予單位】：揚(yáng)州大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R593.22

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10 樊國新;樊愛軍;張艷華;程進(jìn)維;楊德山;陳健;李寶霞;;類風(fēng)濕性關(guān)節(jié)炎的綜合治療與研究[A];第四屆全國中西醫(yī)結(jié)合風(fēng)濕類疾病學(xué)術(shù)會議論文匯編[C];2000年

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