【摘要】：背景:急性心肌梗死(Acute myocardial infarction,AMI)的大多數(shù)病因是不穩(wěn)定動(dòng)脈粥樣硬化斑塊破裂形成血栓,從而中斷冠狀動(dòng)脈血流。而AMI發(fā)病起始和發(fā)展過程中大量炎癥因子相互作用的參與是重要因素。盡管現(xiàn)在患者使用抗栓藥物或者采用冠狀動(dòng)脈介入治療方法能早期使血管再通或使心肌再灌注,但是很多患者還會(huì)發(fā)生不同程度的左室重構(gòu),甚至心力衰竭。其中受損或梗死心肌細(xì)胞釋放炎癥因子,進(jìn)而引發(fā)的炎癥反應(yīng)在心肌重構(gòu)和心肌纖維化中起到了重要作用。為抑制或減少斑塊發(fā)生和發(fā)展,今后防治冠心病的關(guān)鍵環(huán)節(jié)之一是抑制炎性反應(yīng)等不利因素,然而,針對(duì)這些病理環(huán)節(jié)的治療,目前尚未有公認(rèn)的藥物和其他有效的方法。曾有報(bào)道顯示阿托伐他汀在治療冠心病等心血管病過程中也發(fā)揮抗炎、抗氧化和抗纖維化等多樣化效應(yīng),但阿托伐他汀對(duì)AMI大鼠心肌炎癥及纖維化發(fā)展過程是否具有有益作用,其是否影響AMI大鼠心功能和血流動(dòng)力學(xué)狀態(tài)尚待驗(yàn)證,阿托伐他汀否通過調(diào)控TGF-β-smad和notch1信號(hào)通路起到上述有益作用尚還未知。此外,冠心病患者血漿炎性和纖維化因子半乳糖凝集素-3(Galectin-3)變化和他汀對(duì)Galectin-3的作用以及心房顫動(dòng)(Atrial Fibrillation,AF)患者射頻消融(radiofrequency ablationradiofrequency,RFCA)前后Galectin-3變化均尚未見報(bào)道。目的:1、觀察大鼠AMI建模后第一天心功能變化及建模后第5天阿托伐他汀或氯沙坦鉀治療對(duì)大鼠血漿炎癥因子TNF-α,IL-1β的作用;2、觀察阿托伐他汀或氯沙坦鉀治療對(duì)大鼠AMI建模后第14天心功能和血流動(dòng)力學(xué)影響,以及對(duì)心肌細(xì)胞外基質(zhì)金屬蛋白酶mmp2、mmp9及其抑制物TIMP2蛋白表達(dá)和血漿心功能標(biāo)志物BNP的變化;3、觀察大鼠AMI建模后第28天,阿托伐他汀或氯沙坦鉀治療對(duì)大鼠的心功能和血流動(dòng)力學(xué)影響,觀察心肌膠原蛋白CollagenⅠ、CollagenⅢ和notch1、TGF-β1、Smad2、Smad7、Galectin-3蛋白表達(dá)及血漿BNP變化;觀察阿托伐他汀或氯沙坦鉀是否通過抑制notch1-TGF-β-smad信號(hào)通路抑制AMI大鼠心肌炎癥和纖維化反應(yīng);4、觀察阿托伐他汀或氯沙坦鉀對(duì)AMI大鼠建模后第14天、28天心肌細(xì)胞結(jié)構(gòu)和心肌膠原纖維的影響;5、臨床試驗(yàn):觀察冠心病患者包括穩(wěn)定心絞痛組(Stable angina pectoris,SAP)、不穩(wěn)定心絞痛組(Unstable angina pectoris,UAP)和AMI患者血漿炎性因子Galectin-3變化及與病情嚴(yán)重程度的相關(guān)關(guān)系,觀察阿托伐他汀80mg對(duì)AMI患者短期治療前后Galectin-3變化;觀察心房顫動(dòng)(Atrial Fibrillation,AF)患者射頻消融(radiofrequency ablationradiofrequency,RFCA)前后Galectin-3變化。方法:1、大鼠分為四組:對(duì)照組(假手術(shù)組):單純分離前降支,未行結(jié)扎;心肌梗死組(AMI建模組):單純結(jié)扎冠狀動(dòng)脈前降支,建模后無藥物治療;他汀組:前降支結(jié)扎+阿托伐他汀(10mg/kq/d)治療;氯沙坦組:前降支結(jié)扎+氯沙坦鉀治療(5mg/kq/d)。除對(duì)照組大鼠外,其余組入選大鼠EF均≤50%,評(píng)價(jià)建模后各組大鼠第14天、28天心功能和血流動(dòng)力學(xué)變化,并觀察AMI后大鼠心肌細(xì)胞炎癥、纖維化發(fā)展變化過程。2、采用Elisa方法觀察大鼠AMI建模第5天血漿炎癥因子TNF-α、IL-1β變化和建模后第14天、28天血漿BNP變化。3、采用生物學(xué)Q-PCR、western blot技術(shù)和/或免疫組化方法檢測(cè)大鼠AMI建模后心肌細(xì)胞炎癥因子TNF-α、IL-1β、Galectin-3、心肌膠原蛋白CollagenⅠ、CollagenⅢ、金屬基質(zhì)蛋白酶mmp2、mmp9及其抑制物TIMP2和信號(hào)通路蛋白notch1、TGF-β1、Smad2、Smad7,觀察其變化。4、采用HE染色和MASSON染色觀察大鼠AMI建模后第14天、28天不同組大鼠心肌細(xì)胞結(jié)構(gòu)變化和心肌膠原纖維變化。5、臨床試驗(yàn):采用Elisa方法測(cè)定不同冠心病類型患者和AF患者RFCA前后血漿炎性因子Galectin-3含量。AMI患者經(jīng)皮冠狀動(dòng)脈介入(percutaneous coronary intervention,PCI)術(shù)前給予80mg阿托伐他汀治療,用Elisa方法測(cè)定對(duì)AMI患者PCI前后Galectin-3變化;觀察冠心病患者血漿Galectin-3水平與LVEF相關(guān)性。結(jié)果:1、大鼠AMI建模后24h心功能明顯下降,EF、FS值低于正常對(duì)照組;大鼠AMI建模后第5天血漿炎癥因子TNF-α、IL-1β升高,用阿托伐他汀或氯沙坦鉀治療后明顯下降(p0.05);2、大鼠AMI建模后第14天,阿托伐他汀組或氯沙坦鉀治療組心功能均較AMI未治療組提高,血流動(dòng)力學(xué)指標(biāo)dp/dt Max、dp/dtMin等明顯好轉(zhuǎn)(p0.05);應(yīng)用Q-PCR和/或WesternBlot技術(shù)和/或免疫組化方法所檢測(cè)結(jié)果顯示,阿托伐他汀組或氯沙坦治療組大鼠心肌mmp2、mmp9、TNF-α、IL-1β蛋白表達(dá)降低,TIMP2蛋白表達(dá)增加(p0.05);建模14天后血漿心功能標(biāo)志物BNP升高,阿托伐他汀組或氯沙坦治療組大鼠血漿BNP降低(p0.05)。3、大鼠AMI建模28天后,阿托伐他汀組或氯沙坦治療組心功能均較AMI未治療組提高,血流動(dòng)力學(xué)指標(biāo)dp/dt max、dp/dt min等明顯好轉(zhuǎn)(p0.05);應(yīng)用Q-PCR和/或WesternBlot技術(shù)和/或免疫組化方法所檢測(cè)結(jié)果顯示,阿托伐他汀或氯沙坦抑制大鼠心肌膠原蛋白CollagenⅠ、CollagenⅢ表達(dá)(p0.05),并抑制notch1、TGF-β1、Smad2、Galectin-3蛋白表達(dá),增加蛋白Smad7表達(dá)(p0.05);阿托伐他汀或氯沙坦通過抑制notch1-TGF-β-smad信號(hào)通路抑制AMI大鼠心肌炎癥和纖維化反應(yīng);建模28天后血漿心功能標(biāo)志物BNP升高,阿托伐他汀組和氯沙坦治療組大鼠血漿BNP降低(p0.05);4、AMI大鼠建模14天和28天后,阿托伐他汀組或氯沙坦治療組心肌細(xì)胞結(jié)構(gòu)紊亂現(xiàn)象好轉(zhuǎn),炎癥細(xì)胞減少,心肌膠原纖維組織范圍減少;5、臨床試驗(yàn)顯示:AMI組患者血漿Galectin-3含量高于UAP組(p0.05),UAP組患者Galectin-3含量高于SAP組(p0.05);冠狀動(dòng)脈多支病變組患者Galectin-3水平高于單只病變組(p0.05);AF行RFCA術(shù)后轉(zhuǎn)復(fù)為竇性心律患者Galectin-3水平較術(shù)前有所下降,但前后比較無差別(p0.05);AMI患者PCI術(shù)前給予80mg阿托伐他汀治療可降低血漿Galectin-3水平,但前后比較無差別;Galectin-3水平與冠心病患者左室射血分?jǐn)?shù)(Left ventricular ejection fraction,LVEF)值成負(fù)相關(guān)性(r=-0.405,p0.05)。結(jié)論:1、大鼠AMI建模后心肌發(fā)生炎癥、纖維化反應(yīng)、炎癥因子TNF-α、IL-1β、Galectin-3升高和纖維化因子mmp2、mmp9、CollagenⅠ、CollagenⅢ升高,同時(shí)心功能受損,心室發(fā)生重構(gòu),而阿托伐他汀或氯沙坦可通過notch1-TGF-β-smads通路抑制心肌炎癥及纖維化,減少炎癥及纖維化指標(biāo)表達(dá),減輕心肌重構(gòu),在一定程度上對(duì)心功能和血流動(dòng)力學(xué)起到改善作用。2、阿托伐他汀或氯沙坦可改善AMI大鼠建模后心肌細(xì)胞壞死和結(jié)構(gòu)紊亂,并較少心肌膠原纖維范圍;3、臨床試驗(yàn)顯示,冠心病患者血漿中炎癥和纖維化因子Galectin-3含量與心肌缺血、損傷嚴(yán)重程度相關(guān),隨著心肌缺血、損傷加重,Galectin-3含量逐步升高;Galectin-3與冠心病患者LVEF成負(fù)性相關(guān);4、Galectin-3是心肌炎癥和纖維化因子,AF患者Galectin-3水平升高與心房纖維化有關(guān),RFCA術(shù)后Galectin-3水平有所下降,但術(shù)前術(shù)后比較無差別,可能與樣本量較少有關(guān);阿托伐他汀降低AMI患者PCI術(shù)后Galectin-3水平,但前后比較無差別,可能與服藥次數(shù)較少有關(guān)。
[Abstract]:BACKGROUND: Most of the causes of acute myocardial infarction (AMI) are unstable atherosclerotic plaque rupture, resulting in thrombosis, which interrupts coronary flow. The involvement of a large number of inflammatory factors in the initiation and development of AMI is an important factor, although patients now use antithrombotic drugs or take them. Coronary artery interventional therapy can early revascularize or reperfusion myocardium, but many patients also have different degrees of left ventricular remodeling, and even heart failure. Injured or infarcted myocardial cells release inflammatory factors, which in turn trigger inflammatory reactions in myocardial remodeling and myocardial fibrosis play an important role. To prevent or reduce the occurrence and development of plaque, one of the key links in the prevention and treatment of coronary heart disease in the future is to inhibit inflammatory reaction and other adverse factors. However, there are no recognized drugs and other effective methods for the treatment of these pathological links. It has been reported that atorvastatin also plays an anti-inflammatory role in the treatment of cardiovascular diseases such as coronary heart disease. However, whether atorvastatin has beneficial effects on the development of myocardial inflammation and fibrosis in AMI rats, and whether it affects cardiac function and hemodynamic status in AMI rats remains to be verified. Whether atorvastatin plays the above beneficial role by regulating TGF-beta-smad and Notch1 Signaling pathways remains to be determined. In addition, the changes of plasma inflammatory and fibrotic factors galectin-3 (Galectin-3) and the effect of statin on Galectin-3 in patients with coronary heart disease and the changes of Galectin-3 in patients with atrial fibrillation (AF) before and after radiofrequency ablation (RFCA) have not been reported. Changes of cardiac function on the first day after modeling and effects of atorvastatin or losartan potassium on plasma inflammatory factors TNF-a and IL-1 beta in rats on the fifth day after modeling; 2. Effects of atorvastatin or losartan potassium on cardiac function and hemodynamics and extracellular matrix metalloproteinase mmp2, MMP9 in rats with AMI on the fourteenth day after modeling were observed. The expression of TIMP2 protein and the changes of plasma cardiac function marker BNP were observed. 3. The effects of atorvastatin or losartan potassium on cardiac function and hemodynamics were observed on 28 days after AMI in rats, and the expressions of collagen I, Collagen III and notch1, TGF-beta 1, Smad2, Smad7, Galectin-3 protein and plasma BN were observed. To observe whether atorvastatin or losartan potassium can inhibit myocardial inflammation and fibrosis in rats with AMI by inhibiting notch1-TGF-beta-smad signaling pathway; 4. To observe the effects of atorvastatin or losartan potassium on myocardial cell structure and myocardial collagen fibers in rats with AMI on the 14th and 28th days after modeling; 5. Clinical trial: To observe the patients with coronary heart disease. The changes of plasma inflammatory factor Galectin-3 in patients with stable angina pectoris (SAP), unstable angina pectoris (UAP) and AMI and their correlation with the severity of the disease were observed. The changes of Galectin-3 in patients with AMI before and after treatment with atorvastatin 80 mg were observed. Methods: 1. Rats were divided into four groups: control group (sham operation group): isolated anterior descending branch without ligation; myocardial infarction group (AMI modeling group): ligation of anterior descending branch of coronary artery without drug therapy; statin group: ligation of anterior descending branch + atrovir Statin (10mg/kq/d) treatment; Losartan group: anterior descending branch ligation + losartan potassium treatment (5mg/kq/d). Except for the control group rats, the EF of the other groups were all less than 50%. The changes of cardiac function and hemodynamics were evaluated on the 14th and 28th day after modeling, and the changes of myocardial inflammation and fibrosis were observed after AMI. 2. Elisa method was used. The changes of plasma inflammatory factors TNF-a, IL-1 beta and BNP were observed on the fifth day after AMI modeling and on the fourteenth and twenty-eighth days after AMI modeling. 3. Biological Q-PCR, Western blot and/or immunohistochemical methods were used to detect the levels of inflammatory factors TNF-a, IL-1 beta, Galectin-3, Collagen I, Collagen III and metal matrix in myocardial cells of rats after AMI modeling. Proteinase MMP 2, MMP 9 and their inhibitors TIMP 2 and signal pathway proteins notch 1, TGF - beta 1, Smad 2, Smad 7 were observed. 4. HE staining and MASSON staining were used to observe the changes of myocardial cell structure and myocardial collagen fibers in different groups of rats on the 14th and 28th days after AMI modeling. 5. Clinical trial: Elisa method was used to determine different types of coronary heart disease. Levels of plasma inflammatory factor Galectin-3 in patients with type I and AF before and after RFCA were measured by Elisa method. Results: 1, 24 hours after AMI, the cardiac function of rats decreased significantly, EF, FS values were lower than the normal control group; 5 days after AMI, the plasma inflammatory factors TNF-a, IL-1 beta increased, and significantly decreased after treatment with atorvastatin or losartan potassium (p0.05); 2, 14 days after AMI, the cardiac function of atorvastatin group or losartan potassium treatment group were significantly lower than that of AMI untreated rats. The results of Q-PCR and/or Western Blot and/or immunohistochemistry showed that the expression of mmp-2, mmp-9, TNF-alpha, IL-1 beta protein in myocardium of rats in atorvastatin group or losartan treatment group decreased, and the expression of TIMP-2 protein increased 14 days after modeling (p0.05). Plasma BNP was elevated, plasma BNP was decreased in atorvastatin group or losartan treatment group (p0.05). After 28 days of AMI modeling, cardiac function in atorvastatin group or losartan treatment group was improved, and hemodynamic indexes such as dp/dt max, dp/dt min were improved significantly (p0.05). And/or immunohistochemical staining showed that atorvastatin or losartan inhibited the expression of collagen Collagen I and Collagen III in rat myocardium (p0.05), inhibited the expression of notch 1, TGF-beta 1, Smad2, and Galectin-3, and increased the expression of Smad7 (p0.05); atorvastatin or losartan inhibited the notch 1-TGF-beta-smad signaling pathway by inhibiting the expression of Smad7 (p0.05). Myocardial inflammation and fibrosis in AMI rats were induced; plasma BNP increased after 28 days of modeling, plasma BNP decreased in atorvastatin group and losartan group (p0.05); 4. After 14 and 28 days of modeling, the structural disorder of myocardial cells in atorvastatin group or losartan group improved, inflammatory cells decreased, and myocardial glue decreased. 5, clinical trials showed that the level of Galectin-3 in plasma of AMI patients was higher than that of UAP patients (p0.05), and the level of Galectin-3 in UAP patients was higher than that of SAP patients (p0.05); the level of Galectin-3 in coronary artery disease group was higher than that of single lesion group (p0.05); the level of Galectin-3 in AF patients converted to sinus rhythm after RFCA was higher than that before operation. The level of Galectin-3 was negatively correlated with the left ventricular ejection fraction (LVEF) in patients with coronary artery disease (r = - 0.405, P 0.05). Conclusion: 1. Rat AMI was established. Inflammation, fibrosis, elevation of inflammatory factors TNF-alpha, IL-1beta, Galectin-3 and fibrosis factors mmp2, mmp9, Collagen I and Collagen III occur in the myocardium after cardiac infarction. Atorvastatin or losartan can inhibit myocardial inflammation and fibrosis through notch1-TGF-beta-smads pathway and reduce inflammation and fibrosis. Atorvastatin or losartan can improve myocardial cell necrosis and structural disorder in AMI rats, and less myocardial collagen fibers range; 3. Clinical trials showed that inflammation and fibrosis factor Gale in plasma of patients with coronary heart disease. The content of ctin-3 was correlated with the severity of myocardial ischemia and injury, with the increase of myocardial ischemia, the content of Galectin-3 increased gradually; Galectin-3 was negatively correlated with LVEF in patients with coronary heart disease; 4, Galectin-3 was a factor of myocardial inflammation and fibrosis; the elevation of Galectin-3 in AF patients was related to atrial fibrosis, and the level of Galectin-3 decreased after RFCA. Atorvastatin decreased the level of Galectin-3 in patients with AMI after PCI, but there was no difference before and after PCI, which may be related to the fewer times of taking drugs.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R542.22

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2 張浩;劉伏友;彭佑銘;劉映紅;廖琴;;TGF-β_1介導(dǎo)的Smad信號(hào)通路對(duì)人腹膜間皮細(xì)胞細(xì)胞外基質(zhì)的調(diào)控[A];“中華醫(yī)學(xué)會(huì)腎臟病學(xué)分會(huì)2004年年會(huì)”暨“第二屆全國(guó)中青年腎臟病學(xué)術(shù)會(huì)議”論文匯編[C];2004年

3 徐丹;龍庭鳳;柴燕杰;涂穎;顧華;何黎;;日光性角化病、鱗狀細(xì)胞癌中TGF-β/Smad信號(hào)通路因子及相關(guān)因子表達(dá)變化的研究[A];中華醫(yī)學(xué)會(huì)第十八次全國(guó)皮膚性病學(xué)術(shù)年會(huì)論文匯編[C];2012年

4 徐丹;袁瑞紅;劉彤云;涂穎;顧華;何黎;;不同強(qiáng)度紫外線對(duì)日光性角化病中TGF-β/Smad信號(hào)通路及相關(guān)因子表達(dá)變化影響的研究[A];中華醫(yī)學(xué)會(huì)第十八次全國(guó)皮膚性病學(xué)術(shù)年會(huì)論文匯編[C];2012年

5 張維溪;戴歡;賀孝良;方麗;趙瑞雪;李昌崇;;糖皮質(zhì)激素調(diào)控哮喘大鼠氣道重塑中TGF-β 1/Smad信號(hào)通路的研究[A];第六屆江浙滬兒科學(xué)術(shù)會(huì)議暨兒科學(xué)基礎(chǔ)與臨床研究進(jìn)展學(xué)術(shù)班論文匯編[C];2009年

6 鄧穎;于力;張瑤;郝志宏;;福辛普利對(duì)腎小球系膜細(xì)胞TGF-β1/Smad信號(hào)通路的干預(yù)作用[A];中華醫(yī)學(xué)會(huì)第十五次全國(guó)兒科學(xué)術(shù)大會(huì)論文匯編（上冊(cè)）[C];2010年

7 鄧穎;于力;溫捷;;TGF-β/Smad信號(hào)通路在腎小球系膜細(xì)胞的表達(dá)及ACEI對(duì)其影響[A];中華醫(yī)學(xué)會(huì)第十七次全國(guó)兒科學(xué)術(shù)大會(huì)論文匯編（下冊(cè)）[C];2012年

8 陳權(quán);焦安欽;徐俊秀;袁泉;李玲;苗德光;陳則潤(rùn);;腎力康顆粒對(duì)系膜增生性腎小球腎炎患者TGF-β1與CTGF水平影響的臨床研究[A];第10屆全國(guó)中西醫(yī)結(jié)合腎臟病學(xué)術(shù)會(huì)議論文匯編[C];2009年

9 張玉震;孫金龍;李猛;李相坤;王鵬;魏麟;;TGF-β1與慢性交通性腦積水形成機(jī)制研究進(jìn)展[A];中華醫(yī)學(xué)會(huì)神經(jīng)外科學(xué)分會(huì)第九次學(xué)術(shù)會(huì)議論文匯編[C];2010年

10 劉佳琦;胡大海;張戰(zhàn)鳳;官浩;折濤;張軍;白曉智;;IFN-γ對(duì)瘢痕疙瘩成纖維細(xì)胞TGF-β/Smad信號(hào)通路作用的研究[A];中華醫(yī)學(xué)會(huì)燒傷外科學(xué)分會(huì)2009年學(xué)術(shù)年會(huì)論文匯編[C];2009年

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2 奇 云;解讀大鼠基因有助人類攻克疑難病癥[N];大眾科技報(bào);2004年

3 張?zhí)煨?克隆大鼠意義重大[N];中國(guó)醫(yī)藥報(bào);2003年

4 本報(bào)特約撰稿人 陸志城;用大鼠還是用小鼠？[N];醫(yī)藥經(jīng)濟(jì)報(bào);2004年

5 記者 藍(lán)建中;日本研究:骨髓移植使大鼠血管“返老還童”[N];新華每日電訊;2010年

6 記者 姜澎;聰明大鼠 解密大腦記憶功能[N];文匯報(bào);2009年

7 萬姍姍　記者 王春;轉(zhuǎn)基因“聰明大鼠”學(xué)得快記得牢[N];科技日?qǐng)?bào);2009年

8 記者 曹繼軍 顏維琦 通訊員 孫國(guó)根;大鼠基因功能圖譜被成功繪制[N];光明日?qǐng)?bào);2014年

9 記者 白毅 通訊員 孫國(guó)根;大鼠基因功能圖譜繪制成功[N];中國(guó)醫(yī)藥報(bào);2014年

10 記者 孫國(guó)根;將大鼠基因的功能“對(duì)號(hào)入座”[N];健康報(bào);2014年

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2 牛華濤;Notch1在云南宣威女性肺癌中的表達(dá)及作用機(jī)制研究[D];昆明醫(yī)科大學(xué);2015年

3 王曰偉;Notch1和TACE在腹主動(dòng)脈瘤血漿中的變化及意義[D];北京協(xié)和醫(yī)學(xué)院;2016年

4 王學(xué)謙;人參皂苷Rh2通過下調(diào)Notch1信號(hào)通路調(diào)控前列腺癌干細(xì)胞生物學(xué)行為的實(shí)驗(yàn)研究[D];北京中醫(yī)藥大學(xué);2017年

5 王召靜;HSP90抑制劑在T-ALL中靶向NOTCH1的機(jī)制和功能研究及MWCNTs抑制Pgp和MRP4的機(jī)制研究[D];華中科技大學(xué);2016年

6 魏瀟凡;Kindlin-2通過促進(jìn)TGF-β-Smad信號(hào)通路加速腎臟纖維化[D];南方醫(yī)科大學(xué);2011年

7 朱曉燕;靶向TGF-βⅡ型受體的適配子殼聚糖緩釋凝膠對(duì)大鼠濾過術(shù)后結(jié)膜瘢痕的作用研究[D];第三軍醫(yī)大學(xué);2015年

8 姚丙;Elf5抑制TGF-β誘導(dǎo)的前列腺癌上皮間質(zhì)轉(zhuǎn)化的機(jī)制研究[D];天津醫(yī)科大學(xué);2015年

9 宋娓;中國(guó)漢族男性人群TGF-β1基因多態(tài)性與痛風(fēng)遺傳易感性的相關(guān)性研究[D];青島大學(xué);2016年

10 曹延林;p38 MAPK通路介導(dǎo)TGF-β1/CTGF調(diào)控人黃韌帶肥厚增生的實(shí)驗(yàn)研究[D];南方醫(yī)科大學(xué);2015年

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2 李楠;維藥異常黑膽質(zhì)成熟劑對(duì)增生性瘢痕增殖與轉(zhuǎn)化生長(zhǎng)因子β/Smad信號(hào)通路的影響[D];新疆醫(yī)科大學(xué);2015年

3 朱彥;TGF-β-Smad信號(hào)通路相關(guān)細(xì)胞因子在小鼠非酒精性脂肪肝干預(yù)中的差異表達(dá)[D];湖南師范大學(xué);2016年

4 周玲;紫花牡荊素靶向TGF-β/Smad信號(hào)通路減輕肝纖維化的實(shí)驗(yàn)研究[D];南方醫(yī)科大學(xué);2016年

5 陳冰;Smad信號(hào)通路調(diào)控BMP9介導(dǎo)的iSCAP成骨/成牙本質(zhì)分化的機(jī)制研究[D];重慶醫(yī)科大學(xué);2016年

6 沈毅忱;TLR7對(duì)瘢痕疙瘩形成中Smad信號(hào)通路的調(diào)控作用研究[D];浙江大學(xué);2016年

7 班桂飛;HtrA1通過TGF-β1/Smad信號(hào)通路調(diào)節(jié)人牙髓細(xì)胞向成牙本質(zhì)細(xì)胞分化的研究[D];廣西醫(yī)科大學(xué);2017年

8 謝園園;褪黑素對(duì)肝星狀細(xì)胞中TGF-β1/Smad信號(hào)通路的影響[D];安徽醫(yī)科大學(xué);2017年

9 魏緒法;泡球蚴感染中期小鼠纖維化肝組織中TGF-β1/Smad信號(hào)通路的表達(dá)和意義[D];新疆醫(yī)科大學(xué);2011年

10 楊琦;Notch1基因表達(dá)對(duì)T-ALL細(xì)胞增殖及硼替佐米敏感性的影響[D];山西醫(yī)科大學(xué);2015年

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