本文選題：血清淀粉樣蛋白A + 血管內(nèi)皮生長(zhǎng)因子受體2　； 參考：《山東大學(xué)》2016年碩士論文

【摘要】：研究背景動(dòng)脈粥樣硬化是冠狀動(dòng)脈和腦血管疾病最重要的病理過(guò)程,是引發(fā)猝死的主要原因。血管新生是動(dòng)脈粥樣硬化的關(guān)鍵致病因素之一。血管新生是指內(nèi)皮細(xì)胞在原有毛細(xì)血管的基礎(chǔ)上發(fā)生增殖、遷移,形成新的血管的過(guò)程。血管新生的作用有其兩面性,一方面血管新生可用于治療缺血性心臟病,這是一種在治療上需要促進(jìn)的血管新生；另一方面血管新生可以加速動(dòng)脈粥樣硬化中斑塊的進(jìn)展,導(dǎo)致斑塊不穩(wěn)定性增加,進(jìn)而發(fā)生破裂出血等,這是一種在治療上需要抑制的血管新生。根據(jù)其兩面性,可以將血管新生分為生理性和病理性兩種。探究病理性血管新生的發(fā)生機(jī)制可能為控制動(dòng)脈粥樣硬化的進(jìn)展提供新的靶點(diǎn)。血清淀粉樣蛋白A (Serum amyloid A, SAA)是一組極其保守的急性時(shí)相反應(yīng)蛋白家族,有SAA1、SAA2、SAA3及SAA4四個(gè)不同的亞型,其中SAA1是最主要的亞型。SAA主要由肝細(xì)胞合成分泌,在機(jī)體受到炎癥刺激時(shí)其血清濃度能迅速增加1000倍左右。因此,循環(huán)血液中高濃度的SAA是急性和慢性炎癥疾病的重要標(biāo)志物。作為一種急性時(shí)相蛋白,SAA在多種疾病(如類風(fēng)濕關(guān)節(jié)炎、巨細(xì)胞動(dòng)脈炎等)中可以促進(jìn)病理性血管新生。因此,探究SAA促進(jìn)血管新生的機(jī)制尤為重要。血管內(nèi)皮生長(zhǎng)因子(Vascular endothelial growth factor, VEGF)是促進(jìn)內(nèi)皮細(xì)胞血管新生的關(guān)鍵調(diào)控因子。血管內(nèi)皮生長(zhǎng)因子受體2 (Vascular endothelial growth factor receptor 2, VEGFR2)是VEGF的受體之一,是VEGF促血管新生信號(hào)轉(zhuǎn)導(dǎo)通路的門戶。VEGF/VEGFR2信號(hào)通路活化后,能夠發(fā)揮促內(nèi)皮細(xì)胞遷移、增殖和血管新生等作用。VEGFR2主要在血管內(nèi)皮細(xì)胞上表達(dá),但是其表達(dá)調(diào)控的機(jī)制尚待完善。以往研究顯示,SAA能夠促進(jìn)人頸動(dòng)脈內(nèi)皮細(xì)胞(Human carotid artery endothelial,HCtAE)中VEGF的表達(dá)；同時(shí),SAA能夠通過(guò)激活p38 MAPK信號(hào)轉(zhuǎn)導(dǎo)通路促進(jìn)內(nèi)皮細(xì)胞血管新生。因此我們推測(cè)SAA可能會(huì)影響VEGFR2的表達(dá)進(jìn)而引起血管新生的變化。目前,SAA, VEGFR2與血管新生的研究存在以下亟待解決的問(wèn)題：①SAA能否影響VEGFR2的表達(dá);②SAA影響VEGFR2表達(dá)的相關(guān)信號(hào)轉(zhuǎn)導(dǎo)通路；③SAA是否能夠通過(guò)影響VEGFR2的表達(dá)引起血管新生的變化。研究目的1.探討SAA對(duì)VEGFR2表達(dá)的影響；2.探索SAA影響VEGFR2表達(dá)的相關(guān)信號(hào)轉(zhuǎn)導(dǎo)通路；3.探索SAA引起的VEGFR2表達(dá)變化在血管新生中的作用。材料方法1.培養(yǎng)人臍靜脈內(nèi)皮細(xì)胞在內(nèi)皮完全培養(yǎng)基(Endothelial complete medium,ECM)中培養(yǎng)人臍靜脈內(nèi)皮細(xì)胞(Human umbilical vein endothelial cells, HUVECs),每2-3天換液一次并置于含有5% CO2的37℃溫箱中。待細(xì)胞達(dá)到合適密度時(shí)加入SAA1或待研究信號(hào)通路的激動(dòng)劑以及抑制劑刺激細(xì)胞。2.實(shí)時(shí)定量PCR (Real-time PCR)檢測(cè)利用Trizol法從HUVECs中提取出mRNA,并獲得相應(yīng)的cDNA。利用GAPDH為內(nèi)參檢測(cè)VEGFR2的mRNA表達(dá)。3.蛋白印記(Western blot)檢測(cè)收集內(nèi)皮細(xì)胞,提取蛋白,以GAPDH蛋白表達(dá)為內(nèi)參檢測(cè)VEGFR2的蛋白表達(dá)；以相應(yīng)總蛋白為內(nèi)參檢測(cè)p-ERK1/2, p-JNK及p-p38的蛋白表達(dá)。4.成管實(shí)驗(yàn)(Tube formation assay)在96孔板中鋪入matrigel基質(zhì)膠,待膠凝固后每孔加入密度為2×104的細(xì)胞量,以未加任何刺激的組為對(duì)照顯微鏡下觀察各實(shí)驗(yàn)組的成管情況。5.統(tǒng)計(jì)學(xué)分析所有數(shù)值均用Prism version 5和SPSS 18.0軟件進(jìn)行統(tǒng)計(jì)學(xué)分析。用單因素方差分析來(lái)確定有無(wú)統(tǒng)計(jì)學(xué)意義。結(jié)果用均值±標(biāo)準(zhǔn)差來(lái)表示,P0.05代表數(shù)據(jù)間具有統(tǒng)計(jì)學(xué)差異。結(jié)果1.SAA上調(diào)HUVECs細(xì)胞中VEGFR2的表達(dá)使用不同濃度梯度(0,5,10和50μg/ml)的SAA刺激HUVECs,24小時(shí)后收集細(xì)胞,提取蛋白和mRNA。通過(guò)Western blot及Real-time PCR發(fā)現(xiàn),與對(duì)照組相比,SAA呈劑量依賴性的方式上調(diào)VEGFR2的表達(dá)(P0.01)；以固定濃度的SAA (10μg/ml)刺激細(xì)胞,選擇不同時(shí)間點(diǎn)(0,2,3,6,12和24小時(shí))收集細(xì)胞,提取蛋白和mRNA。通過(guò)Western blot及Real-time PCR發(fā)現(xiàn),與對(duì)照組相比,SAA呈時(shí)間依賴性的方式上調(diào)VEGFR2的表達(dá)(P0.05)。2.膜受體FPRL1能夠介導(dǎo)SAA誘導(dǎo)的VEGFR2表達(dá)上調(diào)用膜受體FPRL1的特異性抑制劑WRW4預(yù)刺激細(xì)胞,通過(guò)Western blot發(fā)現(xiàn),與單獨(dú)SAA刺激組相比,WRW4能顯著抑制SAA誘導(dǎo)的VEGFR2的表達(dá)上調(diào)(P0.01)。用FPRL1特異性的激動(dòng)劑WKYMVm刺激細(xì)胞,WKYMVm組較對(duì)照組能明顯上調(diào)VEGFR2的表達(dá)(P0.01)。這一結(jié)果表明,FPRL1能夠介導(dǎo)SAA誘導(dǎo)的VEGFR2表達(dá)上調(diào)。3 HAPKs信號(hào)通路能夠介導(dǎo)SAA誘導(dǎo)的VEGFR2表達(dá)上調(diào)使用SAA刺激細(xì)胞后,通過(guò)Western blot發(fā)現(xiàn),與對(duì)照組相比,ERK1/2, JNK及p38的磷酸化水平顯著增強(qiáng)且在1小時(shí)達(dá)到高峰(P0.01)。然后分別使用三者特異性的抑制劑PD98059, SP600125以及SB203580刺激細(xì)胞6,12及24小時(shí)。Western blot結(jié)果顯示,加用三種抑制劑組較單獨(dú)SAA刺激組均能不同程度的降低VEGFR2的表達(dá)(P0.05)。這一結(jié)果表明,MAPKs信號(hào)通路能夠介導(dǎo)SAA誘導(dǎo)的VEGFR2表達(dá)上調(diào)。4.膜受體FPRL1能夠調(diào)控下游MAPKs信號(hào)通路的活化利用受體FPRL1的特異性抑制劑WRW4預(yù)處理細(xì)胞,Western blot結(jié)果顯示,WRW4組較單獨(dú)SAA刺激組能明顯抑制MAPKs信號(hào)通路的磷酸化(P0.05)。另外,我們用FPRL1的特異性激動(dòng)劑WKYMVm處理細(xì)胞,Western blot結(jié)果顯示,與對(duì)照組相比,用WKYMVm處理細(xì)胞組能夠顯著上調(diào)MAPKs信號(hào)通路的磷酸化水平(P0.01)。這一結(jié)果表明,FPRL1作為上游信號(hào)分子能夠調(diào)控MAPKs信號(hào)通路的活化。5.SAA誘導(dǎo)的VEGR2:表達(dá)增多能夠促進(jìn)內(nèi)皮細(xì)胞的血管新生利用受體VEGFR2的特異性抑制劑BIBF1120及FPRL1/MAPKs信號(hào)通路的激動(dòng)劑和抑制劑刺激細(xì)胞,成管實(shí)驗(yàn)結(jié)果顯示,較單獨(dú)SAA刺激組相比,加用BIBF1120, WRW4, PD98059, SP600125及SB20358均能夠顯著抑制內(nèi)皮細(xì)胞成管(P0.01)。而WKYMVm處理組較對(duì)照組相比則顯著促進(jìn)內(nèi)皮細(xì)胞成管(P0.01)。這些結(jié)果證實(shí)SAA誘導(dǎo)的VEGFR2的表達(dá)及相關(guān)信號(hào)通路能夠促進(jìn)內(nèi)皮細(xì)胞的血管新生。結(jié)論1.SAA能夠上調(diào)HUVECs細(xì)胞中VEGFR2的表達(dá)；2. FPRL1/MAPKs信號(hào)通路介導(dǎo)了SAA誘導(dǎo)的VEGFR2表達(dá)上調(diào)；3.SAA誘導(dǎo)的VEGFR2表達(dá)上調(diào)能夠促進(jìn)內(nèi)皮細(xì)胞的血管新生。
[Abstract]:Background atherosclerosis is the most important pathological process of coronary and cerebrovascular diseases. It is the main cause of sudden death. Angiogenesis is one of the key pathogenic factors of atherosclerosis. Angiogenesis is the process of proliferation, migration and formation of new blood vessels on the basis of the original capillary. On the one hand, angiogenesis can be used to treat ischemic heart disease. It is a kind of angiogenesis that needs to be promoted in treatment. On the other hand, angiogenesis can accelerate the progress of plaque in atherosclerosis, cause plaque instability to increase, break bleeding and so on. This is a kind of treatment. Angiogenesis may be divided into two physiological and pathological types based on its dual nature. Exploring the mechanism of pathological angiogenesis may provide a new target for controlling the progress of atherosclerosis. Serum amyloid A (Serum amyloid A, SAA) is an extremely conservative group of acute phase reactive protein families There are four different subtypes of SAA1, SAA2, SAA3 and SAA4, of which SAA1 is the main subtype.SAA mainly synthesized and secreted by liver cells, and the serum concentration can be increased by about 1000 times when the body is stimulated by inflammation. Therefore, the high concentration of SAA in the circulating blood is an important marker of acute and slow inflammatory diseases. Phase protein, SAA can promote pathological angiogenesis in a variety of diseases, such as rheumatoid arthritis, giant cell arteritis and so on. Therefore, it is particularly important to explore the mechanism of SAA to promote angiogenesis. Vascular endothelial growth factor (Vascular endothelial growth factor, VEGF) is a key regulator of endothelial cell angiogenesis. Growth factor receptor 2 (Vascular endothelial growth factor receptor 2, VEGFR2) is one of the receptors of VEGF. It is the activation of the portal.VEGF/VEGFR2 signaling pathway of angiogenesis pathway of VEGF promoting angiogenesis. It can express endothelial cell migration, proliferation and angiogenesis, but it is mainly expressed on vascular endothelial cells by.VEGFR2, but it is mainly expressed on vascular endothelial cells. The mechanism of expression regulation remains to be improved. Previous studies have shown that SAA can promote the expression of VEGF in human Human carotid artery endothelial (HCtAE), and SAA can promote the angiogenesis of endothelial cells by activating the p38 MAPK signal transduction pathway. Therefore, we speculate that SAA may affect the expression of VEGFR2 to induce the expression of VEGFR2. Changes in angiogenesis. At present, there are some problems to be solved in SAA, VEGFR2 and angiogenesis: (1) whether SAA can affect the expression of VEGFR2; (2) the correlation signal transduction pathway that SAA affects the expression of VEGFR2; (3) whether SAA can affect the changes of blood vessels by affecting the expression of VEGFR2. Purpose 1. to explore the expression of SAA to VEGFR2 2. to explore the correlation signal transduction pathway that SAA affects VEGFR2 expression; 3. explore the role of SAA induced VEGFR2 expression in angiogenesis. Material method 1. cultured human umbilical vein endothelial cells cultured human umbilical vein endothelial cells (Human umbilical vein endoth) in the endothelial complete medium (Endothelial complete medium, ECM) Elial cells, HUVECs), once every 2-3 days, the liquid was replaced once every 2-3 days and placed in a temperature box containing 5% CO2. When the cell reached the appropriate density, the SAA1 or the excitant to study the signal pathway and the real-time quantitative PCR (Real-time PCR) of the inhibitor stimulated cell.2. were detected by Trizol method from HUVECs, and the corresponding utilization was obtained. The mRNA expression of.3. protein imprint (Western blot) was used to detect the endothelial cells and extract the protein. The protein expression was detected by the expression of GAPDH protein as the internal parameter, and the protein expression was expressed as the internal parameter of the.3.. The protein expression of the corresponding total protein was used as the internal parameter for the detection of p-ERK1/2, and the protein expression of p-JNK and p-p38 was tested in the 96 hole plate. After the gel was solidified, the cell volume of each hole was 2 * 104, and the control group without any stimulation was used as the control microscope to observe the tube formation of each experiment group.5.. All the values were statistically analyzed with Prism version 5 and SPSS 18 software. Mean mean standard deviation, P0.05 represents the statistical difference between the data. Results 1.SAA up-regulated the expression of VEGFR2 in HUVECs cells using SAA stimulated HUVECs with different concentration gradient (0,5,10 and 50 u g/ml) and collected cells after 24 hours. The extraction of protein and mRNA. was found by Western blot and Real-time. The expression of VEGFR2 (P0.01) was up-regulated in the manner of the dependability; the cells were stimulated by a fixed concentration of SAA (10 mu g/ml), and the cells were collected at different time points (0,2,3,6,12 and 24 hours). The extraction of protein and mRNA. was found by Western blot and Real-time PCR. PRL1 can mediate SAA induced VEGFR2 expression by invoking a specific inhibitor of the membrane receptor FPRL1, WRW4 prestimulating cells. Through Western blot, it is found that WRW4 significantly inhibits SAA induced VEGFR2 expression up-regulation (P0.01), compared with the individual SAA stimulation group. VEGFR2 expression (P0.01). This result shows that FPRL1 can mediate SAA induced VEGFR2 expression up regulation of.3 HAPKs signaling pathway can mediate SAA induced VEGFR2 expression up-regulated the use of SAA stimulation cells, by Western blot, compared with the control group, the level of phosphorylation is significantly enhanced and reached the peak at 1 hours. 01). Then using three specific inhibitors PD98059, SP600125 and SB203580 stimulating cells 6,12 and 24 hours.Western blot, the results showed that the addition of three inhibitor groups could reduce the expression of VEGFR2 in varying degrees (P0.05). This result shows that MAPKs signaling pathway can mediate SAA VEGFR2 table. Up regulation of the.4. membrane receptor FPRL1 can regulate the activation of the downstream MAPKs signaling pathway by activating the receptor FPRL1 specific inhibitor WRW4 pretreated cells. Western blot results show that WRW4 group can significantly inhibit the phosphorylation of MAPKs signaling pathway (P0.05) than the single SAA stimulus group. Furthermore, we use the specific agonist of FPRL1 to treat cells. RN blot results showed that compared with the control group, the WKYMVm treated cell group could significantly increase the phosphorylation level of the MAPKs signaling pathway (P0.01). This result shows that FPRL1 as a upstream signal molecule can regulate the increase of VEGR2: expression induced by the activated.5.SAA of the MAPKs signaling pathway and can promote the angiogenesis of endothelial cell receptor VEGFR. 2 of the stimulants and inhibitors of the specific inhibitor BIBF1120 and FPRL1/MAPKs signaling stimulated the cells. The results of the tube test showed that the addition of BIBF1120, WRW4, PD98059, SP600125 and SB20358 to the individual SAA stimulation group could significantly inhibit the endothelial cell formation (P0.01). The WKYMVm treatment group significantly promoted the endothelium compared with the control group. Cell formation (P0.01). These results confirm that the expression of SAA induced VEGFR2 and the related signaling pathway can promote the angiogenesis of endothelial cells. Conclusion 1.SAA can up regulate the expression of VEGFR2 in HUVECs cells; 2. FPRL1/MAPKs signal pathway mediates the up regulation of VEGFR2 expression induced by SAA, and the up regulation of VEGFR2 expression induced by 3.SAA can be promoted. The vascular neovascularization of the skin cells.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：R543.5

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6 蘇葉翔;徐丹;成宜娟;尤啟冬;孫麗萍;;基于雜環(huán)并嘧啶類VEGFR-2抑制劑的設(shè)計(jì)及合成方法學(xué)研究[A];2012長(zhǎng)三角藥物化學(xué)研討會(huì)論文集[C];2012年

7 劉斌;趙怡芳;張文峰;;口腔頜面部淋巴管畸形的VEGF-C和VEGFR-3表達(dá)[A];2002全國(guó)口腔頜面部血管瘤治療與研究學(xué)術(shù)研討會(huì)論文匯編[C];2002年

8 郭海霞;李文益;薛紅漫;黎陽(yáng);夏焱;徐令;;慢病毒載體攜帶的VEGFR_2 sRNA對(duì)HL60的抑制作用[A];中華醫(yī)學(xué)會(huì)第十四次全國(guó)兒科學(xué)術(shù)會(huì)議論文匯編[C];2006年

9 陶蓓蓓;劉姝媛;張彩彩;付偉;蔡文杰;王益;沈慶;王銘潔;陳瑩;張利佳;朱依諄;朱依純;;H2S促血管新生的機(jī)制研究——H2S“受體”VEGFR2的發(fā)現(xiàn)[A];中國(guó)生理學(xué)會(huì)張錫鈞基金第十二屆全國(guó)青年優(yōu)秀生理學(xué)學(xué)術(shù)論文交流及評(píng)獎(jiǎng)會(huì)議綜合摘要[C];2013年

10 王熙才;劉馨;陳艷;金從國(guó);陳曉群;黃尤光;周永春;;口服型VEGFR-3 DNA疫苗在抑制肺癌中的作用[A];第十六屆中國(guó)科協(xié)年會(huì)——分3環(huán)境污染及職業(yè)暴露與人類癌癥學(xué)術(shù)研討會(huì)論文集[C];2014年

相關(guān)博士學(xué)位論文 前10條

1 趙文娟;氧濃度對(duì)人內(nèi)皮祖細(xì)胞VEGFR-1、VEGFR-2和CXCR4受體表達(dá)調(diào)控的研究[D];山東大學(xué);2015年

2 高國(guó)銳;激酶PI3K和VEGFR-2抑制劑的設(shè)計(jì)合成及生物活性研究[D];華東理工大學(xué);2015年

3 張祿卿;血管內(nèi)皮細(xì)胞生長(zhǎng)因子受體-3在血管新生與淋巴管新生中的不同機(jī)制研究[D];南京大學(xué);2011年

4 趙劍峰;非諾貝特對(duì)人RPE細(xì)胞及BN大鼠CNV模型VEGF-C和VEGFR-3表達(dá)變化影響的體內(nèi)、體外實(shí)驗(yàn)研究[D];昆明醫(yī)科大學(xué);2016年

5 艾軍華;VEGFR-1活化誘導(dǎo)上皮—間質(zhì)表型轉(zhuǎn)化促進(jìn)肝細(xì)胞癌侵襲轉(zhuǎn)移的研究[D];第三軍醫(yī)大學(xué);2008年

6 魏春山;葉下珠及其復(fù)方對(duì)HBx介導(dǎo)肝癌VEGFR3表達(dá)的影響[D];廣州中醫(yī)藥大學(xué);2012年

7 石小燕;VEGF-C及其受體VEGFR-3/Flt-4與腫瘤淋巴管生成、增殖及轉(zhuǎn)移關(guān)系的研究[D];華中科技大學(xué);2006年

8 王玲;HLECs分離培養(yǎng)及VEGFR-3結(jié)合肽靶向卵巢癌新生淋巴管分子顯像的實(shí)驗(yàn)研究[D];第三軍醫(yī)大學(xué);2009年

9 伍星;靶向VEGFR2超聲分子顯像小鼠H22移植瘤實(shí)驗(yàn)研究[D];重慶醫(yī)科大學(xué);2009年

10 范良生;靶向VEGFR-3的多肽TMTP2在惡性腫瘤靶向治療中的應(yīng)用研究[D];華中科技大學(xué);2012年

相關(guān)碩士學(xué)位論文 前10條

1 蘇婷婷;基于識(shí)別血管內(nèi)皮生長(zhǎng)因子受體2（VEGFR2）的腫瘤靶向治療研究[D];西南大學(xué);2015年

2 章偉慧;PKGⅡ?qū)ξ赴┘?xì)胞VEGFR2介導(dǎo)的信號(hào)轉(zhuǎn)導(dǎo)通路的影響及分子機(jī)制[D];江蘇大學(xué);2016年

3 呂梅;血清淀粉樣蛋白A對(duì)VEGFR2的表達(dá)及血管新生影響的研究[D];山東大學(xué);2016年

4 余楊瀟;新型芳基脲類VEGFR抑制劑的設(shè)計(jì)、合成及抗腫瘤活性研究[D];廣西醫(yī)科大學(xué);2016年

5 張瑋;文昌魚VEGF與VEGFR的時(shí)空表達(dá)與功能初探[D];中國(guó)海洋大學(xué);2012年

6 王定平;VEGFR1陽(yáng)性造血祖細(xì)胞在大腸癌肝轉(zhuǎn)移中的作用[D];瀘州醫(yī)學(xué)院;2012年

7 李鋼;新疆多民族食管鱗癌VEGFR-2與臨床病理生物學(xué)關(guān)系的研究[D];新疆醫(yī)科大學(xué);2015年

8 胡偉偉;VEGFR-Fc在DG44細(xì)胞中的表達(dá)及其生物活性檢測(cè)[D];安徽大學(xué);2013年

9 黃大偉;VEGFR_2siRNA腺病毒載體的構(gòu)建及其對(duì)腫瘤血管生成的影響[D];第四軍醫(yī)大學(xué);2005年

10 付春茂;弱激光照射對(duì)兔正畸牙周組織中VEGF受體VEGFR-2（VEGFR-2/KDR）表達(dá)影響的研究[D];吉林大學(xué);2005年

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