本文選題：甘草酸 + 肺間質(zhì)纖維化　； 參考：《大連醫(yī)科大學(xué)》2016年博士論文

【摘要】：肺間質(zhì)纖維化(Pulmonary fibrosis)是一種慢性疾病,病程逐漸發(fā)展、不可逆轉(zhuǎn),是間質(zhì)性肺疾病的終末期,據(jù)統(tǒng)計(jì)其平均生存期短,不足5年。肺間質(zhì)纖維化的患者呼吸困難明顯,生活難以自理,且花費(fèi)大,給社會(huì)、家庭、及個(gè)人帶來沉重的精神及經(jīng)濟(jì)負(fù)擔(dān)。因此延緩肺間質(zhì)纖維化進(jìn)展、降低死亡率是我國(guó)肺病防治所面臨的巨大挑戰(zhàn)和重大需求。雖然導(dǎo)致肺間質(zhì)纖維化的病因不甚清楚,但肺間質(zhì)纖維化的病理表現(xiàn)與信號(hào)通路主要表現(xiàn)為:肺間質(zhì)中大量炎癥細(xì)胞浸潤(rùn),肌成纖維細(xì)胞顯著增多從而產(chǎn)生過多的細(xì)胞外基質(zhì)積聚,最終出現(xiàn)纖維化的病理改變。目前尚無有效手段阻止其進(jìn)展。因此,闡明肺間質(zhì)纖維化發(fā)生、發(fā)展機(jī)制,尋找有效的新的干預(yù)治療策略,對(duì)阻止疾病發(fā)展、降低死亡率有著重大的意義。但是,目前我們尚不十分明確有關(guān)肺間纖維化這一疾病的發(fā)病機(jī)制。肺間質(zhì)纖維化疾病病程中關(guān)鍵的病理改變包括肌成纖維細(xì)胞大量、異常增多。目前針對(duì)肌成纖維細(xì)胞的來源的研究較多,說法不一,爭(zhēng)議較大。其研究結(jié)果顯示多數(shù)觀點(diǎn)傾向主要來源為肺泡上皮細(xì)胞,即EMT(epithelial to mesenchymaltransition)。肺泡上皮細(xì)胞活化后的一個(gè)重要效應(yīng)是:轉(zhuǎn)化為肌成纖維細(xì)胞,促進(jìn)細(xì)胞外基質(zhì)合成,同時(shí)活化多種參與固有免疫、炎癥的基因等,促進(jìn)炎癥、氧化應(yīng)激損傷,從而加重肺間質(zhì)纖維化進(jìn)展。由此推測(cè):肺泡上皮細(xì)胞轉(zhuǎn)分化(EMT)是肺間質(zhì)中肌成纖維細(xì)胞的主要來源。深入研究EMT的機(jī)制及其活化后導(dǎo)致的重要分子生物學(xué)效應(yīng),是尋求干預(yù)靶點(diǎn)的重要防治策略。綜上所述,肺間質(zhì)纖維化是一種難治、復(fù)雜的疾病。目前傳統(tǒng)激素及單通路受體阻滯劑(如吉非替尼)可能獲得部分療效,但不能阻止肺間質(zhì)纖維化的進(jìn)展。近年來有關(guān)我國(guó)中草藥方劑及其單體活性成分在疾病治療中的研究越來越多,其在肺間質(zhì)纖維化的治療中的作用也越來越引起大家的重視。本課題組前期實(shí)驗(yàn)證實(shí)活血化瘀方劑(黃芪、川芎、丹參、當(dāng)歸、紅景天、浙貝母、甘草)對(duì)肺間質(zhì)纖維化有治療作用。其中甘草酸(Glycyrrhizic acid,GA)作為甘草中最主要的活性成分,大量研究表明甘草酸對(duì)臟器纖維化(如肝臟)有顯著的治療作用。但甘草酸對(duì)肺間質(zhì)纖維化是否有改善作用我們尚不清楚。因此我們提出以下科學(xué)問題:多種炎癥、多條信號(hào)通路的過度激活是肺間質(zhì)纖維化的重要基礎(chǔ),EMT又是導(dǎo)致肺間質(zhì)纖維化的重要途徑,是什么調(diào)控了這些炎癥因子和信號(hào)通路活性?甘草酸是否能夠找到控制它們活性的共同靶點(diǎn)?近年,糖蛋白組學(xué)的飛速發(fā)展為我們解答以上問題提供了新的研究方向。核心巖藻糖基化(core fucosylation,CF)是一種重要的蛋白質(zhì)糖修飾,是由α-1,6巖藻糖轉(zhuǎn)移酶(Fucosyltransferase8,FUT8)特異性地催化轉(zhuǎn)移巖藻糖,將其連接在靶蛋白的特定氨基酸位點(diǎn)的核心糖鏈上,從而完成靶蛋白質(zhì)的折疊、空間構(gòu)象。我們課題組研究表明臟器纖維化中其關(guān)鍵蛋白均為糖蛋白,所以,我們思考:甘草酸是否通過CF修飾調(diào)控這些炎癥因子及信號(hào)通路的活性?要解決上述科學(xué)問題,本實(shí)驗(yàn)擬通過建立博來霉素(Bleomycin,BLM)誘導(dǎo)肺間質(zhì)纖維化大鼠模型明確甘草酸對(duì)肺間質(zhì)纖維化有無作用;在大鼠肺間質(zhì)纖維化模型上觀察甘草酸對(duì)EMT的影響;在此基礎(chǔ)上,通過觀察甘草酸對(duì)CF的影響進(jìn)而深入解析甘草酸抑制EMT的具體機(jī)制。本實(shí)驗(yàn)首次發(fā)現(xiàn)甘草酸能減輕BLM誘導(dǎo)的肺間質(zhì)纖維化及抑制EMT;其次從糖生物學(xué)全新的角度闡釋了甘草酸治療肺間質(zhì)纖維化的機(jī)制,填補(bǔ)了糖生物學(xué)在肺間質(zhì)纖維化領(lǐng)域的空白,為臨床研發(fā)新藥提供了全新思路。第一部分甘草酸減輕BLM致肺間質(zhì)纖維化目的:探討甘草酸對(duì)BLM致大鼠肺間質(zhì)纖維化的病理影響,明確甘草酸對(duì)肺間質(zhì)纖維化有無干預(yù)作用。方法:利用BLM致大鼠肺間質(zhì)纖維化模型,成功獲得肺臟大體標(biāo)本,使用不同劑量甘草酸觀察其對(duì)肺臟病理的影響及明確對(duì)肺間質(zhì)纖維化是否有治療作用。首先大體觀察甘草酸濕/干重比的影響;使用HE、Masson染色方法觀測(cè)甘草酸對(duì)肺臟病理的影響;利用免疫組化及免疫印跡技術(shù)檢測(cè)膠原蛋白Ⅰ、Ⅲ的變化;其次利用ELISA法檢測(cè)大鼠的肺組織中Hyp含量,明確甘草酸對(duì)肺間質(zhì)纖維化是否有干預(yù)作用。結(jié)果:與正常組相比,BLM誘導(dǎo)的大鼠肺間質(zhì)纖維化中肺濕/干重比明顯升高;HE、Masson染色顯示肺臟病理明顯加重;免疫組化及免疫印跡顯示膠原蛋白Ⅰ、Ⅲ表達(dá)明顯增加;ELISA檢測(cè)Hyp的含量明顯升高。經(jīng)甘草酸治療后,肺濕/干重比明顯降低;,肺臟病理明顯減輕,膠原蛋白Ⅰ、Ⅲ及Hyp表達(dá)較纖維化組明顯降低,并隨甘草酸劑量的升高而明顯減輕,其中高劑量甘草酸具有顯著的抑制作用。結(jié)論:在BLM致大鼠肺間質(zhì)纖維化的模型中,甘草酸對(duì)抑制及保護(hù)肺間質(zhì)纖維化起到了一定作用,并呈劑量依賴性。第二部分甘草酸對(duì)EMT的影響目的:闡述甘草酸對(duì)肺上皮細(xì)胞轉(zhuǎn)分化的影響,明確甘草酸阻抑EMT。方法:在用博來霉素制備的大鼠肺間質(zhì)纖維化模型中,使用特有標(biāo)記物E-cadherin定位肺泡上皮,觀察不同劑量甘草酸在肺泡上皮細(xì)胞轉(zhuǎn)分化成肌成纖維細(xì)胞中的影響,明確甘草酸阻抑EMT進(jìn)而減輕肺間質(zhì)纖維化。免疫熒光共染方法檢測(cè)不同劑量甘草酸對(duì)各組肺組織中E-cadherin、α-SMA的表達(dá)變化,免疫印跡方法對(duì)各組肺標(biāo)本中上述蛋白采用定量分析,明確不同劑量甘草酸對(duì)上皮細(xì)胞轉(zhuǎn)分化現(xiàn)象的影響;免疫熒光檢測(cè)各組大鼠肺組織中p-Smad2/3、β-catenin的表達(dá)變化,利用免疫印跡方法對(duì)上述蛋白進(jìn)行定量分析,明確不同劑量甘草酸對(duì)肺臟纖維化關(guān)鍵蛋白的影響。結(jié)果:免疫熒光及免疫印跡結(jié)果顯示正常肺組織E-cadherin中等量表達(dá),α-SMA低量表達(dá)。與正常組相比較,BLM致大鼠肺間質(zhì)纖維化模型中α-SMA表達(dá)顯著升高,E-cadherin表達(dá)顯著下降;經(jīng)甘草酸治療后,免疫熒光及免疫印跡顯示上述兩種蛋白呈逆向變化,對(duì)EMT現(xiàn)象有明顯抑制作用。免疫熒光及免疫印跡結(jié)果顯示正常肺組織中p-Smad2/3、β-catenin低量表達(dá)。與正常組相比,BLM誘導(dǎo)大鼠肺間質(zhì)纖維化模型中p-Smad2/3、β-catenin蛋白的表達(dá)顯著升高;經(jīng)甘草酸治療后,免疫熒光及免疫印跡顯示甘草酸明顯抑制上述兩種蛋白的表達(dá)。上述指標(biāo)均顯示與甘草酸的劑量相關(guān)。結(jié)論:在BLM致大鼠肺間質(zhì)纖維化中,EMT通路關(guān)鍵蛋白起到重要作用,甘草酸能夠干預(yù)EMT及上述蛋白的活化。第三部分甘草酸通過CF修飾調(diào)控EMT的機(jī)制目的:探討核心巖藻糖基化修飾對(duì)EMT關(guān)鍵信號(hào)通路的影響,深入解析甘草酸調(diào)控FUT8阻抑EMT。方法:利用BLM致大鼠肺間質(zhì)纖維化模型,觀察核心巖藻糖基化修飾水平變化及核心巖藻糖基化修飾對(duì)TGF-β/Smad2/3、Wnt/β-catenin信號(hào)通路的影響,深入解析甘草酸對(duì)核心巖藻糖基化修飾的水平變化。首先免疫熒光雙染法觀察大鼠肺臟中CF表達(dá)及甘草酸對(duì)大鼠肺臟CF修飾水平的變化;其次應(yīng)用免疫熒光、免疫印跡檢測(cè)TGF-βR、WNT核心巖藻糖基化水平及甘草酸對(duì)上述受體蛋白及CF修飾水平變化。結(jié)果:正常肺臟組織中存在中等量的CF修飾水平。與正常組比較,BLM致大鼠肺間質(zhì)纖維化中,CF修飾水平明顯增加;大鼠肺臟中TGF-βR、WNT及其核心巖藻糖基化水平顯著升高(p0.001);甘草酸能明顯抑制BLM誘導(dǎo)纖維化大鼠肺臟中TGF-βR、WNT受體蛋白的核心巖藻糖基化修飾水平(p0.01),但是并未影響受體本身的表達(dá)。結(jié)論:在BLM致大鼠肺間質(zhì)纖維化模型中,關(guān)鍵受體蛋白TGF-βR、WNT翻譯后CF修飾在EMT中起到關(guān)鍵作用,甘草酸調(diào)控TGF-βR、WNT核心巖藻糖基化修飾后能夠干預(yù)EMT,進(jìn)而減輕肺間質(zhì)纖維化。
[Abstract]:Pulmonary interstitial fibrosis (Pulmonary fibrosis) is a chronic disease. The course of the disease is gradually developing and irreversible. It is the end stage of interstitial lung disease. It is estimated that the average life period is short and less than 5 years. The patients with pulmonary fibrosis are difficult to breathe, and the life is difficult to take care of themselves, and it is costly to bring to society, families, and individuals. It is a great challenge and great demand for the prevention and control of pulmonary diseases in China. Although the cause of pulmonary fibrosis is not clear, the pathological manifestations and signal pathways of pulmonary fibrosis are mainly manifested in the infiltration of inflammatory cells and myofibroblast in the interstitial lung. There has been a significant increase in the accumulation of extra extracellular matrix and the eventual pathological changes of fibrosis. There is no effective means to prevent its progress. Therefore, it is of great significance to elucidate the development of interstitial lung fibrosis, the development mechanism, and the search for effective new intervention strategies for preventing the development of the disease and reducing the mortality. We are not very clear about the pathogenesis of the disease of pulmonary fibrosis. The key pathological changes in the course of pulmonary fibrosis include myofibroblast and abnormal increase. There are many studies on the origin of myofibroblast. The source is alveolar epithelial cells, that is, EMT (epithelial to mesenchymaltransition). An important effect of the activation of alveolar epithelial cells is: transforming into myofibroblast, promoting the synthesis of extracellular matrix, activating a variety of genes involved in inherent immunity and inflammation, promoting inflammation, oxidative stress injury, and aggravating pulmonary fibrosis. It is speculated that pulmonary alveolar epithelial cell transdifferentiation (EMT) is the main source of myofibroblast in the interstitial lung. The in-depth study of the mechanism of EMT and the important molecular biological effects caused by activation is an important strategy to seek intervention targets. To sum up, pulmonary interstitial fibrosis is a refractory, complex disease. And single pathway receptor blockers (such as gefitinib) may have some effect, but it does not prevent the progress of pulmonary fibrosis. In recent years, more and more studies have been made about Chinese herbal prescription and its monomer active components in the treatment of disease. The role of the Chinese herbal medicine in the treatment of pulmonary fibrosis has also attracted more and more attention. The previous experiments confirmed that activating blood and removing stasis prescription (Huang Qi, chuanxiong, Salvia miltiorrhiza, angelica, Rhodiola, Fritillaria thunbergii, licorice) has a therapeutic effect on pulmonary fibrosis. Glycyrrhizic acid (GA) is the most important active ingredient in Glycyrrhiza. A large number of studies have shown that glycyrrhizic acid has a significant therapeutic effect on visceral fibrosis (such as liver). It is not clear whether oxalic acid has an improved effect on pulmonary fibrosis. Therefore, we propose the following scientific questions: multiple inflammation, excessive activation of multiple signal pathways is an important basis for pulmonary fibrosis, and EMT is an important way of inducing interstitial fibrosis. What regulates the activity of these inflammatory factors and signaling pathways? Can oxalic acid find common targets to control their activity? In recent years, the rapid development of glycoproteins provides us with new research directions for solving the above problems. Core fucosylation (CF) is an important protein sugar modification, which is specific to alpha -1,6 fucose transferase (Fucosyltransferase8, FUT8). We catalyze the transfer of fucose and connect it to the core sugar chain of the specific amino acid site of the target protein to complete the folding and space conformation of the target protein. Our research group studies show that the key proteins in the visceral fibrosis are glycoproteins. Therefore, we think whether glycyrrhizic acid can regulate these inflammatory factors and signal through CF modification. To solve these scientific problems, the experiment is to establish a rat model of pulmonary fibrosis induced by Bleomycin (BLM) to determine whether glycyrrhizic acid has an effect on pulmonary fibrosis, and to observe the effect of glycyrrhizic acid on EMT in rat pulmonary fibrosis model, and on this basis, the effect of glycyrrhizic acid on CF is observed. It is the first time that glycyrrhizic acid can reduce BLM induced pulmonary fibrosis and inhibit EMT. Secondly, the mechanism of glycyrrhizin in the treatment of interstitial fibrosis of the lung is explained from a new angle of sugar biology, which fills the gap in the field of pulmonary fibrosis in sugar biology and develops new drugs for the clinical development of EMT. In the first part, glycyrrhizic acid alleviates BLM induced pulmonary fibrosis: the pathological effects of glycyrrhizic acid on pulmonary fibrosis in rats induced by BLM and the effect of glycyrrhizic acid on interstitial fibrosis of the lungs. Methods: the lung interstitial fibrosis model of rats was made by BLM, and the gross specimens of lung were successfully obtained and the different doses were used. The effects of glycyrrhizic acid on lung pathology and the treatment of pulmonary fibrosis were observed. First, the effects of glycyrrhizin wet / dry weight ratio were observed. The effects of glycyrrhizic acid on lung pathology were observed by HE and Masson staining, and the changes of collagen I and III were detected by immunohistochemistry and immunoblotting techniques, and then EL was used. The ISA assay was used to detect the Hyp content in the lung tissue of rats and the effect of glycyrrhizin on pulmonary fibrosis. Results: compared with the normal group, the lung wet / dry weight ratio in pulmonary fibrosis induced by BLM was significantly higher than that in the normal group; HE, Masson staining showed that the lung pathology was obviously aggravated; immunohistochemistry and immunoblotting showed the expression of collagen I and III The content of Hyp was significantly increased by ELISA. After glycyrrhizic acid treatment, the lung wet / dry weight ratio decreased obviously, the lung pathology obviously decreased, the expression of collagen I, III and Hyp decreased significantly compared with the fibrosis group, and obviously decreased with the increase of glycyrrhizic acid, and the high dose glycyrrhizic acid had significant inhibitory effect. Conclusion: in BLM In the model of pulmonary fibrosis in rats, glycyrrhizic acid plays a role in inhibiting and protecting pulmonary fibrosis, and is dose-dependent. Second the effect of glycyrrhizic acid on EMT: the effect of glycyrrhizic acid on the transdifferentiation of lung epithelial cells, and the method of glycyrrhizin inhibition EMT.: the pulmonary interstitial fiber in rats prepared with bleomycin The effects of different doses of glycyrrhizic acid on the transformation of the alveolar epithelial cells into myofibroblasts were observed in the alveolar epithelium using a specific marker E-cadherin, and the inhibition of glycyrrhizic acid to inhibit EMT and then reduce pulmonary fibrosis. The immunofluorescence CO staining method was used to detect E-cadherin, alpha -S in different doses of glycyrrhizic acid in each group of lung tissues. The expression of MA and Western blot were quantified to determine the effects of glycyrrhizin on the transdifferentiation of epithelial cells, and the changes in the expression of p-Smad2/3 and beta -catenin in lung tissues of each group were detected by immunofluorescence, and the above protein was quantified by immunoblotting. The effect of different doses of glycyrrhizin on the key protein of lung fibrosis. Results: the results of immunofluorescence and immunoblotting showed that the expression of E-cadherin in normal lung tissue was equal and the expression of alpha -SMA was low. Compared with the normal group, the expression of alpha -SMA in the pulmonary interstitial fibrosis model of BLM rats increased significantly, the expression of E-cadherin decreased significantly, and the treatment was treated with glycyrrhizic acid. After the treatment, immunofluorescence and immunoblotting showed that the above two proteins were reversed and had obvious inhibitory effect on the EMT phenomenon. The results of immunofluorescence and immunoblotting showed the low expression of p-Smad2/3 and beta -catenin in normal lung tissue. Compared with the normal group, BLM induced the expression of p-Smad2/3 and beta -catenin protein in the pulmonary interstitial fibrosis model of rats. After the treatment of glycyrrhizic acid, immunofluorescence and immunoblotting showed that glycyrrhizic acid obviously inhibited the expression of the above two proteins. All of these indexes were related to the dose of glycyrrhizin. Conclusion: the key protein of EMT pathway plays an important role in BLM induced pulmonary interstitial fibrosis in rats, and glycyrrhizic acid can interfere with the activation of EMT and the above proteins. The three part of glycyrrhizic acid modified the mechanism of regulating EMT through CF modification: To explore the effect of core fucoidylation on the key signaling pathway of EMT, and to deeply analyze the FUT8 inhibition of EMT. by glycyrrhizin: using BLM to induce rat pulmonary fibrosis model, and observe the changes in the level of the core fucose trimming and the core fucose modification of the core fucose to TGF- beta /Smad2/3, the effect of Wnt/ beta -catenin signaling pathway, the level of glycyrrhizinate modification was deeply analyzed. First, the expression of CF in the lungs of rats was observed by immunofluorescence and the changes of glycyrrhizic acid on the level of CF modification in the lungs of rats. Secondly, immunofluorescence and immunoblotting were used to detect TGF- beta R and WNT core fucose base water. The changes in the levels of the receptor protein and CF modification were observed. Results: the level of CF modification in normal lung tissues was equal. Compared with the normal group, the level of CF modification in BLM induced pulmonary fibrosis in rats was significantly increased; the TGF- beta R, WNT and its core fucose levels in the lungs of rats increased significantly (p0.001), and glycyrrhizic acid could be obvious. Inhibition of BLM induced TGF- beta R, WNT receptor protein core fucose modification level (P0.01), but did not affect the expression of the receptor itself. Conclusion: the key receptor protein TGF- beta R in rat pulmonary fibrosis model induced by BLM and the key role of CF modification after WNT translation, glycyrrhizic acid regulates TGF- beta. Heart fucose modification can interfere with EMT, thereby reducing pulmonary interstitial fibrosis.

【學(xué)位授予單位】：大連醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R563

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1 寧亮,羅勇,賀大林;EMT在胚胎發(fā)育及腫瘤發(fā)生過程中的生物學(xué)作用[J];現(xiàn)代泌尿外科雜志;2005年05期

2 姜瑩;李曉燕;何慶南;譚愛斌;周頻;易著文;;白蛋白超載對(duì)人腎小管上皮細(xì)胞EMT及激素耐藥相關(guān)因素的影響[J];中國(guó)現(xiàn)代醫(yī)學(xué)雜志;2010年21期

3 林媛媛;婁遠(yuǎn)蕾;梁昌達(dá);謝淑佩;謝安;;人誘導(dǎo)多能干細(xì)胞自然分化過程中EMT變化研究[J];實(shí)驗(yàn)與檢驗(yàn)醫(yī)學(xué);2013年06期

4 周明利;盧先州;張樹友;;HIF-1α與EMT在腫瘤中的作用及意義研究進(jìn)展[J];中國(guó)普通外科雜志;2012年09期

5 李俊琴;李華;;脂肪酸合成酶在腫瘤EMT中作用機(jī)制的研究進(jìn)展[J];現(xiàn)代腫瘤醫(yī)學(xué);2014年08期

6 史秀芬;孫麗華;;EMT相關(guān)不孕癥20例治療觀察[J];山東醫(yī)藥;2007年12期

7 陳靖;樊英;李佳;黃仲曦;姚開泰;;鼻咽癌EMT相關(guān)基因的篩選及生物信息學(xué)分析[J];熱帶醫(yī)學(xué)雜志;2010年04期

8 梁革;;EMT相關(guān)分子與卵巢癌的研究進(jìn)展[J];社區(qū)醫(yī)學(xué)雜志;2012年24期

9 姚嬋;來茂德;;上皮間質(zhì)轉(zhuǎn)化(EMT)及其分子機(jī)制[J];國(guó)際遺傳學(xué)雜志;2006年04期

10 夏慶華;蔣偉;;丙戊酸逆轉(zhuǎn)EMT抑制前列腺癌的侵襲轉(zhuǎn)移[J];泌尿外科雜志(電子版);2012年01期

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1 徐向明;林建江;;EMT和腫瘤進(jìn)展[A];2011年浙江省肛腸外科學(xué)術(shù)大會(huì)暨結(jié)直腸肛門疾病診治新進(jìn)展學(xué)習(xí)班論文匯編[C];2011年

2 任陳;申洪;;上皮——間質(zhì)轉(zhuǎn)化(EMT)與腫瘤的研究進(jìn)展[A];中華醫(yī)學(xué)會(huì)病理學(xué)分會(huì)2009年學(xué)術(shù)年會(huì)論文匯編[C];2009年

3 沈源明;周建松;王培;李陽;葉楓;王芬芬;萬小云;程曉東;呂衛(wèi)國(guó);謝幸;;MiR-375調(diào)控EMT參與宮頸癌泰素繼發(fā)耐藥[A];中華醫(yī)學(xué)會(huì)第十次全國(guó)婦產(chǎn)科學(xué)術(shù)會(huì)議婦科腫瘤會(huì)場(chǎng)（婦科腫瘤學(xué)組、婦科病理學(xué)組）論文匯編[C];2012年

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1 記者 馬曉芳;揭秘華為架構(gòu)變動(dòng)：與EMT并行 董事會(huì)走向臺(tái)前[N];第一財(cái)經(jīng)日?qǐng)?bào);2011年

2 ;愛立信力助愛沙尼亞EMT推出商用HSDPA[N];人民郵電;2006年

3 記者 馬曉芳;董事會(huì)取代EMT 華為向公眾公司邁進(jìn)[N];第一財(cái)經(jīng)日?qǐng)?bào);2011年

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1 許金紅;姜黃素-3對(duì)高轉(zhuǎn)移非小細(xì)胞肺癌細(xì)胞EMT的作用及機(jī)制研究[D];第三軍醫(yī)大學(xué);2015年

2 劉茜;胃癌中AURKA通過組蛋白修飾調(diào)節(jié)EMT進(jìn)程的機(jī)制研究[D];天津醫(yī)科大學(xué);2016年

3 高麗麗;甘草酸抑制糖基化修飾調(diào)控EMT的機(jī)制研究[D];大連醫(yī)科大學(xué);2016年

4 殷濤;上皮向間葉轉(zhuǎn)化（EMT）在胰腺癌侵襲和轉(zhuǎn)移過程中的發(fā)生及機(jī)制研究[D];華中科技大學(xué);2007年

5 李晗;上皮—間質(zhì)轉(zhuǎn)化（EMT）在慢性鼻—鼻竇炎中的作用和機(jī)制研究[D];復(fù)旦大學(xué);2012年

6 卜芳芳;miR-205下調(diào)ASPP2表達(dá)促進(jìn)食管癌轉(zhuǎn)移及EMT的作用及機(jī)制研究[D];第二軍醫(yī)大學(xué);2013年

7 馬衣努爾·買提托合提;上皮間質(zhì)化（EMT）在宮頸癌發(fā)生發(fā)展中誘導(dǎo)腫瘤干細(xì)胞的作用及其機(jī)制研究[D];華中科技大學(xué);2013年

8 孟蕾;miRNA-134對(duì)人腫瘤細(xì)胞上皮—間質(zhì)轉(zhuǎn)化（EMT）過程影響的研究[D];湖南大學(xué);2012年

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1 王萍;維生素D通過抑制EMT延緩卵巢表面上皮細(xì)胞的惡性轉(zhuǎn)化[D];蘇州大學(xué);2015年

2 王海南;卵泡抑素樣蛋白1通過EMT通路在前列腺癌骨轉(zhuǎn)移中的研究[D];南京醫(yī)科大學(xué);2015年

3 楊健;缺氧誘導(dǎo)因子2（HIF-2α）在胰腺癌中調(diào)控上皮間質(zhì)轉(zhuǎn)化（EMT）的機(jī)制研究[D];蘇州大學(xué);2016年

4 章琦君;FAM83D通過調(diào)控EMT過程促進(jìn)肝細(xì)胞肝癌對(duì)索拉菲尼耐藥[D];浙江大學(xué);2016年

5 劉尊東;Fucoidan逆轉(zhuǎn)人肝癌HepG2細(xì)胞EMT表型及機(jī)制研究[D];大連醫(yī)科大學(xué);2016年

6 譚愛斌;免疫抑制劑對(duì)白蛋白超載所致人腎小管上皮細(xì)胞EMT和激素耐藥的預(yù)防和逆轉(zhuǎn)作用[D];中南大學(xué);2009年

7 翟小龍;子宮內(nèi)膜異位癥的中西醫(yī)研究近況及琥珀散治療EMT的臨床分析[D];黑龍江中醫(yī)藥大學(xué);2001年

8 戴育蘭;補(bǔ)腎調(diào)周化瘀法治療EMT的臨床研究[D];南京中醫(yī)藥大學(xué);2006年

9 徐思云;人多聚免疫球蛋白受體pIgR介導(dǎo)EMT的作用研究及機(jī)制初探[D];中國(guó)海洋大學(xué);2008年

10 周鑫;烯醇化酶ENO1影響非小細(xì)胞肺癌細(xì)胞EMT的研究[D];北京協(xié)和醫(yī)學(xué)院;2013年

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