本文選題：胎盤 + 合體滋養(yǎng)層細胞��； 參考：《復(fù)旦大學(xué)》2014年博士論文

【摘要】：研究背景根據(jù)世界衛(wèi)生組織提供的數(shù)據(jù)顯示,全球每年約有1500萬例早產(chǎn)兒,其中又有約100萬例嬰兒死于早產(chǎn)并發(fā)癥,且這個數(shù)字仍在逐年上升。然而由于目前人類分娩啟動機制尚未完全解析,因此一直缺乏有效的防治早產(chǎn)的手段。于是,解析人類分娩啟動機制便成為近年來國際生殖生物學(xué)領(lǐng)域的研究熱點之一。在大多數(shù)哺乳類動物包括人類中,妊娠末期不斷增加的雌激素在分娩啟動過程中發(fā)揮著重要作用。雌激素誘導(dǎo)子宮肌層由靜息狀態(tài)向收縮狀態(tài)轉(zhuǎn)變,從而為分娩啟動做好準(zhǔn)備。因此,研究妊娠末期胎盤雌激素合成的調(diào)控對闡明分娩啟動機制至關(guān)重要。之前的研究已經(jīng)表明,在某些動物如綿羊中,糖皮質(zhì)激素是分娩啟動的關(guān)鍵激素,它能夠促進胎盤細胞色素P450c17羥化酶的表達,該酶催化胎盤孕激素向雌激素轉(zhuǎn)化,從而使得糖皮質(zhì)激素在降低孕激素水平的同時增加雌激素的合成與分泌。然而,靈長類動物包括人類的胎盤缺乏P450c1 7羥化酶,因此無法直接利用孕激素合成雌激素,取而代之的是,人類胎盤可以利用胎兒和母體腎上腺來源的脫氫表雄酮硫酸酯為前體,經(jīng)過一系列酶促反應(yīng)尤其是芳香化酶的作用最后生成雌激素。在人類胎盤中,糖皮質(zhì)激素能否通過影響芳香化酶的表達來促進胎盤雌激素的合成從而參與人類分娩啟動過程目前還未見報道。本研究以人胎盤組織及胎盤合體滋養(yǎng)層細胞為研究模型,采用免疫組織化學(xué)染色、體外胎盤滋養(yǎng)層細胞培養(yǎng)、實時熒光定量PCR (quantitative real time PCR, qRT-PCR)、蛋白印跡雜交(Western blotting)、酶聯(lián)免疫測定(Enzyme immunoassay, EIA)、小干擾RNA (small interfering RNA, siRNA)轉(zhuǎn)染、啟動子熒光素酶報告基因活性測定、化學(xué)發(fā)光微粒子免疫法(Chemiluminescent Microparticle immunoassay, CMIA)以及染色質(zhì)免疫共沉淀(chromatin immunoprecipitation, ChIP)等實驗技術(shù),聯(lián)合類固醇激素及其受體拮抗劑、信號通路激動劑及其拮抗劑和轉(zhuǎn)錄因子抑制劑等工具藥,研究了糖皮質(zhì)激素對人類胎盤合體滋養(yǎng)層細胞芳香化酶的表達調(diào)控作用及其分子機制。研究結(jié)果1.人胎盤組織的免疫組織化學(xué)染色結(jié)果表明,芳香化酶主要在胎盤絨毛小葉的合體滋養(yǎng)層中大量表達,而絨毛小葉的細胞滋養(yǎng)層細胞、間質(zhì)細胞和胎兒血管幾乎無表達。此外,通過qRT-PCR和Western blotting的測定發(fā)現(xiàn),芳香化酶的mRNA和蛋白水平隨著細胞滋養(yǎng)層細胞向合體滋養(yǎng)層細胞的分化而不斷增加。2. qRT-PCR和Western blotting測定結(jié)果表明,皮質(zhì)醇(0.01-1μM,24h)能夠劑量依賴性誘導(dǎo)人胎盤合體滋養(yǎng)層細胞芳香化酶mRNA和蛋白的表達。而且,EIA的測定結(jié)果表明,皮質(zhì)醇(1μM,24h)也可以誘導(dǎo)胎盤合體滋養(yǎng)層細胞中DHEA向雌二醇的轉(zhuǎn)化。3.免疫組織化學(xué)、普通PCR以及Western blotting的實驗表明,人胎盤合體滋養(yǎng)層細胞表達大量的糖皮質(zhì)激素受體(GR)；在此基礎(chǔ)上,我們采用qRT-PCR、Western blotting以及GR siRNA轉(zhuǎn)染細胞等實驗方法研究發(fā)現(xiàn),皮質(zhì)醇(0.1μM,24h)對人胎盤合體滋養(yǎng)層細胞芳香化酶mRNA和蛋白表達的誘導(dǎo)作用能夠被GR拮抗劑RU486 (1 μM)和GR siRNA(120 nM)阻斷；此外,皮質(zhì)醇對芳香化酶mRNA的誘導(dǎo)作用可以被蛋白質(zhì)合成抑制劑放線菌酮CHX(10 μM)阻斷,這些結(jié)果提示皮質(zhì)醇對人胎盤合體滋養(yǎng)層細胞芳香化酶mRNA表達的誘導(dǎo)作用需要GR參與介導(dǎo),但此介導(dǎo)作用可能是通過誘導(dǎo)其它蛋白合成間接實現(xiàn)的。4. qRT-PCR和Western blotting的檢測結(jié)果表明,cAMP的類似物db-cAMP(100μM,24h)和腺苷酸環(huán)化酶的激動劑Forskolin (l00 μM,24h)都能夠顯著。促進胎盤合體滋養(yǎng)層細胞芳香化酶的表達；此外,我們利用EIA方法測定胞內(nèi)cAMP水平發(fā)現(xiàn),皮質(zhì)醇(1μM,12h)可以顯著增加胎盤合體滋養(yǎng)層細胞的胞內(nèi)cAMP水平；進一步研究顯示,PKA的抑制劑H89(10μM)以及Gαs的抑制劑NF449(20 μM)均可以阻斷皮質(zhì)醇(1μM,24h)對胎盤芳香化酶表達的誘導(dǎo)作用。這些結(jié)果提示,皮質(zhì)醇對胎盤合體滋養(yǎng)層細胞中芳香化酶的表達調(diào)控是間接通過cAMP/PKA信號通路實現(xiàn)的。5.眾所周知,糖皮質(zhì)激素的經(jīng)典作用需要通過細胞內(nèi)的GR受體介導(dǎo),于是我們推測在胎盤合體滋養(yǎng)層細胞中,糖皮質(zhì)激素很可能通過GR誘導(dǎo)了與cAMP/PKA信號通路激活相關(guān)的激素的合成與分泌從而來促進胎盤芳香化酶的表達和雌激素的合成。已有報道,皮質(zhì)醇可以通過GR誘導(dǎo)胎盤合體滋養(yǎng)層細胞CRH和hCG的表達與分泌,并且CRH和hCG的受體都能激活cAMP/PKA信號通路。因此,我們對CRH和hCG是否參與了皮質(zhì)醇對人胎盤合體滋養(yǎng)層細胞芳香化酶的表達調(diào)控作用進行了研究。通過qRT-PCR測定發(fā)現(xiàn),皮質(zhì)醇(0.01-1μM,12h)可以劑量依賴性的誘導(dǎo)胎盤合體滋養(yǎng)層細胞CRH和hCG a與β亞基的表達,進一步用EIA和CMIA測定發(fā)現(xiàn),皮質(zhì)醇(1μM)處理胎盤合體滋養(yǎng)層細胞12小時后就可以顯著增加胎盤合體滋養(yǎng)層細胞CRH和hCG的分泌,且該作用可以一直持續(xù)到24小時。而且,qRT-PCR、 Western blotting以及EIA測定結(jié)果表明,CRH受體的非選擇性拮抗劑x-h-CRH (1 μM)和hCG抗體(1：100)單獨都可以部分阻斷皮質(zhì)醇(1gM)對胞內(nèi)cAMP水平和芳香化酶表達的誘導(dǎo)作用；當(dāng)這兩者聯(lián)合用藥時,則不僅可以降低胎盤合體滋養(yǎng)層細胞胞內(nèi)cAMP的基礎(chǔ)水平和芳香化酶的基礎(chǔ)表達,還能進一步完全阻斷皮質(zhì)醇對cAMP水平和芳香化酶表達的誘導(dǎo)作用。這些結(jié)果提示CRH和hCG不僅通過cAMP/PKA信號通路共同維持著胎盤合體滋養(yǎng)層細胞芳香化酶的基礎(chǔ)表達,而且還介導(dǎo)了皮質(zhì)醇對胎盤合體滋養(yǎng)層細胞芳香化酶的誘導(dǎo)作用。6.由于胎盤芳香化酶基因可以利用不同的轉(zhuǎn)錄起始位點來進行轉(zhuǎn)錄,因此我們通過設(shè)計識別不同轉(zhuǎn)錄產(chǎn)物的特異引物進行PCR,研究發(fā)現(xiàn)胎盤合體滋養(yǎng)層細胞主要表達芳香化酶基因啟動子PI.1的轉(zhuǎn)錄產(chǎn)物,并伴有少量啟動子PI.2和P2a的表達產(chǎn)物,qRT-PCR檢測結(jié)果還表明皮質(zhì)醇(1μM,24h)對包含芳香化酶基因外顯子I.1和包含外顯子2a的轉(zhuǎn)錄產(chǎn)物具有誘導(dǎo)作用,而對包含芳香化酶基因外顯子I.2的轉(zhuǎn)錄產(chǎn)物則無作用；此外,熒光素酶報告基因活性測定實驗發(fā)現(xiàn)皮質(zhì)醇(1μM,24h)和Forskolin (100 μM,24h)都可以顯著誘導(dǎo)胎盤合體滋養(yǎng)層細胞芳香化酶基因-501bp啟動子PI.1的活性,這說明皮質(zhì)醇通過作用于芳香化酶基因啟動子PI.1誘導(dǎo)了胎盤芳香化酶的表達。7.我們對芳香化酶基因啟動子PI.1序列生物信息學(xué)分析發(fā)現(xiàn),此序列上具有多個Sp1結(jié)合位點,因此進一步研究了Sp1在胎盤芳香化酶表達調(diào)控中的作用。用qRT-PCR和Western blotting的方法研究發(fā)現(xiàn),皮質(zhì)醇(1 μM)、 db-cAMP(100μM)和Forskolin (100 μM)處理細胞24h后都能夠顯著誘導(dǎo)胎盤合體滋養(yǎng)層細胞Sp1的表達,且皮質(zhì)醇對Sp1的誘導(dǎo)作用也可以被H89以及NF449所阻斷；此外,Sp1的拮抗劑光神霉素A (Mythramycin A, M,50μM)和Sp1的siRNA (60 nM)不僅能夠抑制胎盤芳香化酶的基礎(chǔ)表達,而且還能夠抑制皮質(zhì)醇和Forskolin對芳香化酶表達的促進作用。進一步用ChIP方法研究發(fā)現(xiàn),皮質(zhì)醇(1μM)以及db-cAMP(l00 μM)和Forskolin (100 μM)處理胎盤合體滋養(yǎng)層細胞24h都能促進Sp1與芳香化酶基因啟動子PI.1的結(jié)合。同時,a-h-CRH (1 μM)以及hCG抗體(1：100)單獨都可以部分阻斷皮質(zhì)醇對Sp1表達的誘導(dǎo)作用以及皮質(zhì)醇對Sp1與芳香化酶基因啟動子PI.1結(jié)合的促進作用；且當(dāng)兩者聯(lián)合給藥時,則不僅可以降低Sp1的基礎(chǔ)表達以及Sp1與芳香化酶基因啟動子PI.1基礎(chǔ)結(jié)合,而且還可以進一步完全阻斷皮質(zhì)醇對Sp1的誘導(dǎo)作用以及皮質(zhì)醇對Sp1與芳香化酶基因啟動子PI.1結(jié)合的促進作用。這些結(jié)果說明,Sp1介導(dǎo)了皮質(zhì)醇對胎盤合體滋養(yǎng)層細胞芳香化酶表達的誘導(dǎo)作用。皮質(zhì)醇(1 μM Forskolin (100 μM)和db-cAMP (100 μM)除了可以增加Sp1與胎盤合體滋養(yǎng)層細胞芳香化酶基因啟動子PI.1的結(jié)合外,還可以增加胎盤芳香化酶基因啟動子PI.1上組蛋白3第九位賴氨酸的乙酰化(Acetyl H3K9)水平,并降低組蛋白3第九位賴氨酸的雙甲基化(Dimethyl H3K9)水平,同時還能增加RNA聚合酶II(Pol Ⅱ)與芳香化酶基因啟動子PI.1的結(jié)合,這說明胎盤芳香化酶啟動子PI.1上組蛋白3的乙�；碗p甲基化也參與了皮質(zhì)醇對胎盤芳香化酶基因的表達調(diào)控。結(jié)論我們的研究結(jié)果表明,人胎盤芳香化酶主要在胎盤合體滋養(yǎng)層細胞中表達,且隨著胎盤滋養(yǎng)層細胞向合體滋養(yǎng)層細胞的融合而逐漸增加,此外,在合體滋養(yǎng)層細胞中,芳香化酶基因主要表達包含外顯子I.1的轉(zhuǎn)錄產(chǎn)物。我們的研究結(jié)果還表明,在人類胎盤合體滋養(yǎng)層細胞中,皮質(zhì)醇可以上調(diào)胎盤芳香化酶的表達,從而增加雌激素的合成。皮質(zhì)醇通過結(jié)合其自身受體GR,進而誘導(dǎo)了胎盤合體滋養(yǎng)層細胞中CRH和hCG的合成與分泌,分泌到細胞外的CRH和hCG激活胎盤合體滋養(yǎng)層細胞胞內(nèi)cAMP/PKA信號通路,該通路導(dǎo)致Sp1表達的增加以及Sp1與芳香化酶基因啟動子PI.1的結(jié)合的增加,并改變芳香化酶基因啟動子PI.1上組蛋白的表觀遺傳修飾,增強了芳香化酶基因啟動子PI.1的轉(zhuǎn)錄活性,從而使得胎盤芳香化酶的表達上調(diào)。本研究提供了糖皮質(zhì)激素上調(diào)人胎盤芳香化酶的表達從而促進雌激素合成的證據(jù),為糖皮質(zhì)激素參與人分娩啟動提供了新觀點,這些發(fā)現(xiàn)也可能為臨床干預(yù)早產(chǎn)提供新的思路。
[Abstract]:According to the research background, according to data provided by the WHO, there are about 15 million premature infants worldwide each year, of which about 1 million infants died of premature birth complications and the number is still rising year by year. However, due to the lack of complete parturition mechanism in human childbirth, there has been a lack of effective means to prevent premature delivery. The analysis of the initiation mechanism of human childbirth has become one of the hot topics in the field of International Reproductive Biology in recent years. In most mammals including humans, the increasing estrogen in the end of pregnancy plays an important role in the process of childbirth. The estrogen induces the uterine myometrium to change from resting state to contraction. Delivery is prepared. Therefore, the study of the regulation of estrogen synthesis at the end of pregnancy is essential to elucidate the mechanism of birth start. Previous studies have shown that glucocorticoid is the key hormone in some animals such as sheep, which can promote the expression of placental cytochrome P450c17 hydroxylase, which catalyzes the pregnancy of placenta pregnancy. However, primates, including human placenta, lack P450c1 7 hydroxylase, and therefore can not make direct use of progestin to synthesize estrogen, instead, the human placenta can use the fetus and mother's kidney. Glandular dehydroepiandrosterone sulfate is a precursor, and a series of enzymatic reactions, especially aromatase, are used to produce estrogens. In human placenta, whether glucocorticoids can promote the synthesis of placental estrogens by affecting the expression of aromatase to participate in the process of human childbirth has not yet been reported. The human placental tissue and the placental trophoblast cells were used as the research model, using immunohistochemical staining, cultured in vitro placental trophoblast cells, real-time fluorescent quantitative PCR (quantitative real time PCR, qRT-PCR), Western blot hybridization (Western blotting), enzyme immunoassay (Enzyme immunoassay, EIA), small interference RNA. Ng RNA, siRNA) transfection, promoter luciferase reporter gene activity assay, chemiluminescent particle immunization (Chemiluminescent Microparticle immunoassay, CMIA) and chromatin immunoprecipitation (chromatin immunoprecipitation, ChIP), combined with steroid hormone and its receptor antagonist, signal pathway agonist and The effect of glucocorticoid on the expression of aromatase in human placental syncytiotrophoblast and its molecular mechanism. The results of immunohistochemical staining of 1. human placental tissues showed that aromatase was mainly in the syncytiotrophoblast of placental villi. In addition, the mRNA and protein levels of aromatase increased with the differentiation of cell trophoblast cells to syncytrotrophoblast cells and the results of.2. qRT-PCR and Western blotting measured by qRT-PCR and Western blotting. Cortisol (0.01-1 mu M, 24h) can induce the expression of aromatase mRNA and protein in human placental trophoblast cells in a dose-dependent manner. Moreover, the results of EIA assay showed that cortisol (1 u M, 24h) can also induce the conversion of DHEA to estradiol in placental chimeric cells by.3. immunohistochemistry, ordinary PCR and Western blotting. The results show that human placental syncytiotrophoblast cells express a large number of glucocorticoid receptor (GR). On this basis, we use qRT-PCR, Western blotting and GR siRNA transfected cells to study the results of the results that the induction of cortisol (0.1 mu M, 24h) on the expression of the aromatase mRNA and protein expression of human placental syncytiotrophoblast cells can be G. R antagonists, RU486 (1 u M) and GR siRNA (120 nM), are blocked. In addition, the induction of cortisol to aromatase mRNA can be blocked by the protein synthesis inhibitor actinomycete CHX (10 u M). These results suggest that the inducement of cortisol to the expression of aromatase mRNA for human placental syncytiotrophoblastic cells requires GR involvement, but this mediating action The results of.4. qRT-PCR and Western blotting, which may be indirectly achieved by inducing other protein synthesis, showed that cAMP analogues db-cAMP (100 mu M, 24h) and adenylate cyclase, Forskolin (l00 mu M, 24h), were all significant. The intracellular cAMP level showed that cortisol (1 mu M, 12h) could significantly increase the intracellular cAMP level of the placental syncytiotrophoblast cells. Further studies showed that PKA inhibitor H89 (10 mu M) and G alpha s inhibitor NF449 (20 mu M) could block the induction of cortisol (1 mu M) on the expression of placental aromatase. These results suggest that the skin of the placental aromatase is induced. The regulation of aromatase in placental syncytiotrophoblast cells is known as.5., which is known indirectly through the cAMP/PKA signaling pathway. The classic role of glucocorticoids is mediated by intracellular GR receptors. Therefore, we speculate that glucocorticoids are likely to be induced by GR in placental syncytiotrophoblast cells by GR It has been reported that cortisol can induce the expression and secretion of CRH and hCG in the placental syncytiotrophoblast cells by GR, and that both CRH and hCG receptors can activate cAMP/PKA signaling pathways. Therefore, we are on CRH and hCG. The effect of cortisol on the regulation of the expression of aromatase in human placental syncytiotrophoblast was studied. The qRT-PCR assay showed that cortisol (0.01-1 M, 12h) could induce the expression of CRH and hCG A and beta subunits in placental chimeric trophoblast cells in a dose-dependent manner, and were detected by EIA and CMIA, and the treatment of cortisol (1 mu M). The placental syncytrotrophoblast cells can significantly increase the secretion of CRH and hCG in the placental trophoblast cells for 12 hours, and the effect can last for 24 hours. Moreover, qRT-PCR, Western blotting and EIA results show that the non selective antagonist of CRH receptor x-h-CRH (1 u M) and hCG antibody (1:100) can be partially isolated. The inhibitory effect of cortisol (1gM) on the intracellular cAMP level and aromatase expression, when the combination of these two drugs, can not only reduce the basal level of intracellular cAMP and the basic expression of aromatase in the placental syncytiotrophoblast cells, but also further completely block the induction of cortisol on the level of cAMP and aromatase expression. These results suggest that CRH and hCG not only maintain the basic expression of aromatase in the placental syncytiotrophoblastic cells through the cAMP/PKA signaling pathway, but also mediate the effect of cortisol on the aromatase of the placental syncytiotrophoblast cells,.6., as the placental aromatase gene can be transcribed with different transcriptional starting sites. So by designing specific primers that identify different transcripts for PCR, we found that placental syncytiotrophoblast cells mainly express the transcriptional products of aromatase gene promoter PI.1, accompanied by a small number of promoter PI.2 and P2a expression products. The qRT-PCR detection results also indicate that cortisol (1 mu M, 24h) is outside the inclusion of aromatase genes. The transcriptional products of the exon I.1 and the exon 2A were induced, while the transcriptional products containing the aromatase exon I.2 had no effect. In addition, the luciferase reporter gene activity assay found that cortisol (1 mu M, 24h) and Forskolin (100 mu M, 24h) could significantly induce the aromatase base of the placental syncytiotrophoblast cells. The activity of the -501bp promoter PI.1 suggests that cortisol induced the expression of placental aromatase by the role of the aromatase gene promoter PI.1.7.. We found that there are multiple Sp1 binding sites on the PI.1 sequence of the aromatase gene promoter, and thus further studies the Sp1 aromatase in the placenta. The expression of qRT-PCR and Western blotting showed that cortisol (1 mu M), db-cAMP (100 u M) and Forskolin (100 mu M) can significantly induce the expression of Sp1 of the placental syncytiotrophoblast cells, and the induction of cortisol to Sp1 can also be blocked by H89 and the antagonists. A (Mythramycin A, M, 50 mu M) and siRNA (60 nM) of Sp1 not only inhibit the basic expression of placental aromatase, but also inhibit the promotion of cortisol and Forskolin on the expression of aromatase. Further ChIP methods have been used to study the treatment of Corticosterol (1 mu M) and db-cAMP (100 mu). The placental syncytiotrophoblast cell 24h can promote the binding of Sp1 with the aromatase gene promoter PI.1. At the same time, a-h-CRH (1 mu M) and hCG antibody (1:100) alone can partially block the induction of cortisol to Sp1 expression and the promotion of cortisol to the combination of Sp1 and aromatase promoter PI.1. The drug can not only reduce the basic expression of Sp1 and the combination of Sp1 with the aromatase gene promoter PI.1, but also further completely block the induction of cortisol to Sp1 and the promotion of cortisol on the binding of Sp1 to the aromatase gene promoter PI.1. These results suggest that Sp1 mediates the combination of cortisol to placenta. The induction of aromatase expression in the trophoblast cells. Cortisol (1 M Forskolin (100 u M) and db-cAMP (100 mu M) can increase the binding of Sp1 to the PI.1 of the aromatase gene of the placental syncytiotrophoblast cell, and increase the acetylation of the histone 3 and ninth lysine (A) on the placental aromatase gene of the promoter PI.1 (A). Cetyl H3K9) level and decrease the level of dimethylation (Dimethyl H3K9) of the histone 3 ninth bits lysine and increase the binding of RNA polymerase II (Pol II) with the aromatase gene promoter PI.1, which indicates that the acetylation and dimethylation of histone 3 on the placental aromatase promoter are also involved in cortisol to placental aromatase. Conclusion our results show that the human placental aromatase is mainly expressed in the placental syncytial trophoblast cells and gradually increases with the fusion of placental trophoblast cells to the syncytrotrophoblast cells. In addition, in the syncytial cells, the aromatase gene mainly expresses the transcriptional production of exon I.1. Our results also show that in human placental syncytiotrophoblast cells, cortisol can increase the expression of placental aromatase and increase the synthesis of estrogen. Cortisol, by combining its own receptor GR, induces the synthesis and secretion of CRH and hCG in the placental syncytiotrophoblast cells, and secretes CRH and hCG out of cells. Activating the intracellular cAMP/PKA signaling pathway of the placental syncytial cells leads to an increase in the expression of Sp1 and the increase of the binding of Sp1 to the aromatase gene promoter PI.1, and changes the epigenetic modification of the histone on the aromatase gene promoter PI.1, and enhances the transcriptional activity of the aromatase gene promoter PI.1, thus making it possible to increase the transcriptional activity of the aromatase gene promoter PI.1. This study provides evidence that glucocorticoids up the expression of human placental aromatase to promote estrogen synthesis, providing new ideas for the involvement of glucocorticoids in human birth, and these findings may also provide new ideas for clinical intervention in preterm labor.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R714.21

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