【摘要】：心力衰竭(心衰,heart failure, HF)是21世紀危害人類健康的重要心血管疾病,心衰患者5年生存率約為50%,其中D期心衰患者惡性心律失常的發(fā)生率明顯增加,近50%患者死于惡性心律失常所導(dǎo)致的心源性猝死。電生理重構(gòu)導(dǎo)致的惡性心律失常是心一衰患者死亡的重要原因之一。電生理重構(gòu)是指在心衰時,由于病理生理機制發(fā)生變化,導(dǎo)致心肌細胞電沖動產(chǎn)生及傳導(dǎo)機制發(fā)生的改變,涉及多種離子通道和細胞信號轉(zhuǎn)導(dǎo)系統(tǒng)的功能改變,其中L型鈣電流改變和動作電位時程(Action potential duration, APD)延長是關(guān)鍵環(huán)節(jié)。目前仍缺乏針對心衰電生理重構(gòu)的有效藥物可供臨床選擇,中醫(yī)藥研究有可能是解決這一問題的突破口。中醫(yī)認為心氣虛是心衰的基本病機,貫穿于心衰發(fā)生發(fā)展始終,益氣藥是中醫(yī)防治心衰的一類基本藥物,能夠改善心衰患者心功能及臨床癥狀,提高患者生存質(zhì)量。黃芪、黨參、人參是臨床常用的益氣藥。目前已知的中醫(yī)藥作用機制具有多層次、多環(huán)節(jié)、多靶點等特點,前期研究從能量代謝和肌漿網(wǎng)鈣轉(zhuǎn)運角度探討了益氣藥改善心衰模型心功能的作用機制,但從電生理重構(gòu)角度探討益氣藥改善心衰模型預(yù)后的機制研究還未見諸報道。本研究通過復(fù)制結(jié)扎冠脈所致心梗后心衰、縮窄主動脈所致壓力負荷心衰兩種小鼠模型,運用小動物超聲心動圖、心電圖、全細胞膜片鉗技術(shù)及Western Blot分子生物學(xué)方法,從整體、細胞、分子層面進行研究,以驗證“益氣藥可能通過抑制鈣/鈣調(diào)素依賴性蛋白激酶Ⅱ(calcium/calmodulin-dependent protein kinase II, CaMKII)過表達,調(diào)控心衰細胞L型鈣電流,縮短心衰心肌細胞及心臟復(fù)極時間,改善心衰電生理重構(gòu)”的科學(xué)假說。方法1.動物造模：采用冠脈結(jié)扎術(shù)、主動脈縮窄術(shù)分別復(fù)制心梗后心衰、壓力負荷心衰兩種小鼠模型；2.分組和給藥：(1)冠脈結(jié)扎術(shù)后小鼠隨機分為模型組、假手術(shù)組、益氣組(黃芪+黨參)、西藥組(美托洛爾)4組,術(shù)后給予相應(yīng)藥物干預(yù)4周；(2)主動脈縮窄術(shù)后小鼠隨機分為模型組、假手術(shù)組、黃芪組(黃芪)、人參組(人參)、黨參組(黨參)、西藥組(美托洛爾)6組,術(shù)后給予相應(yīng)藥物干預(yù)4周；3.檢測方法：(1)冠脈結(jié)扎術(shù)后4周小鼠和主動脈縮窄術(shù)后4周小鼠記錄體重、死亡等一般情況,利用小動物超聲心動圖檢測心臟收縮、舒張功能及心室重構(gòu)情況,利用心電圖檢測QT間期及室性心律失常發(fā)生率；(2)主動脈縮窄術(shù)后4周小鼠急性分離心肌細胞,利用全細胞膜片鉗技術(shù)的電流鉗模式記錄心肌細胞APD,利用全細胞電壓鉗模式記錄L型鈣電流密度、失活時間常數(shù)(T)以及電壓依賴性激活-失活曲線;(3)主動脈縮窄術(shù)后4周小鼠處死取心肌組織,應(yīng)用Western Blot技術(shù)檢測L型鈣通道、CaMKII的蛋白表達水平。結(jié)果1.心衰模型的評價：(1)冠脈結(jié)扎術(shù)后4周模型小鼠與假手術(shù)組相比左室射血分數(shù)(left ventricular ejection fraction, LVEF)顯著下降(p0.01),舒張末左室內(nèi)徑顯著增加(p0.01),校正QT間期(QTc)顯著延長(p0.01)；(2)主動脈縮窄術(shù)后4周模型小鼠與假手術(shù)組相比LVEF顯著下降(p0.01),收縮末左室內(nèi)徑增加(p0.05),左室前壁厚度顯著增加(p0.01),Ea顯著降低(p0.01), QTc顯著延長(p0.01)。2. 益氣藥對心衰小鼠心功能及QT間期的干預(yù)作用：(1)冠脈結(jié)扎術(shù)后4周,益氣組與模型組相比LVEF有升高趨勢但無統(tǒng)計學(xué)意義,西藥組與模型組相比LVEF無顯著差異,益氣組、西藥組與模型組相比QTc均顯著縮短(p0.01)；(2)主動脈縮窄術(shù)后4周,黃芪組與模型組相比LVEF升高(p0.05),Ea顯著升高(p0.01),黨參組與模型組相比LVEF顯著升高(p0.01)；黃芪組、人參組、黨參組與模型組相比QTc均顯著縮短(p0.01)。3.益氣藥對心衰細胞APD及L型鈣電流的干預(yù)作用：(1)APD:模型組與假手術(shù)組相比,在0.21、2.0Hz頻率刺激下心肌細胞動作電位復(fù)極90%時間(APD90)均顯著延長(p0.01)；黃芪組與模型組相比,在0.2Hz、2.0Hz頻率刺激下心肌細胞APD90縮短(p0.05)；黨參組與模型組相比,在0.2Hz、2.0Hz頻率刺激下心肌細胞APD90顯著縮短(p0.01),并且在異丙腎上腺素(isoprenaline, ISO)干預(yù)下與模型組相比APD90縮短(p0.05);(2) ICa,L電流密度：模型組與假手術(shù)組相比,在0.1Hz、1.0Hz刺激下ICa,L電流密度均顯著增大(p0.01);黃芪組與模型組相比,1.0Hz刺激下ICa,L電流密度顯著減小(p0.01);黨參組與模型組相比,0.1 Hz、1.0Hz刺激下ICa,L電流密度均減小(p0.01、p0.05),并且在ISO干預(yù)下ICa,L電流密度與模型組相比減小(p0.05)；(3)Ica,L失活時間常數(shù)：模型組與假手術(shù)組相比ICa,L快速失活時間常數(shù)(τ1)和慢速失活時間常數(shù)(τ 2)均顯著延長(p0.01),黃芪組、人參組、黨參組與模型組相比,τ 1、τ 2均顯著縮短(p0.01);(4)電壓依賴性激活-失活：模型組與假手術(shù)組相比半數(shù)激活電位降低(p0.01),黃芪組、人參組、黨參組、西藥組與模型組相比,半數(shù)激活電位均顯著升高(p0.01)。4.益氣藥對心衰小鼠L型鈣通道及CaMKⅡ表達的干預(yù)作用：(1)模型組與假手術(shù)組相比CANCA1C (L型鈣通道主要亞基)表達水平無統(tǒng)計學(xué)差異,各給藥組與模型組相比CANCA1C表達水平無統(tǒng)計學(xué)差異；(2)模型組與假手術(shù)組相比CaMKⅡ蛋白表達水平顯著升高(p0.01),黃芪組、人參組、黨參組、西藥組與模型組相比CaMKⅡ蛋白表達水平均顯著降低(p0.01)。結(jié)論1.益氣藥(黃芪+黨參)能夠縮短心梗后心衰心臟復(fù)極時間,但對心梗后心衰模型心功能無明顯改善效果；黃芪、人參、黨參均能縮短壓力負荷致心衰心臟復(fù)極時間,改善心衰電生理重構(gòu),并且黃芪能夠同時改善心臟收縮和舒張功能,黨參能夠改善心臟收縮功能；2.益氣藥黃芪、人參、黨參能夠不同程度地干預(yù)心衰細胞L型鈣電流密度,失活速度,電壓依賴性激活、失活,改善心衰細胞L型鈣電流重構(gòu),并且縮短心衰細胞動作電位復(fù)極時間,干預(yù)心衰細胞電生理重構(gòu),其中黨參、黃芪的干預(yù)效果顯著；3.益氣藥黃芪、人參、黨參對L型鈣通道的調(diào)控作用可能是通過抑制CaMKⅡ過表達實現(xiàn)的。
[Abstract]:Heart failure (heart failure (heart failure), heart failure, HF) is an important cardiovascular disease that endangers human health in twenty-first Century. The 5 year survival rate of patients with heart failure is about 50%. The incidence of malignant arrhythmia in D patients with heart failure is significantly increased, and nearly 50% patients die from sudden cardiac sudden death caused by malignant arrhythmia. It is one of the important reasons for the death of the patients with heart failure. Electrophysiological remodeling refers to the changes in the electrical impulse and conduction mechanism of cardiac myocytes in the heart failure, which involves changes in the function of various ion channels and cell signal transduction systems, in which the L type calcium current changes and the action potential time (Acti) On potential duration, APD) is the key link. At present, there is still a lack of effective drugs for electrophysiological remodeling of heart failure for clinical selection. The study of traditional Chinese medicine may be the breakthrough point to solve this problem. Chinese medicine thinks that qi deficiency is the basic pathogenesis of heart failure, which runs through the development of heart failure, and Yiqi medicine is one of the prevention and treatment of heart failure in Chinese medicine. Basic drugs can improve cardiac function and clinical symptoms and improve the quality of life of patients with heart failure. Astragalus membranaceus, Codonopsis and ginseng are commonly used medications in clinical practice. At present, the mechanism of traditional Chinese medicine has the characteristics of multilevel, multi link, multi target and so on. The earlier study has discussed the improvement of Qi and drug from the angle of energy metabolism and sarcoplasmic reticulum calcium transport. The mechanism of cardiac function of heart failure model, but the mechanism of improving the prognosis of heart failure model has not been reported from the angle of electrophysiologic reconstruction. Two mice models of heart failure after coronary artery infarction and coarctation of the aorta caused by the coarctation of the aorta were used in this study. Cell patch clamp technique and Western Blot molecular biology methods have been studied from the whole, cell and molecular level to verify that "Yiqi drugs may inhibit the over expression of calcium / calmodulin dependent protein kinase II (calcium/calmodulin-dependent protein kinase II, CaMKII), regulate the L type calcium current of heart failure cells and shorten the heart failure of cardiac myocytes. The scientific hypothesis of cardiac repolarization time, improving electrophysiological remodeling of heart failure. Method 1. animal model: coronary ligation, aortic coarctation, heart failure after myocardial infarction and pressure load heart failure in two mice; 2. groups and administration: (1) the mice were divided into model group, sham operation group and Qi supplementing group (astragalus + party) after coronary artery ligation. The 4 groups in the western medicine group (Mei TORO M) were given the corresponding drug intervention for 4 weeks after operation; (2) the mice were randomly divided into model group, sham operation group, Huang Qi group (Huang Qi), ginseng group (ginseng), Panax Codonopsis (Codonopsis) group (Codonopsis pilosula) and Western medicine group (Mei TORO M) for 4 weeks after operation, and 3. test methods: (1) 4 weeks after coronary ligation. 4 weeks after the coarctation of the rat and the aorta, the mice were recorded body weight, death and other general conditions. The cardiac contractions, diastolic and ventricular remodeling were detected by the echocardiography of small animals. The incidence of QT interval and ventricular arrhythmia was detected by electrocardiogram. (2) 4 Zhou Xiaoshu acute isolated myocardial cells after coarctation of aorta and full cell diaphragm were used. The clamp technique was used to record the APD of myocardial cells, and the L calcium current density, the inactivation time constant (T) and the voltage dependent activation inactivation curve were recorded by the whole cell voltage forceps mode. (3) the myocardium was taken for 4 weeks after the coarctation of the aorta, and the L calcium channel was detected by Western Blot technique and the protein expression level of CaMKII. The evaluation of 1. heart failure model: (1) the left ventricular ejection fraction (left ventricular ejection fraction, LVEF) in the model mice of the 4 weeks after coronary artery ligation decreased significantly (P0.01), the left ventricular inner diameter increased significantly (P0.01), and the corrected QT interval (QTc) was significantly prolonged (P0.01); (2) the model mice and the artificial hand after the coarctation of the aorta were 4 weeks after the operation. Compared with LVEF (P0.01), left ventricular inner diameter increased (P0.05), left ventricle anterior wall thickness increased significantly (P0.01), Ea significantly decreased (P0.01), QTc significantly prolonged (P0.01) the intervention effect of.2. (P0.01).2. supplementing drug on heart function and QT interval of heart failure mice: (1) 4 weeks after coronary artery ligation, the supplementing Qi group was higher than the model group. Compared with the model group, there was no significant difference in LVEF between the western medicine group and the model group, and the QTc was significantly shorter than the model group (P0.01). (2) at 4 weeks after the coarctation of the aorta, the LVEF increased (P0.05) and the Ea increased significantly (P0.01) compared with the model group, and the LVEF group was significantly higher than the model group (P0.01); the Astragalus group and the ginseng group were significantly higher than the model group. Compared with the model group, QTc significantly shortened the effect of (P0.01).3. supplementing on APD and L type calcium current of heart failure cells: (1) compared with the sham group, APD: model group was significantly longer (P0.01) when the 0.21,2.0Hz frequency stimulated the repolarization of cardiac action potential (APD90), and the astragalus group was compared with the model group in 0.2Hz, 2.0Hz frequency. Myocardial cell APD90 shortened (P0.05) under the rate of rate stimulation. Compared with the model group, the APD90 significantly shortened (P0.01) under the 0.2Hz and 2.0Hz frequency stimulation, and the APD90 shortened (P0.05) compared with the model group under the intervention of isoproterenol (isoprenaline, ISO); (2) ICa, L current density: the model group was compared with the sham operation group. The current density of ICa and L increased significantly (P0.01) under the stimulation of Z, and the current density of L decreased significantly (P0.01) in ICa under 1.0Hz stimulation compared with the model group. Compared with the model group, the group of Codonopsis and Codonopsis were 0.1 Hz, 1.0Hz stimulated ICa, and the L current density decreased. Inactivation time constant: the model group was compared with the sham group ICa, the L rapid inactivation time constant (tau 1) and the slow inactivation time constant (tau 2) were significantly prolonged (P0.01). Compared with the model group, the Astragalus group, the ginseng group and the Codonopsis group were significantly shorter than the model group (P0.01); (4) the voltage dependent activation deactivation: the model group was half activated compared to the sham operation group. Potential decrease (P0.01), Astragalus group, ginseng group, Codonopsis group, and Western medicine group compared with the model group, the median activation potential increased significantly (P0.01) the intervention effect of.4. supplementing drug on L calcium channel and CaMK II expression in heart failure mice: (1) there was no statistical difference between the model group and the sham group CANCA1C (the main subunit of the L type calcium channel), and the difference between the model group and the sham group. There was no significant difference in the level of CANCA1C expression in the drug group compared with the model group. (2) the expression level of CaMK II protein in the model group was significantly higher than that in the sham group (P0.01). The expression level of the CaMK II protein in the Astragalus group, the ginseng group, the Codonopsis group, the western medicine group and the model group were all significantly lower (P0.01). Conclusion the conclusion of the drug (Astragalus membranaceus + Codonopsis) can shorten the myocardial infarction (P0.01). Heart failure repolarization time, but not significantly improved cardiac function after myocardial infarction, astragalus, ginseng, Codonopsis can shorten the heart failure heart repolarization time, improve heart failure electrophysiological reconfiguration, and Astragalus can improve cardiac contractile and diastolic function, Codonopsis can improve cardiac contractile function; 2. Yiqi medicine yellow Radix astragalus, ginseng, and Codonopsis pilosula can interfere with L type calcium current density, inactivation speed, voltage dependent activation, inactivation, reactivation of L type calcium current in heart failure cells, shorten the repolarization time of action potential of heart failure cells, and intervene electrophysiological reconstruction of heart failure cells, among which, the intervention effect of Radix Codonopsis and Astragalus membranaceus is significant; 3. the Astragalus membranaceus (Astragalus membranaceus) Ginseng and Codonopsis pilosula can regulate L type calcium channel by inhibiting CaMK II overexpression.
【學(xué)位授予單位】：北京中醫(yī)藥大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R541.6

【相似文獻】

相關(guān)期刊論文 前10條

1 黃麗潔,解立新,賈琳,趙曉巍,劉又寧,茍鵬;雜種犬急性呼吸窘迫綜合征模型的建立[J];中國比較醫(yī)學(xué)雜志;2004年04期

2 張臣顥;張曼芳;謝青蓮;成志恒;鄒洪;金玫蕾;;慢性不可預(yù)知溫和應(yīng)激抑郁小鼠模型的建立[J];復(fù)旦學(xué)報(自然科學(xué)版);2011年03期

3 譚瀟;肖建華;;1型糖尿病小鼠模型的構(gòu)建[J];國際檢驗醫(yī)學(xué)雜志;2011年14期

4 任文英,陳香美,邱全瑛,陳揚榮,王新高,師鎖柱,王兆霞;慢性移植物抗宿主病狼瘡樣小鼠模型的誘導(dǎo)[J];中國比較醫(yī)學(xué)雜志;2004年04期

5 王艷春,呂莉;彌散性血管內(nèi)凝血模型的改進[J];第四軍醫(yī)大學(xué)吉林軍醫(yī)學(xué)院學(xué)報;2005年02期

6 陳小囡;;蜂膠對慢性酒精性肝損傷的保護作用及其機制研究[J];健康研究;2009年02期

7 武君;孫長崗;鄭華;;愈寧散對CITP模型小鼠外周血共刺激分子CD86影響的實驗研究[J];實用中醫(yī)內(nèi)科雜志;2010年09期

8 王紫;陳瑜;羅軍;周建華;;槐杞黃干預(yù)小鼠IgA腎病模型的療效觀察以及機制探討[J];中國中西醫(yī)結(jié)合腎病雜志;2011年11期

9 孫旖;夏振娜;袁伯俊;張曉芳;陸國才;;LT-Y008的骨髓保護作用及機制[J];中國藥理學(xué)與毒理學(xué)雜志;2013年03期

10 周厚廣,鮑遠程,陸建明;提高帕金森病動物模型制作成功率的方法學(xué)探討及模型綜合評價[J];國際神經(jīng)病學(xué)神經(jīng)外科學(xué)雜志;2005年04期

相關(guān)會議論文 前10條

1 閻明;張喜紅;劉莉;孟繁立;張莉;朱萍;;美能對酒精性肝纖維化大鼠的干預(yù)及治療研究[A];第五屆全國肝臟疾病臨床暨中華肝臟病雜志成立十周年學(xué)術(shù)會議論文匯編[C];2006年

2 王勇炫;吳偉康;吳以嶺;張選紅;;蜈蚣有效部位抗心肌缺血的NO機制研究[A];2009年全國中藥學(xué)術(shù)研討會論文集[C];2009年

3 周友龍;李建生;高劍峰;;老齡大鼠腦缺血再灌注微血管再生的變化意義[A];中國中西醫(yī)結(jié)合學(xué)會第五屆基礎(chǔ)理論研究專業(yè)委員會學(xué)術(shù)研討會論文集[C];2006年

4 趙萬軍;周輝;韓勇;何永江;;丹參對激素性股骨頭壞死血管內(nèi)凝血的影響[A];2007年浙江省醫(yī)學(xué)會骨科學(xué)學(xué)術(shù)會議暨浙江省抗癌協(xié)會骨軟腫瘤學(xué)術(shù)會議論文匯編[C];2007年

5 孫元瑩;史曉峰;;益肺康顆粒對油酸致兔急性肺損傷實驗研究[A];2003年全國危重病急救醫(yī)學(xué)學(xué)術(shù)會議論文集[C];2003年

6 孫元瑩;史曉峰;;益肺康顆粒對油酸致兔急性肺損傷實驗研究[A];2004年全國危重病急救醫(yī)學(xué)學(xué)術(shù)會議論文集[C];2004年

7 李玉中;;復(fù)方甘正對非酒精性脂肪性肝炎的治療作用[A];第五次全國中青年檢驗醫(yī)學(xué)學(xué)術(shù)會議論文匯編[C];2006年

8 孫旖;夏振娜;袁伯俊;張曉芳;陸國才;;LT-Y008的骨髓保護作用及機制[A];2013年（第三屆）中國藥物毒理學(xué)年會暨藥物非臨床安全性評價研究論壇論文摘要[C];2013年

9 孫旖;夏振娜;袁伯俊;張曉芳;陸國才;;LT-Y008的骨髓保護作用及機制[A];中國藥理學(xué)與毒理學(xué)雜志(2013年6月第27卷第3期)[C];2013年

10 羅道樞;王瑋;;細胞外信號調(diào)節(jié)激酶在三叉神經(jīng)痛動物模型中的活化[A];2007年中國解剖學(xué)會第十屆全國組織學(xué)與胚胎學(xué)青年學(xué)術(shù)研討會論文摘要匯編[C];2007年

相關(guān)重要報紙文章 前1條

1 武漢市中西醫(yī)結(jié)合醫(yī)院 單萍;黃角顆�？鼓X梗死作用機理[N];中國中醫(yī)藥報;2007年

相關(guān)博士學(xué)位論文 前10條

1 沈斌;肝豆靈對銅負荷大鼠肝組織的miRNA-122和代謝組學(xué)的影響[D];湖北中醫(yī)藥大學(xué);2015年

2 趙賓賓;地五養(yǎng)肝膠囊抑制2-AAF/PH大鼠肝癌前病變的作用及機制[D];湖北中醫(yī)藥大學(xué);2015年

3 李思耐;基于L型鈣電流研究益氣藥干預(yù)心衰電生理重構(gòu)機制[D];北京中醫(yī)藥大學(xué);2016年

4 烏日圖那順;蒙藥“伊赫湯”對酒精性脂肪肝作用機理的實驗研究[D];北京中醫(yī)藥大學(xué);2015年

5 胡文軍;復(fù)方腦康膠囊治療Alzheimer's病的藥效學(xué)研究[D];南方醫(yī)科大學(xué);2012年

6 王濤;普利醇抗帕金森病的藥效學(xué)及其機制研究[D];中國協(xié)和醫(yī)科大學(xué);2009年

7 張志慧;老年性癡呆腦微血管發(fā)病機制及通心絡(luò)干預(yù)研究[D];河北醫(yī)科大學(xué);2010年

8 程靜;從津液代謝角度探討肺與大腸相表里的理論和實驗研究[D];湖北中醫(yī)藥大學(xué);2010年

9 張軍芳;芪藶強心膠囊對心力衰竭微血管損傷、心室重構(gòu)及代謝重構(gòu)的影響[D];河北醫(yī)科大學(xué);2013年

10 侯燕;冠狀動脈粥樣硬化模型豬膽固醇代謝異常對Aβ的影響及復(fù)方干預(yù)研究[D];遼寧中醫(yī)藥大學(xué);2015年

相關(guān)碩士學(xué)位論文 前10條

1 張子洋;醒腦液對APPswe/PS1ΔE9雙轉(zhuǎn)基因小鼠腦內(nèi)Aβ及其降解酶NEP表達的影響[D];河北聯(lián)合大學(xué);2014年

2 韓金麗;急性胰腺炎大鼠神經(jīng)降壓素水平與腸黏膜損傷關(guān)系的實驗研究[D];河北醫(yī)科大學(xué);2015年

3 潘彩彬;膝關(guān)節(jié)炎治療儀對膝骨性關(guān)節(jié)炎軟骨形態(tài)及關(guān)節(jié)液細胞因子影響的實驗研究[D];福建中醫(yī)藥大學(xué);2015年

4 浦飛飛;敬釗纓毛蜘蛛毒素-V對LTP和認知行為改善作用的分子機制研究[D];北京協(xié)和醫(yī)學(xué)院;2015年

5 崔慶飛;酒精聯(lián)合高脂飲食誘導(dǎo)小鼠脂肪肝模型的建立及發(fā)病機制探討[D];河北醫(yī)科大學(xué);2015年

6 劉翠華;谷氨酰胺對膿毒癥小鼠氧化應(yīng)激作用效果的研究[D];河北醫(yī)科大學(xué);2015年

7 岳萌;Bufalin通過ERK/RSK2通路對ECA109細胞和裸鼠移植瘤作用的研究[D];河北醫(yī)科大學(xué);2015年

8 左玲;Xyloketal B對NAFLD的療效觀察和機制研究[D];暨南大學(xué);2015年

9 郎艷松;通心絡(luò)聯(lián)合阿托伐他汀、阿司匹林對新西蘭兔動脈粥樣硬化早期頸動脈外膜滋養(yǎng)血管新生相關(guān)炎癥機制的影響[D];河北醫(yī)科大學(xué);2015年

10 趙祥梅;結(jié)直腸炎相關(guān)結(jié)直腸腫瘤模型的建立與機制初步探討[D];廣西醫(yī)科大學(xué);2015年

，

本文編號：2135578