本文選題：抑胃多肽 + 葡萄糖依賴性的促胰島素分泌多肽��； 參考：《第二軍醫(yī)大學(xué)》2010年博士論文

【摘要】： [背景]抑胃多肽(gastric inhibitory peptide;又稱葡萄糖依賴性促胰島素分泌多肽,glucose-dependent insulinotropic polypeptide; GIP)是由分布于十二指腸和空腸的K細(xì)胞分泌的一種含42個(gè)氨基酸的直鏈多肽。血液中GIP的濃度與飲食成份密切相關(guān),進(jìn)餐的質(zhì)與量決定了餐后GIP分泌的高低。葡萄糖、脂肪或氨基酸的攝入,均可促使GIP釋放,其中高脂飲食會(huì)明顯增加GIP的分泌；而低脂飲食,則GIP的分泌量偏低。GIP是一種較為重要的調(diào)控糖脂代謝的腸促胰島素(incretin)。GIP通過與其七次跨膜的G蛋白偶聯(lián)受體(GIPR)結(jié)合,發(fā)揮著調(diào)節(jié)脂肪細(xì)胞的分化成熟；調(diào)控脂肪細(xì)胞的脂解及再酯化；增加脂蛋白酯酶(LPL)的合成、分泌及活性,從而促進(jìn)甘油三酯(TG)的貯存；以及促進(jìn)脂肪細(xì)胞對(duì)葡萄糖(G)的攝取等作用�，F(xiàn)有的研究結(jié)果表明,GIP可能是過剩營養(yǎng)導(dǎo)致肥胖一個(gè)關(guān)鍵激素。在動(dòng)物試驗(yàn)中,采用GIP受體基因敲除鼠、GIP受體拮抗劑、減少小腸K細(xì)胞GIP的分泌等方法,均能有效抑制脂肪合成、控制肥胖、減少體重增加等。因此,阻斷或削弱GIP生物活性的方法可能是今后肥胖藥物治療的又一新靶點(diǎn),干擾GIP/GIPR信號(hào)通路在抗肥胖治療方面具有潛在研究前景。 基因工程疫苗領(lǐng)域的快速發(fā)展為抗肥胖領(lǐng)域研究提供了另一種可能的藥物治療策略。采用疫苗免疫獲得抗體,中和自身內(nèi)源性的GIP的方法,為戰(zhàn)勝肥胖及其相關(guān)并發(fā)癥帶來了新希望。目前已有研究者以噬菌體-病毒樣顆粒(Qβ-VLP)或卵清蛋白(ovalbumin)為載體,分別與GIP1-15位多肽序列或GIP1-11位多肽序列,采用化學(xué)耦聯(lián)方式結(jié)合,構(gòu)建蛋白疫苗,在小鼠模型上進(jìn)行了抗肥胖相關(guān)研究,兩種疫苗形式均能使小鼠打破免疫耐受,產(chǎn)生針對(duì)GIP的特異性抗體,從而獲得了抗肥胖或改善血糖的作用。疫苗治療的主要優(yōu)勢在于其僅需短期治療,卻可獲得長期收益,從而使患者依從性問題得到很好的解決。但這一點(diǎn)也使得疫苗的免疫治療存在一定潛在風(fēng)險(xiǎn),免疫治療產(chǎn)生的抗體后會(huì)在較長時(shí)間內(nèi)持續(xù)發(fā)揮效應(yīng),如一旦產(chǎn)生不良作用,短期之內(nèi)則難以祛除,因此GIP靶向的免疫治療在應(yīng)用前尚需在更多動(dòng)物模型上進(jìn)行研究比較,并給與相對(duì)綜合及長期地觀察和評(píng)價(jià)。目前認(rèn)為GIP/GIPR信號(hào)通路除調(diào)控能量代謝外,尚維系著機(jī)體的其他方面的很多重要功能。有研究發(fā)現(xiàn)GIPR在腦組織中廣泛表達(dá),同時(shí)GIP具有調(diào)節(jié)中樞神經(jīng)系統(tǒng)神經(jīng)祖細(xì)胞的增殖,減少有害物質(zhì)神經(jīng)元損傷的作用。因此,從一定程度上推斷,GIP可能具有調(diào)控機(jī)體行為和腦功能的作用。已有實(shí)驗(yàn)證實(shí)GIP過表達(dá)轉(zhuǎn)基因小鼠的感覺運(yùn)動(dòng)協(xié)調(diào)能力、認(rèn)知記憶能力明顯提升,說明高水平的GIP會(huì)引起行為學(xué)的改變。那么,通過免疫的方法改變血循環(huán)中的GIP水平,是否會(huì)對(duì)行為學(xué)及腦功能帶來影響,目前尚無關(guān)于這方面的相關(guān)研究和報(bào)道,因此,本實(shí)驗(yàn)采用構(gòu)建GIP疫苗,主動(dòng)免疫大鼠的方法,觀察免疫治療影響GIP/GIPR信號(hào)通路后對(duì)大鼠體重、行為學(xué)及腦功能發(fā)面的影響。 [目的]以乙肝核心抗原-病毒樣顆粒(HBc-VLP)或鑰孔戚血藍(lán)蛋白(KLH)為載體分別構(gòu)建攜帶GIP序列的蛋白疫苗HBc-GIP及GIP-KLH,主動(dòng)免疫高脂飲食大鼠,觀察疫苗免疫效果；高脂飲食大鼠主動(dòng)免疫GLP-KLH蛋白疫苗后,觀察其在體重、行為學(xué)以及腦功能方面的變化。初步探討以GIP為靶向的免疫干預(yù)治療的可行性及安全性問題,為肥胖的免疫治療提供理論和實(shí)驗(yàn)依據(jù)。 [方法]克隆GIP N端12肽的編碼cDNA序列,并與HBc VLP(1-144a.a.)cDNA序列進(jìn)行融合,通過原核表達(dá)及純化,制備攜帶GIP序列的HBc VLP疫苗(HBc-GIP);采用固相合成方法合成GIP成熟體多肽N端1-12序列,并將其C端與KLH耦聯(lián)構(gòu)建GIP蛋白疫苗(GIP-KLH);免疫高脂飲食大鼠并進(jìn)行免疫學(xué)指標(biāo)評(píng)價(jià)。通過對(duì)高脂飲食大鼠的體重稱量、行為學(xué)試驗(yàn)(開放場測試及Morris水迷宮測試)、正電子發(fā)射計(jì)算機(jī)斷層顯像儀(PET/CT)檢測腦糖利用率、TUNEL及PCNA的方法檢測海馬齒狀回細(xì)胞的增殖和凋亡情況來評(píng)估GIP-KLH疫苗免疫組與對(duì)照組(如期皮下多點(diǎn)注射KLH)在體重、行為學(xué)及腦功能方面存在的差異。 [結(jié)果] 1、成功制備了攜帶GIP抗原序列的HBc-GIP蛋白疫苗,并同時(shí)制備了編碼該融合蛋白序列的核酸疫苗pVAXl-HBc-GIP。兩種疫苗分別免疫或聯(lián)合免疫高脂飲食大鼠后,均可以產(chǎn)生GIP特異性抗體,而做為對(duì)照的HBc免疫組和PBS免疫組則沒有GIP特異性抗體的產(chǎn)生。說明我們制備的GIP核酸疫苗及蛋白疫苗均能夠打破宿主對(duì)自身GIP的免疫耐受而產(chǎn)生抗體。在免疫策略組合上,我們發(fā)現(xiàn)兩次免疫GIP核酸疫苗后再兩次免疫HBc-GIP蛋白疫苗的策略(pV-HBc-GIP*2+HBc-GIP*2)可以有效地誘導(dǎo)高滴度GIP抗體,其抗體滴度在第3輪免疫后開始顯著提高,并在第4輪加強(qiáng)免疫后繼續(xù)上升,最終持續(xù)產(chǎn)生高滴度的GIP特異性抗體,抗體最終滴度優(yōu)于4輪免疫HBc-GIP蛋白疫苗或GIP核酸疫苗的水平(P0.05)。因此,經(jīng)過兩種疫苗的聯(lián)合免疫,可以獲得高滴度的GIP特異性抗體IgG,顯示了良好的免疫效果。 2、成功制備了攜帶GIP抗原序列的GIP-KLH蛋白疫苗,免疫高脂飲食大鼠后,GIP-KLH疫苗組第二次免疫接種后7天,即產(chǎn)生了高滴度GIP特異性抗體,如期繼續(xù)免疫接種,抗體水平進(jìn)一步增高,而KLH對(duì)照組則(如期皮下多點(diǎn)注射KLH)沒有此變化。結(jié)果說明,經(jīng)過多次免疫GIP-KLH蛋白疫苗,可以獲得高滴度的GIP特異性抗體IgG,顯示了的良好免疫效果。 3、各組動(dòng)物在試驗(yàn)中,進(jìn)食情況無明顯統(tǒng)計(jì)學(xué)差異(P0.05), GIP-KLH疫苗免疫組與KLH對(duì)照組(如期皮下多點(diǎn)注射KLH)相比,體重增長減少。在初始體重?zé)o統(tǒng)計(jì)學(xué)差異的前提下,實(shí)驗(yàn)組與對(duì)照組于初次免疫后第63天,體重增長開始出現(xiàn)統(tǒng)計(jì)學(xué)差異(P0.05),在試驗(yàn)結(jié)束時(shí)(即初次免疫后第98天),GIP-KLH疫苗組與KLH對(duì)照組相比,體重少增長了48g(17%)。實(shí)驗(yàn)中GIP-KLH疫苗組空腹血糖及胰島素與KLH對(duì)照組相比無明顯統(tǒng)計(jì)學(xué)差異(P0.05)。 4、在行為學(xué)實(shí)驗(yàn)中,開放場試驗(yàn)(OFT)的測試結(jié)果顯示,GIP-KLH疫苗組與KLH對(duì)照組相比較,總路程(P0.01)、平均速度(P0.01)、活動(dòng)時(shí)間(P0.05)、活動(dòng)次數(shù)(P0.01)、在中央?yún)^(qū)域的活動(dòng)次數(shù)(P0.05)均明顯低于KLH對(duì)照組,休息時(shí)間(P0.05)明顯高于對(duì)照組,具有統(tǒng)計(jì)學(xué)差異。GIP-KLH疫苗組與KLH對(duì)照組相比,自發(fā)活動(dòng)性及在中央?yún)^(qū)域的活動(dòng)次數(shù)減低,因此GIP-KLH疫苗的主動(dòng)免疫影響到了大鼠的行為活動(dòng)及精神狀態(tài)。在Morris水迷宮測試(MWM)中,GIP-KLH疫苗組與KLH對(duì)照組動(dòng)物在4天的訓(xùn)練階段中均表現(xiàn)為逃避潛伏期和游泳距離的縮短(分別為F=6.5；P=0.001 and F=5.3；P=0.002,),以及游泳速度的明顯增快(F=3.3；P=0.024),結(jié)果表明兩組動(dòng)物都在努力學(xué)習(xí)定位隱藏的站臺(tái),但是兩組間無明顯統(tǒng)計(jì)學(xué)差異(P0.05)。在第5天的探索階段,兩組的表現(xiàn)也無明顯統(tǒng)計(jì)學(xué)差異(P0.05)。 5、在高脂飲食大鼠初次免疫后第98天,以18氟-脫氧葡萄糖(18F-FDG)為示蹤劑,通過PET/CT檢測大鼠腦糖利用率。GIP-KLH疫苗組與KLH對(duì)照組相比,海馬區(qū)、大腦皮層的腦糖利用率減低(P0.05),而嗅球及小腦的腦糖利用率無明顯差別(P0.05)。 6、通過末端脫氧核苷�；D(zhuǎn)移酶介導(dǎo)性dUTP切口末端標(biāo)記(TUNEL)和增殖細(xì)胞核抗原(PCNA)的方法,觀察海馬齒狀回顆粒細(xì)胞的增殖及凋亡情況。在GIP-KLH疫苗組與KLH對(duì)照組的病理切片中均可觀察到TUNEL陽性細(xì)胞(細(xì)胞核棕色著色)及PCNA陽性細(xì)胞(細(xì)胞核棕色著色),但GIP-KLH疫苗組TUNEL陽性細(xì)胞數(shù)及PCNA陽性細(xì)胞數(shù)較KLH對(duì)照組明顯增多,說明GIP-KLH疫苗組海馬齒狀回顆粒細(xì)胞的增殖及凋亡均增加。 [結(jié)論]以HBc(1-144a.a.)或KLH為載體,制備GIP疫苗,可以有效地誘導(dǎo)靶向大鼠GIP的特異性體液免疫反應(yīng),打破大鼠自身抗原耐受,誘生GIP特異性抗體。該疫苗可以做為一種新的控制肥胖的免疫干預(yù)藥物來進(jìn)一步深入研究。GIP-KLH主動(dòng)免疫干預(yù)治療高脂飲食大鼠,具有抗肥胖作用,但同時(shí)在一定程度上也影響到大鼠的行為學(xué)及腦功能活動(dòng)。
[Abstract]:[background] gastric polypeptide (gastric inhibitory peptide; also called Glucose dependent insulin secretion polypeptide, glucose-dependent insulinotropic polypeptide; GIP) is a 42 amino acid direct chain polypeptide secreted by K cells distributed in the duodenum and jejunum. The concentration of GIP in the blood is closely related to the dietary ingredients, and meals. Quality and quantity determine the level of GIP secretion after meal. The intake of glucose, fat or amino acids can promote the release of GIP, in which the high fat diet can significantly increase the secretion of GIP; while low fat diet, the low secretion of GIP by.GIP is a more important regulation of glycolipid metabolism of insulin (incretin).GIP through its seven transmembrane G Protein coupled receptor (GIPR) binding, which regulates the differentiation and maturation of adipocytes, regulates adipocyte lysis and re esterification, increases the synthesis, secretion and activity of lipoprotein esterase (LPL), thus promotes the storage of triglycerides (TG), and promotes the uptake of glucose (G) by adipocytes. The existing research results show that GIP In animal trials, the use of GIP receptor knockout mice, GIP receptor antagonists, and reducing the secretion of GIP in small intestinal K cells, can effectively inhibit fat synthesis, control obesity, and reduce weight gain in animal tests. Therefore, the method of blocking or weakening the biological activity of GIP may be a future obesity drug. Another new target of drug therapy is the interference of GIP/GIPR signaling pathway, which has potential research potential in anti obesity therapy.
The rapid development in the field of genetic engineering vaccines provides another possible therapeutic strategy for the field of anti obesity research. The use of vaccine immunization to obtain antibodies and neutralize endogenous GIP has brought new hope to defeat obesity and its related complications. Currently, researchers have phage virus like particles (Q beta -VLP) or egg white. Protein (ovalbumin) was used as a carrier, combined with GIP1-15 bit polypeptide sequence or GIP1-11 bit polypeptide sequence, combined with chemical coupling method to construct a protein vaccine. The anti obesity related research was carried out on the mouse model. The two vaccine forms can make mice break immune tolerance and produce specific antibodies against GIP, thus gaining anti obesity or modification. The main advantage of good blood sugar is that it is the main advantage of the vaccine treatment, but it only needs short-term treatment, but it can obtain long-term benefits, so that the patient compliance problem is well solved. But this also makes the vaccine immunotherapy have a certain potential risk, immune treatment produced antibodies will continue to play a long time after the effect, such as once. It is difficult to remove the adverse effects in the short term, so GIP targeted immunotherapy needs to be compared on more animal models before application, and gives a relatively comprehensive and long-term observation and evaluation. At present, the GIP/GIPR signaling pathway still maintains a lot of other important functions in other aspects of the body besides regulating energy metabolism. It has been found that GIPR is widely expressed in brain tissue, and GIP can regulate the proliferation of neural progenitor cells in the central nervous system and reduce the damage of harmful substance neurons. Therefore, to a certain extent, GIP may play a role in regulating the body's behavior and brain function. It has been proved that GIP overexpressed the sensory transport of transgenic mice. The ability of dynamic coordination and cognitive memory is obviously improved, indicating that high level of GIP can cause behavioral changes. Then, whether the GIP level in the blood circulation can be changed by immune method will affect the behavior and brain function. There is no related research and report on this. Therefore, this experiment uses the construction of GIP vaccine. To observe the effect of immune therapy on body weight, behavior and brain function of rats after immunization with GIP/GIPR signaling pathway.
[Objective] to construct the protein vaccine HBc-GIP and GIP-KLH carrying GIP sequence with hepatitis B core antigen virus like particle (HBc-VLP) or key keyhole hemocyanin (KLH) as the carrier, and actively immunization high fat diet rats and observe the immune effect of the vaccine. The weight, behavior and behavior of the high fat diet rats after the active immunization of the GLP-KLH protein vaccine are observed. The changes in brain function. The feasibility and safety problems of GIP targeted immunotherapy are preliminarily discussed in order to provide theoretical and experimental basis for the immunotherapy of obesity.
[method] the encoding cDNA sequence of GIP N terminal 12 peptide was cloned and the HBc VLP (1-144a.a.) cDNA sequence was fused. The HBc VLP vaccine (HBc-GIP) carrying GIP sequence was prepared by prokaryotic expression and purification. The solid-phase synthesis method was used to synthesize the 1-12 sequence of the GIP mature polypeptide. Lipid diet rats were evaluated by immunological indexes. By weighing the body weight of high fat diet rats, behavioral test (open field test and Morris water maze test), positron emission computed tomography (PET/CT) test of brain sugar utilization, TUNEL and PCNA methods were used to detect the proliferation and apoptosis of hippocampal gyrus, and to evaluate GIP There were differences in body weight, behavior and brain function between -KLH vaccine group and control group (subcutaneous multiple injection KLH).
[results]
1, the HBc-GIP protein vaccine carrying the GIP antigen sequence was successfully prepared, and the nucleic acid vaccine pVAXl-HBc-GIP. of the DNA vaccine encoding the fusion protein was also prepared and two vaccines were immunized or combined with high fat diet rats respectively, all of which could produce GIP specific antibodies, while the HBc immunization group and the PBS immune group did not have the specific resistance to GIP. The GIP nucleic acid vaccine and protein vaccine we prepared can break the host's immune tolerance to the GIP and produce antibodies. In the combination of immunization strategies, we found that the strategy of immunization of HBc-GIP protein (pV-HBc-GIP*2 +HBc-GIP*2) after two immunization of GIP nucleic acid vaccine (pV-HBc-GIP*2 +HBc-GIP*2) can effectively induce high titer GIP resistance. The antibody titer began to increase significantly after third rounds of immunization, and continued to rise after the fourth round of immunization, eventually producing a high titer GIP specific antibody. The final titer of the antibody was superior to the level of the 4 round immune HBc-GIP vaccine or the GIP nucleic acid vaccine (P0.05). Therefore, a high titer could be obtained by combined immunization of two vaccines. The GIP specific antibody IgG showed a good immunological effect.
2, the GIP-KLH protein vaccine carrying the GIP antigen sequence was successfully prepared. After immunization of the high fat diet rats, the GIP-KLH vaccine group produced a high titer GIP specific antibody after 7 days of immunization. The antibody level was further increased, while the KLH control group had no change in the subcutaneous multipoint injection of KLH. Ming, after repeated immunization with GIP-KLH protein vaccine, can obtain high titer of GIP specific antibody IgG, showing good immune effect.
3, there was no significant difference in food intake between the animals in each group (P0.05). The weight increase of the GIP-KLH vaccine group and the KLH control group (KLH as the subcutaneous multipoint injection) decreased, and the weight gain began to appear in the experimental group and the control group on the premise of no statistical difference (P 0.05) at the end of the experiment (the first ninety-eighth days after the first immunization), the GIP-KLH vaccine group increased the weight less 48g (17%) compared with the KLH control group. There was no significant difference between the fasting blood glucose and the insulin in the GIP-KLH vaccine group compared with the KLH control group (P0.05).
4, in the behavioral experiment, the open field test (OFT) test showed that the GIP-KLH vaccine group was compared with the KLH control group, the total distance (P0.01), the average speed (P0.01), the activity time (P0.05), the activity times (P0.01), the activity times in the central region (P0.05) were obviously lower than the KLH control group, and the rest time (P0.05) was obviously higher than that of the control group, and the rest time (P0.05) was significantly higher than that of the control group. Compared with the KLH control group, the spontaneous activity and the number of activities in the central region decreased in the.GIP-KLH vaccine group, so the active immunity of the GIP-KLH vaccine affected the behavior and the mental state of the rats. In the Morris water maze test (MWM), the GIP-KLH and KLH control groups were all fleeing in the 4 day training stage. The shortening of the incubation period and swimming distance (F=6.5; P=0.001 and F=5.3; P=0.002) and the rapid increase of swimming speed (F=3.3; P=0.024) showed that the two groups of animals were trying to learn to locate the hidden platform, but there was no significant difference between the two groups (P0.05). The performance of the two groups was not obvious at the fifth day of the exploration stage. Statistical difference (P0.05).
5, ninety-eighth days after the first immunization of high fat diet rats, 18 fluoro deoxyglucose (18F-FDG) was used as tracer. Compared with the KLH control group, the brain sugar utilization rate of the rat brain was compared with the control group of the KLH control group. The brain sugar utilization rate of the hippocampus and the cerebral cortex was decreased (P0.05), but the brain sugar utilization rate of the olfactory bulb and cerebellum was not significantly different (P0.05).
6, the proliferation and apoptosis of hippocampal dentate gyrus were observed by terminal deoxy nucleoside acyl transferase mediated dUTP incision terminal labeling (TUNEL) and proliferating cell nuclear antigen (PCNA). The TUNEL positive cells (brown color of nuclei) and PCNA positive cells were observed in the pathological sections of the GIP-KLH vaccine group and the KLH control group. The number of TUNEL positive cells and the number of PCNA positive cells in the GIP-KLH vaccine group were significantly higher than those in the KLH control group, indicating that the proliferation and apoptosis of the dentate gyrus cells in the GIP-KLH vaccine group were all increased.
[Conclusion] the preparation of GIP vaccine with HBc (1-144a.a.) or KLH as a carrier can effectively induce the specific humoral immune response of the target rat GIP, break the rat's self antigen tolerance and induce the GIP specific antibody. This vaccine can be used as a new immune intervention agent for controlling obesity to further study the.GIP-KLH active immune intervention treatment. The rats fed high-fat diet had anti obesity effects, but at the same time, they also affected the behavior and brain function of rats.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2010
【分類號(hào)】：R392

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