本文選題：血管通透性增高 + LPS　； 參考：《第三軍醫(yī)大學(xué)》2014年博士論文

【摘要】：血管通透性增高是嚴(yán)重創(chuàng)傷、膿毒癥患者的重要病理改變，表現(xiàn)為血管內(nèi)皮屏障受損，對液體、血漿蛋白、大分子物質(zhì)的通透性增高，導(dǎo)致組織水腫，促進內(nèi)環(huán)境紊亂等合并癥發(fā)生，研究闡明血管通透性增高的發(fā)生機制有助于維持內(nèi)環(huán)境穩(wěn)定、改善療效和提高存活率。脂多糖(lipopolysaccharide, LPS)是膿毒癥的重要啟動因子，目前認為LPS引起血管通透性增高主要有兩條途徑：“細胞間”途徑和“跨細胞”途徑。其中，“細胞間”途徑開放主要由內(nèi)皮細胞張力絲形成并收縮引起，并認為是調(diào)節(jié)血管通透性增高的主要途徑。然而近來研究發(fā)現(xiàn)，細胞張力絲聚合發(fā)生在LPS作用后的早期，4h后細胞骨架解聚重構(gòu)，張力絲消失，提示LPS誘導(dǎo)血管通透性增高還存在其他調(diào)節(jié)機制。 根據(jù)基礎(chǔ)研究，黏附連接是血管內(nèi)皮細胞間(除血腦屏障外)的主要連接方式，其主要結(jié)構(gòu)蛋白血管內(nèi)皮鈣粘蛋白(vascular endothelial cadherin, VE-cad)被胞吞可以引起黏附連接強度降低、細胞間隙開放和血管通透性增高。以往研究表明，VE-cad在細胞質(zhì)膜的表達取決于被胞吞的多少，而VE-cad的胞吞主要受網(wǎng)格蛋白介導(dǎo)，但近來有研究發(fā)現(xiàn)，上皮鈣粘蛋白(epithelial cadherin, E-cad)的胞吞可以通過非網(wǎng)格蛋白途徑——細胞質(zhì)膜微囊(caveolae，簡稱微囊)途徑完成，例如在人表皮樣癌細胞和胰腺導(dǎo)管癌上皮細胞，微囊可以胞吞E-cad，引起上皮細胞間黏附連接破壞、細胞分離和腫瘤轉(zhuǎn)移。那么，網(wǎng)格蛋白介導(dǎo)和微囊介導(dǎo)的VE-cad胞吞是否參與了LPS誘導(dǎo)的血管通透性增高，機制如何？ 據(jù)此，我們以CRL-2922內(nèi)皮細胞株為研究對象，研究內(nèi)容為以下三部分：①觀察網(wǎng)格蛋白介導(dǎo)和微囊介導(dǎo)的VE-cad胞吞在LPS誘導(dǎo)血管通透性增高中的作用；②探討網(wǎng)格蛋白介導(dǎo)和微囊介導(dǎo)的VE-cad胞吞導(dǎo)致LPS作用后不同程度的血管通透性增高的機制；③探討LPS作用后網(wǎng)格蛋白介導(dǎo)和微囊介導(dǎo)的VE-cad胞吞途徑轉(zhuǎn)換的機制。 主要實驗方法： 第一部分網(wǎng)格蛋白介導(dǎo)和微囊介導(dǎo)的VE-cad胞吞在LPS誘導(dǎo)血管通透性增高中的作用 (一)網(wǎng)格蛋白介導(dǎo)的VE-cad胞吞在LPS誘導(dǎo)血管通透性增高中的作用 1.采用人血管內(nèi)皮細胞株CRL-2922，檢測LPS (10μg/mL)作用不同時間(1h、2h、4h和6h)后VE-cad質(zhì)膜蛋白表達、單層細胞通透性，觀察變化規(guī)律。 2.采用人血管內(nèi)皮細胞株CRL-2922，觀察LPS作用不同時間(1h、2h、4h和6h)后網(wǎng)格蛋白與VE-cad的免疫共沉淀和共定位。 3.采用網(wǎng)格蛋白胞吞抑制劑CPZ (100μmol/L)和網(wǎng)格蛋白重鏈siRNA (50nmol/L)，觀察其對LPS作用(1h和4h)后網(wǎng)格蛋白與VE-cad的免疫共沉淀、VE-cad質(zhì)膜蛋白表達，以及單層細胞通透性的影響。 (二)微囊介導(dǎo)的VE-cad胞吞在LPS誘導(dǎo)血管通透性增高中的作用 1.采用人血管內(nèi)皮細胞株CRL-2922，觀察LPS作用不同時間(1h、2h、4h和6h)后Cav1與VE-cad的免疫共沉淀和共定位。 2.采用微囊抑制劑filipin (5μg/mL)和Cav1siRNA (50nmol/L)，觀察其對LPS作用(1h和4h)后Cav1與VE-cad的免疫共沉淀、VE-cad質(zhì)膜蛋白表達，以及單層細胞通透性的影響。 3.采用人血管內(nèi)皮細胞株CRL-2922，觀察LPS作用不同時間(1h、2h、4h和6h)后微囊主要結(jié)構(gòu)蛋白Cav1的蛋白表達和磷酸化(Tyr14)，以及Src的蛋白表達的變化，并觀察Src抑制劑SU6656(2μmol/L)和TLR4抑制劑CLI-095(5μg/mL)對LPS作用(1h和4h)后的Cav1磷酸化(Tyr14)、Cav1與VE-cad的免疫共沉淀、P-Cav1與VE-cad的免疫共沉淀、VE-cad質(zhì)膜蛋白表達，以及單層細胞通透性的影響。 第二部分網(wǎng)格蛋白介導(dǎo)和微囊介導(dǎo)的VE-cad胞吞導(dǎo)致LPS作用后不同程度的血管通透性增高的機制 1.采用人血管內(nèi)皮細胞株CRL-2922，觀察LPS作用不同時間(1h、2h、4h和6h)后VE-cad與Rab11(循環(huán)內(nèi)顆粒標(biāo)志物)的免疫共沉淀、VE-cad與LAMP2(次級內(nèi)顆粒/溶酶體標(biāo)志物)的免疫共沉淀的變化。 2.采用網(wǎng)格蛋白胞吞抑制劑CPZ和微囊抑制劑filipin，觀察其對LPS作用(1h和4h)后VE-cad與Rab11的免疫共沉淀、VE-cad與LAMP2的免疫共沉淀的影響。 第三部分LPS作用后網(wǎng)格蛋白介導(dǎo)和微囊介導(dǎo)的VE-cad胞吞途徑轉(zhuǎn)換的機制 1.采用人血管內(nèi)皮細胞株CRL-2922，觀察LPS作用不同時間(1h、2h、4h和6h)后細胞骨架的動態(tài)變化。 2.采用細胞骨架解聚劑Cyt D (2μmol/L)和細胞骨架穩(wěn)定劑Jasp (1μmol/L)，觀察其對LPS作用(1h和4h)后網(wǎng)格蛋白與VE-cad的免疫共沉淀、Cav1與VE-cad的免疫共沉淀、VE-cad與Rab11的免疫共沉淀、VE-cad與LAMP2的免疫共沉淀、VE-cad質(zhì)膜蛋白表達，以及單層細胞通透性的影響。 主要結(jié)果： 一、網(wǎng)格蛋白介導(dǎo)和微囊介導(dǎo)的VE-cad胞吞在LPS誘導(dǎo)血管通透性增高中的作用 (一)網(wǎng)格蛋白介導(dǎo)的VE-cad胞吞在LPS誘導(dǎo)血管通透性增高中的作用 1.正常對照組中VE-cad在質(zhì)膜蛋白表達高，LPS (10μg/mL)作用后VE-cad質(zhì)膜蛋白表達逐漸降低(P0.05)，VE-cad的總蛋白表達也逐漸降低(P0.05)。LPS作用后單層細胞通透性呈時間依賴性的增高(P0.05)。 2. LPS作用后網(wǎng)格蛋白的表達逐漸降低(P0.05)；網(wǎng)格蛋白與VE-cad的免疫共沉淀在LPS作用1h后增高(P0.05)，然后逐漸降低；免疫組合激光共聚焦顯微鏡觀察到網(wǎng)格蛋白與VE-cad的共定位在LPS作用1h后增高，在LPS作用4h后降低。 3.網(wǎng)格蛋白胞吞抑制劑CPZ (100μmol/L)和網(wǎng)格蛋白重鏈siRNA (50nmol/L)可以顯著降低LPS作用1h后網(wǎng)格蛋白與VE-cad的免疫共沉淀(P0.05)，增高LPS作用1h后VE-cad質(zhì)膜蛋白表達(P0.05)，改善LPS作用1h后的單層細胞通透性(P0.05)；但對LPS作用4h后網(wǎng)格蛋白與VE-cad的免疫共沉淀、VE-cad質(zhì)膜蛋白表達，以及單層細胞通透性沒有顯著影響。 (二)微囊介導(dǎo)的VE-cad胞吞在LPS誘導(dǎo)血管通透性增高中的作用 1. LPS作用后，Cav1與VE-cad的免疫共沉淀在正常對照組中幾乎未見，隨著LPS作用時間延長而逐漸增高(P0.05)，免疫組化激光共聚焦顯微鏡觀察其共定位也發(fā)現(xiàn)在LPS作用4h后有明顯的共定位。 2.微囊抑制劑非律平(5μg/mL)和Cav1siRNA (50nmol/L)可以顯著降低LPS作用4h后Cav1與VE-cad的免疫共沉淀，并增高VE-cad質(zhì)膜蛋白表達，以及改善單層細胞通透性(P0.05)。 3. LPS作用后，微囊主要的蛋白成分Cav1的蛋白表達無顯著變化，但其Tyr14位點磷酸化水平卻逐漸增高(P0.05)，Src蛋白表達呈時間依賴性的增高(P0.05)，TLR4抑制劑CLI-095(5μg/mL)可顯著降低LPS作用4h后增高的Src蛋白表達。Src抑制劑SU6656(2μmol/L)和TLR4抑制劑CLI-095(5μg/mL)可顯著降低LPS作用4h后的Cav1磷酸化(Tyr14)，減少Cav1與VE-cad的免疫共沉淀以及P-Cav1與VE-cad的免疫共沉淀(P0.05)，增加VE-cad質(zhì)膜蛋白表達(P0.05)，以及單層細胞通透性顯著降低(P0.05)。 二、網(wǎng)格蛋白介導(dǎo)和微囊介導(dǎo)的VE-cad胞吞導(dǎo)致LPS作用后不同程度的血管通透性增高的機制 1. LPS作用后，VE-cad與Rab11的免疫共沉淀在1h增高(P0.05)，隨后逐漸降低；VE-cad與LAMP2的免疫共沉淀在正常時幾乎未見，但隨LPS作用時間延長，呈時間依賴性的增高(P0.05)。 2. LPS作用1h后增高的VE-cad與Rab11免疫共沉淀可以被網(wǎng)格蛋白胞吞抑制劑CPZ顯著抑制(P0.05)，，但不受微囊抑制劑非律平的影響；LPS作用4h后增高的VE-cad與LAMP2的免疫共沉淀可以被微囊抑制劑顯著抑制(P0.05)，但不受網(wǎng)格蛋白胞吞抑制劑的影響。 三、LPS作用后網(wǎng)格蛋白介導(dǎo)和微囊介導(dǎo)的VE-cad胞吞途徑轉(zhuǎn)換的機制 1.正常對照組中，肌動蛋白呈均勻散在分布，細胞骨架無明顯的聚合；LPS作用1h后，肌動蛋白聚集呈點片狀，發(fā)生明顯聚合，可見細胞中細長的張力絲形成；4h后肌動蛋白重新顯示出散在分布的趨勢，細胞骨架解聚，張力絲幾近消失。 2.細胞骨架解聚劑Cyt D可顯著抑制LPS作用1h后增高的網(wǎng)格蛋白與VE-cad以及VE-cad與Rab11免疫共沉淀(P0.05)，顯著增高Cav1與VE-cad以及VE-cad與LAMP2的免疫共沉淀(P0.05)，顯著降低VE-cad質(zhì)膜蛋白表達(P0.05)，并加重LPS作用1h后的單層細胞通透性增高(P0.05)。在LPS作用1h后給予細胞骨架穩(wěn)定劑Jasp處理，可以顯著降低LPS作用4h后的Cav1與VE-cad以及VE-cad與LAMP2的免疫共沉淀(P0.05)，增高LPS作用4h后的VE-cad質(zhì)膜蛋白表達(P0.05)，并改善LPS作用4h后的單層細胞通透性(P0.05)。 結(jié)論： 1.網(wǎng)格蛋白介導(dǎo)和微囊介導(dǎo)的VE-cad胞吞均參與了LPS誘導(dǎo)的血管通透性增高，網(wǎng)格蛋白介導(dǎo)的VE-cad胞吞主要發(fā)生在LPS作用的早期(1～2h)，而微囊介導(dǎo)的VE-cad胞吞主要發(fā)生在LPS作用后期(4h)，并由LPS-TLR4-Src信號途徑激活。 2. VE-cad經(jīng)網(wǎng)格蛋白介導(dǎo)的胞吞后位于循環(huán)內(nèi)顆粒中，導(dǎo)致LPS作用早期(1～2h)VE-cad質(zhì)膜蛋白表達丟失和單層細胞通透性有限的增高，而VE-cad經(jīng)微囊介導(dǎo)的胞吞后位于次級內(nèi)顆粒/溶酶體中，導(dǎo)致后期(4h)嚴(yán)重的VE-cad質(zhì)膜蛋白表達丟失和單層細胞通透性增高。 3. LPS作用后細胞骨架先發(fā)生聚合然后解聚，這種動態(tài)變化調(diào)節(jié)VE-cad胞吞由網(wǎng)格蛋白介導(dǎo)向微囊介導(dǎo)轉(zhuǎn)換。
[Abstract]:The increase of vascular permeability is a serious trauma. The important pathological changes of patients with sepsis are the damage of the vascular endothelial barrier, the increase in the permeability of the liquid, plasma protein and macromolecules, the edema of the tissue and the disturbance of the internal environment. The study of the mechanism of the increase of the permeability of the blood tube helps to maintain the stability of the internal environment. Lipopolysaccharide (LPS) is an important promoter of sepsis. It is believed that there are two main ways of increasing vascular permeability by LPS: "intercellular" pathway and "cross cell" pathway. Among them, the opening of "intercellular" pathway is mainly formed by the formation and contraction of endothelial cell tension filament. It is considered to be the main way to regulate the increase of vascular permeability. However, recent studies have found that the polymerization of cell tension filament occurs at the early stage after the action of LPS. After 4h, the cytoskeleton disintegration and the disappearance of the tension filament, suggesting that there are other regulatory mechanisms for the increase of vascular permeability induced by LPS.
According to basic research, adhesion connection is the main connection between vascular endothelial cells (except the blood brain barrier). The main structural protein vascular endothelial cadherin (VE-cad) is swallowed, which can cause the adhesion strength to decrease, the intercellular space opening and the vascular permeability increase. The expression of cell plasmalemma depends on the number of endocytosis, and VE-cad's endocytosis is mainly mediated by grulin, but recent studies have found that the endocytosis of epithelial cadherin (E-cad) can be accomplished through the non grid protein pathway, the cell membrane microcapsule (caveolae, for short), for example, in human epidermoid cancer cells And the epithelial cells of pancreatic ductal carcinoma, microcapsules can endocytic E-cad, cause adhesion failure, cell separation and tumor metastasis in epithelial cells. Then, is grid protein mediated and microencapsulated VE-cad endocytosis involved in LPS induced increased vascular permeability, and how is the mechanism?
According to this, we take the CRL-2922 endothelial cell line as the research object. The following three parts are studied: (1) to observe the role of gridin mediated and microcapsule mediated VE-cad endocytosis in the increase of vascular permeability induced by LPS; secondly, to explore the different degree of vascular permeability induced by LPS in the action of grid protein mediated and microcapsule mediated VE-cad endocytosis. The mechanism of increase is discussed. The mechanism of LPS mediated cytosolic mediated and microencapsulated VE-cad endocytosis pathway is discussed.
The main experimental methods:
Part I the role of clathrin mediated and microencapsulated VE-cad endocytosis in LPS induced vascular permeability enhancement
(1) the role of clathrin mediated VE-cad endocytosis in increasing vascular permeability induced by LPS
1. the human vascular endothelial cell strain CRL-2922 was used to detect the expression of the plasma membrane protein (1H, 2h, 4H and 6h), and the permeability of the monolayer cells after different time (1H, 2h, 4H and 6h), and to observe the changes of the changes.
2. human endothelial cell line CRL-2922 was used to observe the co immunoprecipitation and co localization of clathrin and VE-cad after LPS treatment at different time (1H, 2h, 4H and 6h).
3. CPZ (100 mol/L) and gridin heavy chain siRNA (50nmol/L) were used to observe the effects of the immunoprecipitation, the expression of VE-cad plasma membrane protein and the permeability of the monolayer cells after LPS action (1H and 4h).
(two) the role of microencapsulation mediated VE-cad endocytosis in LPS induced vascular permeability enhancement
1. human endothelial cell line CRL-2922 was used to observe the immunoprecipitation and co localization of Cav1 and VE-cad after LPS treatment at different time (1H, 2h, 4H and 6h).
2. the effects of microcapsule inhibitor filipin (5 g/mL) and Cav1siRNA (50nmol/L) on the immunoprecipitation of Cav1 and VE-cad after LPS action (1H and 4h), the expression of VE-cad plasma membrane protein, and the permeability of monolayer cells were observed.
3. the human vascular endothelial cell line CRL-2922 was used to observe the protein expression and phosphorylation (Tyr14) of the major structural protein Cav1 of the microcapsules (Tyr14) and the changes in the expression of Src in different time (1H, 2h, 4H and 6h), and to observe the phosphorylation of the Src inhibitor SU6656 (2 micron) and the inhibitory agent (5 micron). The co immunoprecipitation of Cav1 and VE-cad, the immunoprecipitation of P-Cav1 and VE-cad, the expression of plasma membrane protein of VE-cad, and the permeability of monolayer cells.
The second part is the mechanism of vascular permeability enhanced by clathrin mediated and microencapsulated VE-cad endocytosis after LPS.
1. the human vascular endothelial cell strain CRL-2922 was used to observe the immunoprecipitation of VE-cad and Rab11 (the granule markers in circulation), and the changes of co precipitation between VE-cad and LAMP2 (the secondary granules / lysosome markers) after the action of LPS at different time (1H, 2h, 4H and 6h).
2. the effects of the immunoprecipitation of VE-cad and Rab11 after the action of LPS (1H and 4h) and the immunoprecipitation of VE-cad and LAMP2 were observed by using the trellis endocytosis inhibitor CPZ and the microcapsule inhibitor filipin.
The third part is the mechanism of LPS mediated mesocytosis and microencapsulated VE-cad endocytosis pathway.
1. human endothelial cell line CRL-2922 was used to observe the dynamic changes of cytoskeleton after LPS treatment at different time (1H, 2h, 4H and 6h).
2. the cytoskeleton depolymerization agent Cyt D (2 mu mol/L) and cytoskeleton stabilizer Jasp (1 mu mol/L) were used to observe the immunoprecipitation of the gridin and VE-cad after the action of LPS (1H and 4h), the immunoprecipitation of Cav1 and VE-cad, the immunoprecipitation of VE-cad and immunization, the expression of plasma membrane protein, and the monolayer cells. The influence of permeability.
Main results:
First, the role of clathrin mediated and microencapsulated VE-cad endocytosis in LPS induced vascular permeability enhancement.
(1) the role of clathrin mediated VE-cad endocytosis in increasing vascular permeability induced by LPS
1. in the normal control group, the expression of VE-cad in the plasma membrane protein was high, and the expression of VE-cad plasma membrane protein decreased gradually after the action of LPS (10 g/mL). The total protein expression of VE-cad decreased gradually (P0.05) after the action of.LPS, and the permeability of the monolayer was time dependent (P0.05).
After the action of 2. LPS, the expression of gridin was gradually reduced (P0.05); the immunoprecipitation of gridin and VE-cad increased (P0.05) after 1h (P0.05), and then decreased gradually. The co localization of gridin and VE-cad increased after LPS action 1H and decreased after LPS action 4H.
3. grid protein endocytosis inhibitor CPZ (100 mu mol/L) and gridin heavy chain siRNA (50nmol/L) can significantly reduce the immunoprecipitation (P0.05) of the gridin and VE-cad after LPS action 1H, and increase the expression of VE-cad plasma membrane protein after LPS action 1H (P0.05). Immunoprecipitation with VE-cad showed no significant effect on VE-cad plasma membrane protein expression and permeability of monolayer cells.
(two) the role of microencapsulation mediated VE-cad endocytosis in LPS induced vascular permeability enhancement
After the action of 1. LPS, the immunoprecipitation of Cav1 and VE-cad was hardly seen in the normal control group, and gradually increased with the prolongation of the time of LPS action (P0.05). The co localization of the immuno confocal laser scanning microscope also found that there was a clear co location after the action of LPS on 4H.
2. microcapsule inhibitor (5 g/mL) and Cav1siRNA (50nmol/L) can significantly reduce the immunoprecipitation of Cav1 and VE-cad after 4h, and increase the expression of VE-cad plasma membrane protein, and improve the permeability of monolayer cells (P0.05).
After the action of 3. LPS, the protein expression of the main protein component of the microcapsule, Cav1, had no significant changes, but the phosphorylation level of the Tyr14 site increased gradually (P0.05), the expression of Src protein showed a time dependent increase (P0.05), and the TLR4 inhibitor CLI-095 (5 micron) could significantly reduce the LPS as the Src protein expression inhibitor (2 mu) and the increase of Src protein expression (2 mu). The R4 inhibitor CLI-095 (5 mu g/mL) can significantly reduce the Cav1 phosphorylation (Tyr14) after LPS action 4h, reduce the immunoprecipitation of Cav1 and VE-cad, and P-Cav1 and VE-cad immunoprecipitation (P0.05), increase the expression of plasma membrane protein, and decrease the permeability of monolayer cells significantly.
Two, the mechanism of increased permeability of vascular endothelial cells induced by LPS mediated by clathrin and microencapsulation mediated VE-cad endocytosis.
After the action of 1. LPS, the immunoprecipitation of VE-cad and Rab11 increased in 1H (P0.05), and then gradually decreased, and the immunoprecipitation of VE-cad and LAMP2 was hardly seen at normal time, but with the prolongation of LPS action time, it showed a time dependent increase (P0.05).
2. LPS and Rab11 immunoprecipitation could be significantly inhibited by the VE-cad and Rab11 immunoprecipitation (P0.05), but not affected by the microcapsule inhibitor (P0.05), but the immune coprecipitation of VE-cad and LAMP2 after LPS action 4H could be significantly suppressed by microcapsule inhibitors (P0.05), but not by the trellis endocytosis inhibitors. Influence.
Three, the mechanism of LPS mediated mesocytosis and microencapsulated VE-cad endocytosis pathway.
1. in the normal control group, the actin was distributed evenly and the cytoskeleton was not obviously polymerized; after the LPS action 1H, the actin aggregation was a bit flaky, obviously polymerized, and the elongated ttene formed in the cells; after 4h, actin reshowed the distribution of the trend, the cytoskeleton depolymerized and the tension filament nearly disappeared.
2. cytoskeleton depolymerization agent Cyt D significantly inhibited the increase of LPS after 1h and VE-cad, VE-cad and Rab11 immunoprecipitation (P0.05), significantly increased Cav1 and VE-cad as well as VE-cad and LAMP2 immunoprecipitation, significantly reduced the expression of plasma membrane protein, and increased the permeability of monolayer cells after the action. P0.05). The cytoskeleton stabilizer Jasp treatment after the action of 1H can significantly reduce the immune coprecipitation (P0.05) of Cav1 and VE-cad as well as VE-cad and LAMP2 after LPS action 4h, and increase the expression of plasma membrane protein after LPS, and improve the permeability of monolayer cells after the action of LPS.
Conclusion:
1. grid protein mediated and microcapsule mediated VE-cad endocytosis participated in the increase of vascular permeability induced by LPS. The VE-cad endocytosis mediated by gridin occurred mainly in the early stage of LPS (1 to 2H), while microcapsule mediated VE-cad endocytosis occurred mainly in the late stage of LPS (4h) and activated by the LPS-TLR4-Src signal pathway.
2. VE-cad, which is located in the inner circulatory particles after the mesocytosis of the grid protein, leads to the loss of the expression of VE-cad plasma membrane protein and the limited permeability of the monolayer cells in the early stage of the LPS action, and VE-cad is located in the secondary granules / lysosomes after the endocytosis of the microcapsule, leading to the loss of the late (4h) expression of the VE-cad plasma membrane protein and the single VE-cad protein expression. The permeability of layer cells increased.
After 3. LPS, the cytoskeleton first polymerized and then depolymerized. This dynamic change regulates VE-cad cytosis mediated by clathrin mediated microencapsulation.

【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R459.7

【共引文獻】

相關(guān)期刊論文 前10條

1 劉志鋒;曾平;劉亞偉;唐柚青;童華生;蘇磊;;脂多糖和熱打擊聯(lián)合作用對人腸上皮細胞細胞骨架的影響[J];廣東醫(yī)學(xué);2010年18期

2 黃曉娟;宮兆華;陳劍;孫等軍;耿冬梅;成瑜;孫萍;張良明;;貝伐單抗聯(lián)合順鉑腹腔灌注治療惡性腹水療效觀察[J];中國醫(yī)藥科學(xué);2013年05期

3 趙醒;焦春敬;李春輝;胡潺潺;;150例食管鱗癌Caveolin-1和PCNA蛋白的表達及其生物學(xué)意義[J];重慶醫(yī)學(xué);2013年32期

4 吳憲巍;劉哲麗;;CCR3在濕性年齡相關(guān)性黃斑變性中的研究進展[J];國際眼科雜志;2014年03期

5 李柳葉;黃亞絹;;膽固醇對滋養(yǎng)細胞凋亡及尿酸產(chǎn)生的影響[J];國際婦產(chǎn)科學(xué)雜志;2014年02期

6 李佳;李言;張高峰;楊錫蘭;趙士弟;陳前芬;;法舒地爾對脂多糖誘導(dǎo)的大鼠急性肺損傷的影響[J];蚌埠醫(yī)學(xué)院學(xué)報;2014年06期

7 Sujana S Gunta;Robert H Mak;;Hypertension in children with obesity[J];World Journal of Hypertension;2014年02期

8 樂波;葛璞;艾青;林玲;張力;;過氧化氫酶:二甲雙胍藥理效應(yīng)新靶點?[J];醫(yī)學(xué)爭鳴;2015年02期

9 王盼;李言;張永;;Rho GTP酶調(diào)節(jié)肺血管內(nèi)皮屏障的研究進展[J];蚌埠醫(yī)學(xué)院學(xué)報;2015年05期

10 戴春光;肖軍;;Rho/Rho激酶信號通路與急性肺損傷/急性呼吸窘迫綜合征[J];華夏醫(yī)學(xué);2015年02期

相關(guān)博士學(xué)位論文 前10條

1 田曉峰;Caveolin-1在鼠視網(wǎng)膜新生血管形成中調(diào)控作用的研究[D];中南大學(xué);2011年

2 肖錚錚;垂體瘤卒中發(fā)病機制的研究[D];華中科技大學(xué);2012年

3 孫玉;Caveolin-1在氧化應(yīng)激致肺血管通透性增加中的作用和調(diào)控機制[D];山東大學(xué);2010年

4 李力;生物電場促進皮膚創(chuàng)面修復(fù)的細胞機制[D];第三軍醫(yī)大學(xué);2012年

5 陳鈞;中醫(yī)圓道理論指導(dǎo)下模擬微重力對骨髓間充質(zhì)干細胞分化潛能的影響[D];第四軍醫(yī)大學(xué);2012年

6 張又枝;NF-κB和PPAR-γ交叉對話調(diào)控LDL穿胞及其在動脈粥樣硬化中的作用[D];華中科技大學(xué);2013年

7 李琳;1、多灶肺癌的基因組學(xué)研究2、EMP2基因在非小細胞肺癌腫瘤轉(zhuǎn)移中的作用[D];北京協(xié)和醫(yī)學(xué)院;2013年

8 付思祺;皮膚組織擴張與細胞牽拉培養(yǎng)對表皮細胞生長及表達硫氧還蛋白影響的實驗研究[D];北京協(xié)和醫(yī)學(xué)院;2013年

9 徐慧敏;非小細胞肺癌放射性肺損傷的臨床特征、治療轉(zhuǎn)歸及生物學(xué)相關(guān)因素分析[D];北京協(xié)和醫(yī)學(xué)院;2013年

10 余利娃;CTEN調(diào)節(jié)EGF誘導(dǎo)的乳腺癌細胞上皮間質(zhì)轉(zhuǎn)化[D];天津醫(yī)科大學(xué);2013年

相關(guān)碩士學(xué)位論文 前10條

1 文雪;shRNA沉默p115基因表達抑制胃癌血管生成的體外研究[D];重慶醫(yī)科大學(xué);2011年

2 王茜;窖蛋白-1在波動性高糖誘導(dǎo)的內(nèi)皮細胞氧化應(yīng)激損傷中的作用及機制[D];大連醫(yī)科大學(xué);2011年

3 韓文峰;磷酸肌酸鈉對小鼠移植性S_（180）肉瘤血管生成的作用及其機制研究[D];河北醫(yī)科大學(xué);2009年

4 金玉峰;胰島素局部應(yīng)用對大鼠慢性創(chuàng)面愈合的影響及初步探討[D];第四軍醫(yī)大學(xué);2009年

5 高兵;負壓創(chuàng)面治療對慢性創(chuàng)面HIF-1α和VEGF表達的影響[D];重慶醫(yī)科大學(xué);2009年

6 胡智慧;125I粒子植入對人纖維肉瘤裸鼠模型微血管生成的影響[D];河北醫(yī)科大學(xué);2010年

7 清水汪;胃癌患者血清VEGF-A、VEGF-D、VEGFR-1表達及其臨床意義[D];第二軍醫(yī)大學(xué);2012年

8 柴旺;基于髓樣抑制細胞的黃芪多糖抗B16-F10黑色素瘤機制研究[D];北京化工大學(xué);2012年

9 雷文暉;PSTAT3和VEGF蛋白在腎癌中的表達及其臨床意義[D];福建醫(yī)科大學(xué);2012年

10 張量;缺氧對HUVECs生物學(xué)特性及VEGFR表達影響的體外實驗研究[D];瀘州醫(yī)學(xué)院;2012年

本文編號：1874242