本文選題：ATRQβ-001疫苗 + 糖尿病腎病��； 參考：《華中科技大學(xué)》2016年博士論文

【摘要】：第一部分ATRQβ-001疫苗對(duì)STZ誘導(dǎo)的糖尿病腎病大鼠有效性研究目的：前期工作中我們研制出一種針對(duì)人血管緊張素Ⅱ受體1型的短肽治療性疫苗ATRQβ-001,本研究旨在驗(yàn)證ATRQβ-001疫苗在糖尿病腎病模型老鼠上是否有效,以鏈脲佐菌素(STZ)腹腔注射方法建立糖尿病腎病模型。方法：將ATR-001短肽與Qp-2aa病毒樣顆粒(VLP)用化學(xué)耦聯(lián)劑Sulfo-SMCC耦聯(lián)制備ATRQβ-001疫苗。Sprague Dawley大鼠隨機(jī)分為對(duì)照組和糖尿病組,糖尿病組用鏈脲佐菌素(60mg/kg)腹腔注射,1周后,模型組又隨機(jī)分為4組,每組15只老鼠：(1)糖尿病腎病(DN)組：等劑量皮下注射生理鹽水干預(yù)；(2)奧美沙坦(OM)組：按5mg/kg/d給予灌胃；(3) ATRQP-001組：將ATRQβ-001疫苗與氫氧化鋁佐劑乳化后,按400μg/只于第0、14、21天皮下多點(diǎn)免疫；(4) Qβ VLP (VLP)組：將QβVLP與氫氧化鋁佐劑乳化,按4001μg/只于第0、14、21天皮下多點(diǎn)免疫。干預(yù)后繼續(xù)觀(guān)察14周。所有大鼠每周稱(chēng)量體重,監(jiān)測(cè)血糖,每?jī)芍軠y(cè)定ATR-001特異性抗體滴度,每四周測(cè)定血壓,于第4、8、14周代謝籠測(cè)定老鼠尿量及24小時(shí)尿蛋白量。飼養(yǎng)結(jié)束后,檢測(cè)血肌酐、尿素氮水平和腎臟病理結(jié)構(gòu)改變。結(jié)果：ATRQP-001疫苗可產(chǎn)生較高滴度抗ATR-001抗體,并可有效降低糖尿病老鼠的血壓水平,最高降幅達(dá)19.4mmHg。疫苗免疫后不影響血糖血脂水平,但可降低24小時(shí)尿蛋白量、血肌酐、尿素氮水平,并減輕腎體比,逆轉(zhuǎn)nephrin、podocin表達(dá)下降,減輕足細(xì)胞損傷和系膜擴(kuò)張,且與奧美沙坦治療組無(wú)明顯統(tǒng)計(jì)學(xué)差異。結(jié)論：ATRQβ-001疫苗可有效改善鏈脲佐菌素(STZ)誘導(dǎo)的糖尿病腎病模型大鼠的腎功能和血壓水平,并減輕腎臟病理?yè)p害,與奧美沙坦治療組無(wú)明顯差異。第二部分ATRQP-001疫苗腎臟保護(hù)機(jī)制研究目的：本研究旨在探討ATRQβ-001疫苗的作用機(jī)制,主要從炎癥纖維化和對(duì)RAS系統(tǒng)的調(diào)控兩方面研究,并在體外用抗ATR-001抗體在大鼠腎臟系膜細(xì)胞系上進(jìn)一步評(píng)價(jià)。方法：檢測(cè)血漿中腎素活性(PRA)、血管緊張素(Ang)Ⅱ、Ang (1-7)、腎臟皮質(zhì)AngⅡ和Ang(1-7)含量,其中PRA和Ang Ⅱ用放射免疫分析方法檢測(cè),Ang(1-7)用高壓液相色譜技術(shù)檢測(cè)。Masson三色染色觀(guān)察腎臟纖維化,免疫組化檢測(cè)腎臟TGF-β1表達(dá)和單核巨噬細(xì)胞浸潤(rùn)情況,蛋白免疫印跡(western blot)檢測(cè)RAS相關(guān)蛋白表達(dá)和ERK1/2、p38 MAPK磷酸化水平,實(shí)時(shí)定量聚合酶鏈反應(yīng)(qRT-PCR)檢測(cè)RAS成分、促炎細(xì)胞因子和促纖維化生長(zhǎng)因子mRNA表達(dá)水平。體外實(shí)驗(yàn)評(píng)估抗ATR-001抗體(Anti-ATR-001)對(duì)高糖誘導(dǎo)的大鼠腎臟系膜細(xì)胞影響,western blot檢測(cè)TGF-β1和磷酸化ERK、Smad3水平,qRT-PCR檢測(cè)TGF-β1、膠原蛋白(Collagen)Ⅳ和纖連蛋白(Fibronectin)表達(dá)。結(jié)果：與奧美沙坦相比,ATRQβ-001疫苗并不增加循環(huán)中PRA和Ang Ⅱ濃度,二者均可降低腎臟組織中下調(diào)腎臟Ang Ⅱ濃度,并增加Ang(1-7)含量,抑制腎臟局部ACE-AngⅡ-ATIR軸表達(dá),上調(diào)ACE2-Ang (1-7)-mas軸。ATRQβ-001疫苗可有效減輕腎臟間質(zhì)纖維化水平,并減少腎小球和間質(zhì)巨噬細(xì)胞浸潤(rùn)數(shù)目,TGF-β1的表達(dá)和活性氧產(chǎn)生亦明顯減少。腎臟組織炎性細(xì)胞因子和促纖維生長(zhǎng)因子mRNA表達(dá)也在經(jīng)ATRQp-001疫苗和奧美沙坦治療后有所下降,且與兩組之間無(wú)統(tǒng)計(jì)學(xué)差異。體外實(shí)驗(yàn)中Anti-ATR-001可有效抑制高糖刺激下腎臟系膜細(xì)胞(RMCs) TGF-β1表達(dá)和Smad3磷酸化水平,其下游Collagen IV和Fibronectin的表達(dá)亦下調(diào)結(jié)論：ATRQβ-001疫苗主要通過(guò)調(diào)控RAS雙軸和抑制炎癥纖維化兩方面起到腎臟保護(hù)作用。第三部分ATRQβ-001疫苗的安全性研究目的：ATRQβ-001疫苗可減輕STZ誘導(dǎo)的糖尿病腎病模型大鼠腎臟病理?yè)p害,將進(jìn)一步在Sprague Dawley (SD)大鼠上觀(guān)察疫苗的安全性。方法：將ATR-001短肽與Qβ-2aa病毒樣顆粒(VLP)用化學(xué)耦聯(lián)劑Sulfo-SMCC耦聯(lián)制備ATRQp-001疫苗。Sprague Dawley大鼠隨機(jī)分為對(duì)照組和ATRQβ-001疫苗組,每組10只老鼠,疫苗組按400μg/只于第0、14、21天皮下多點(diǎn)免疫,對(duì)照組給予等劑量皮下注射生理鹽水。每?jī)芍軠y(cè)定抗ATR-001特異性抗體滴度,每四周測(cè)定血壓。在長(zhǎng)達(dá)150天的觀(guān)察期后,ELISA方法檢測(cè)血清中C3a和C5a含量,并取心臟、肺組織、腎臟、肝臟、脾臟,進(jìn)行HE染色和CD14、CD19免疫組化染色,觀(guān)察各組織臟器有無(wú)明顯炎癥反應(yīng)及炎性細(xì)胞浸潤(rùn)情況,取腎臟組織再進(jìn)行Masson三色、PAS染色和電鏡檢測(cè),確定有無(wú)免疫介導(dǎo)的腎臟病理?yè)p害。結(jié)果：ATRQβ-001疫苗可產(chǎn)生較高滴度抗ATR-001抗體,對(duì)正常老鼠血壓水平無(wú)影響。血清中C3a和C5a含量與對(duì)照組無(wú)明顯差異。HE染色顯示疫苗組各組織未見(jiàn)明顯炎癥反應(yīng),CD14、CD19免疫組化染色亦未見(jiàn)單核細(xì)胞和B細(xì)胞浸潤(rùn),腎臟組織未見(jiàn)系膜擴(kuò)張、間質(zhì)纖維化等病變,電鏡下足突無(wú)融合消失,腎小球系膜區(qū)無(wú)增生,基底膜無(wú)增厚,且未見(jiàn)明顯免疫復(fù)合物沉積。結(jié)論：ATRQβ-001疫苗不降低正常老鼠血壓,未產(chǎn)生明顯免疫介導(dǎo)的組織病理?yè)p害,安全性良好。
[Abstract]:The first part of the study on the efficacy of ATRQ beta -001 vaccine on STZ induced diabetic nephropathy rats: We developed a short peptide therapeutic vaccine against the human angiotensin II receptor 1 (ATRQ beta -001) in the early work. The purpose of this study was to verify whether the ATRQ beta -001 vaccine was effective in diabetic nephropathy model mice, with streptozotocin (S). TZ) the diabetic nephropathy model was established by intraperitoneal injection. Methods: the ATRQ beta -001 vaccine.Sprague Dawley rats were randomly divided into the control group and the diabetes group by the coupling of the ATR-001 short peptide and Qp-2aa virus like particles (VLP) with the chemical coupling agent Sulfo-SMCC, and the diabetic group was intraperitoneally injected with streptozotocin (60mg/kg). After 1 weeks, the model group was randomly divided into two groups. 4 groups, 15 rats in each group: (1) diabetic nephropathy (DN) group: equal dose of subcutaneous injection of saline; (2) O Mei Chatain (OM) group: 5mg/kg/d was given to the stomach; (3) group ATRQP-001: after the emulsification of ATRQ beta -001 vaccine and aluminum hydroxide adjuvant, subcutaneous immunization with 400 mu g/ only on 0,14,21 days; (4) Q beta VLP (VLP) group: Q beta P was emulsified with Al2O3 adjuvant and subcutaneous immunization at 4001 u g/ only on day 0,14,21. After intervention for 14 weeks, all rats were weighed and monitored every week, blood sugar was monitored, the titer of ATR-001 specific antibody was measured every two weeks, blood pressure was measured every week, and the urine volume and protein amount of 24 hours in the 4,8,14 Zhou Dai cage were measured. After the end of feeding, The serum creatinine, urea nitrogen level and renal pathological structure were detected. Results: ATRQP-001 vaccine can produce high titer and anti ATR-001 antibody, and can effectively reduce the blood pressure level of diabetic mice. The maximum decrease of 19.4mmHg. vaccine does not affect blood glucose and blood lipid level, but it can lower the urine protein, serum creatinine and urea nitrogen level by 24 hours. Reducing renal body ratio, reversing nephrin, podocin expression, alleviating foot cell injury and mesangial dilatation, and no significant difference with olmesartan treatment group. Conclusion: ATRQ beta -001 vaccine can effectively improve the renal function and blood pressure level of streptozotocin (STZ) induced diabetic nephropathy model rats, and reduce renal pathological damage, and Austria There is no significant difference in the treatment group of the mesarartan. Second part of the study of the renal protection mechanism of ATRQP-001 vaccine: the purpose of this study is to explore the mechanism of the ATRQ beta -001 vaccine, mainly from two aspects of inflammatory fibrosis and the regulation of the RAS system, and the further evaluation of the anti ATR-001 antibody in the mesangial cell line of the rat kidney in vitro. The contents of renin activity (PRA), angiotensin (Ang) II, Ang (1-7), renal cortex Ang II and Ang (1-7) were detected, of which PRA and Ang II were detected by radioimmunoassay. Ang (1-7) was detected by high pressure liquid chromatography with.Masson trichromatic staining to observe renal fibrosis and immunohistochemical detection of renal TGF- beta 1 and mononuclear macrophages Infiltration, protein immunoblotting (Western blot) detection of RAS related protein expression and ERK1/2, p38 MAPK phosphorylation level, real-time quantitative polymerase chain reaction (qRT-PCR) detection of RAS components, proinflammatory cytokines and fibrotic growth factor mRNA expression level. In vitro test and evaluation of anti ATR-001 antibody (Anti-ATR-001) on high glucose induced rat kidney Western blot detected TGF- beta 1 and phosphorylated ERK, Smad3 level, qRT-PCR detection of TGF- beta 1, collagen (Collagen) IV and fibronectin (Fibronectin) expression. Results: compared with olmesartan, ATRQ beta -001 vaccine did not increase the concentration of PRA in the circulation, and the two could lower the kidneys in the kidneys. Degree, and increase the content of Ang (1-7), inhibit the expression of local ACE-Ang II -ATIR axis of the kidney, up the ACE2-Ang (1-7) -mas axis.ATRQ beta -001 vaccine can effectively reduce the level of renal interstitial fibrosis, and reduce the number of glomerular and interstitial macrophage infiltration, the expression of TGF- beta 1 and the production of reactive oxygen species are also significantly reduced. The expression of VGF mRNA was also decreased after ATRQp-001 vaccine and olmesartan, and there was no statistical difference between the two groups. In vitro, Anti-ATR-001 could effectively inhibit the expression of TGF- beta 1 and Smad3 phosphorylation in renal mesangial cells (RMCs) under high glucose stimulation, and the expression of Collagen IV and Fibronectin downstream in the downstream was also down regulated. The ATRQ beta -001 vaccine plays the role of renal protection mainly through two aspects of regulating RAS biaxe and inhibiting inflammatory fibrosis. The safety of the third part of the ATRQ beta -001 vaccine: the ATRQ beta -001 vaccine can reduce the renal pathological damage in the diabetic nephropathy model rats induced by STZ, and will observe the epidemic in Sprague Dawley (SD) rats. Method: the ATRQp-001 vaccine.Sprague Dawley rats were randomly divided into the control group and the ATRQ beta -001 vaccine group by coupling the ATR-001 short peptide and the Q beta -2aa virus like granule (VLP) with the chemical coupling agent Sulfo-SMCC, each group of 10 mice in each group. The vaccine group was immunized at 400 mu g/ only on the second day of the 0,14,21, and the control group was given the equal dose of the subcutaneous injection. The anti ATR-001 specific antibody titer was measured every two weeks and blood pressure was measured every week. After the observation period of 150 days, the content of C3a and C5a in the serum was detected by ELISA method, and the heart, lung tissue, kidney, liver, spleen, HE staining and CD14, CD19 immunohistochemical staining were used to observe the obvious inflammatory reaction and inflammation in the organs and organs. Masson trichrome, PAS staining and electron microscopy were used to determine the renal pathological damage of renal tissue. Results: the ATRQ beta -001 vaccine could produce high titer and anti ATR-001 antibody and had no effect on the blood pressure level of normal mice. There was no significant difference in serum C3a and C5a content from the control group and the.HE staining showed that the serum content of C3a and C5a in the serum was not significantly different from that of the control group. No obvious inflammatory reaction was found in the tissue of the group. No mononuclear and B cell infiltration was found in CD14, CD19 immunohistochemical staining, no mesangial dilatation, interstitial fibrosis, no fusion disappeared, no hyperplasia of the glomerular mesangial region, no thickening of the basement membrane and no obvious immune complex deposition. Conclusion: ATRQ beta -001 pestilence The seedlings did not reduce the blood pressure of normal mice, and did not produce obvious immune mediated histopathological damage.
【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R587.2;R692.9

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