發(fā)布時(shí)間：2018-05-06 11:10

  本文選題：益氣血法 + 超排卵大鼠��； 參考：《廣州中醫(yī)藥大學(xué)》2017年博士論文

【摘要】：控制性超排卵(controlled ovary hyperstimulation,COH)是體外受精-胚胎移植(In vitro fertilization and embryo transfer,IVF-ET)周期的重要組成部分,已有研究證實(shí)COH可能破壞卵細(xì)胞中染色體的結(jié)構(gòu),影響染色體的功能,導(dǎo)致細(xì)胞中某些基因的表達(dá)缺陷,對(duì)卵細(xì)胞的發(fā)育起負(fù)面影響,降低胚胎的質(zhì)量和其著床能力。因此COH能導(dǎo)致胚胎著床率和妊娠率處于明顯低下的水平。中醫(yī)藥介入IVF-ET周期收效顯著,我們前期研究證實(shí)益氣血補(bǔ)肝腎中藥能提高胚胎移植成功率和妊娠率。本文主要研究經(jīng)后增殖方對(duì)COH卵巢卵丘細(xì)胞(cumulus cells,CCs)凋亡的影響。人CCs與卵母細(xì)胞有密切的關(guān)系,CCs能直接影響卵母細(xì)胞的發(fā)育和成熟,影響胚胎的質(zhì)量,而卵母細(xì)胞也可以分泌卵細(xì)胞分泌因子(oocyte secreted factors,OSFs),通過旁分泌的作用來調(diào)節(jié)周圍CCs的生長(zhǎng)和分化。在卵母細(xì)胞的成熟過程中,兩者互為影響,缺一不可。生長(zhǎng)分化因子9(growth differentiation factor 9,GDF9)是轉(zhuǎn)化生長(zhǎng)因子β(transforming growth factor β,TGFβ)超家族中一個(gè)重要的成員,作為卵母細(xì)胞分泌的細(xì)胞因子,GDF9與卵細(xì)胞的發(fā)育和發(fā)展具有密切關(guān)系,是與卵泡發(fā)育有關(guān)的重要調(diào)節(jié)因子,卵泡液中的GDF9已經(jīng)作為一項(xiàng)重要指標(biāo),用于對(duì)卵母細(xì)胞和胚胎質(zhì)量的預(yù)測(cè)。Bim(Bcl-2 interacting mediator of cell death)是 Bcl-2 家族中的成員,隸屬于BH3-only亞家族。Bim在機(jī)體多種組織包括生殖細(xì)胞中有不同程度的表達(dá),在啟動(dòng)凋亡和調(diào)節(jié)凋亡上具有重要的作用,是一種重要的凋亡調(diào)節(jié)蛋白。本文主要探討益氣血法經(jīng)后增殖方通過調(diào)節(jié)GDF9分泌和Bim表達(dá)抑制COH卵巢CCs凋亡的作用機(jī)制,同時(shí)對(duì)其可能的信號(hào)通路進(jìn)行驗(yàn)證,為其廣泛的臨床應(yīng)用提供分子理論基礎(chǔ)。期望能找到改善IVF-ET中卵母細(xì)胞質(zhì)量及發(fā)育潛能的途徑,進(jìn)一步提高IVF-ET臨床胚胎種植率與妊娠率。目的:觀察益氣血法經(jīng)后增殖方對(duì)COH大鼠卵巢GDF9和Bim分泌的影響,探討經(jīng)后增殖方在抑制COH卵巢CCs凋亡中的作用機(jī)制,并對(duì)其可能的信號(hào)通路進(jìn)行驗(yàn)證。方法:1動(dòng)物實(shí)驗(yàn)研究通過建立COH大鼠模型,同時(shí)應(yīng)用經(jīng)后增殖方進(jìn)行干預(yù),以自然排卵大鼠作為空白對(duì)照,以COH大鼠作為陽(yáng)性對(duì)照,采用TUNEL和qPCR技術(shù)檢測(cè)不同劑量經(jīng)后增殖方干預(yù)的COH大鼠卵巢顆粒細(xì)胞凋亡率及卵巢組織中Bim基因的表達(dá)水平。2細(xì)胞實(shí)驗(yàn)研究2.1通過制備不同濃度經(jīng)后增殖方含藥血清,,對(duì)COH大鼠卵巢顆粒細(xì)胞體外培養(yǎng)進(jìn)行干預(yù),采用qPCR技術(shù)檢測(cè)顆粒細(xì)胞中Bim基因的表達(dá)水平,選出含藥血清最佳作用濃度和時(shí)間,應(yīng)用于后續(xù)實(shí)驗(yàn)。2.2建立COH大鼠模型,獲取卵巢COCs和CCs進(jìn)行體外培養(yǎng),用經(jīng)后增殖方含藥血清和GDF9受體阻斷劑進(jìn)行干預(yù),采用qPCR和Westernblot技術(shù)檢測(cè)COCs和CCs中GDF9基因和蛋白及Bim基因的表達(dá)水平。2.3建立COH大鼠模型,獲取卵巢COCs進(jìn)行體外培養(yǎng),用經(jīng)后增殖方含藥血清和PI3K、PKA、p38MAPK、SMAD和NF-κ B通路阻斷劑進(jìn)行干預(yù),采用qPCR和Westernblot技術(shù)檢測(cè)COCs中GDF9基因和蛋白及Bim基因的表達(dá)水平。結(jié)果:1經(jīng)后增殖方對(duì)COH大鼠卵巢顆粒細(xì)胞凋亡率及卵巢組織中Bim基因表達(dá)的影響1.1經(jīng)后增殖方可降低COH大鼠卵巢顆粒細(xì)胞凋亡率中藥低、中、高劑量組均明顯低于陽(yáng)性對(duì)照組(均為P0.05),中藥高劑量組與空白對(duì)照組比較無(wú)顯著差異(均為P0.05),說明高、中、低劑量經(jīng)后增殖方均可降低COH大鼠卵巢顆粒細(xì)胞凋亡率,且高劑量經(jīng)后增殖方能使COH大鼠卵巢顆粒細(xì)胞凋亡率達(dá)到接近自然排卵大鼠的水平;中藥低、中、高劑量組卵巢顆粒細(xì)胞凋亡率逐漸下降,且各劑量組之間均有顯著差異(P0.01),說明COH大鼠卵巢顆粒細(xì)胞凋亡率凋亡率與經(jīng)后增殖方劑量呈負(fù)相關(guān)。1.2經(jīng)后增殖方可降低COH大鼠卵巢組織Bim基因的表達(dá)中藥低、中、高劑量組均明顯高于空白對(duì)照組(均為PM0.05),明顯低于陽(yáng)性對(duì)照組(均為P0.05),說明高、中、低劑量經(jīng)后增殖方均可降低COH大鼠卵巢組織Bim基因的表達(dá)水平;中藥低、中、高劑量組Bim mRNA相對(duì)表達(dá)水平逐漸下降,但無(wú)顯著差異(均為P0.05),說明高、中、低劑量經(jīng)后增殖方降低COH大鼠卵巢組織Bim基因的表達(dá)水平的作用相當(dāng)。2經(jīng)后增殖方含藥血清經(jīng)p38MAPK和NF-κ B通路的調(diào)控調(diào)節(jié)GDF9和Bim表達(dá)抑制COH大鼠卵巢CCs凋亡2.1經(jīng)后增殖方含藥血清抑制COH大鼠卵巢顆粒細(xì)胞Bim基因表達(dá)的最佳作用濃度和時(shí)間24小時(shí)中藥低、中、高劑量組明顯低于空白血清組(均為P0.01),說明高、中、低劑量經(jīng)后增殖方含藥血清干預(yù)24小時(shí)后Bim基因的表達(dá)水平均有顯著下降;中藥低、中、高劑量組BimmRNA相對(duì)表達(dá)水平逐漸下降,且各組間均有顯著差異(均為P0.01),說明經(jīng)后增殖方含藥血清降低Bim基因表達(dá)水平的效果與濃度呈正相關(guān),高劑量的效果最優(yōu)。48小時(shí)中藥低、中、高劑量組Bim mRNA相對(duì)表達(dá)水平逐漸下降,中藥高劑量組明顯低于其他3組(均為P0.05),其他3組之間無(wú)明顯差異(均為P0.05),說明僅高劑量經(jīng)后增殖方含藥血清在干預(yù)48小時(shí)仍能維持Bim基因表達(dá)的低水平,而中、低劑量經(jīng)后增殖方含藥血清48小時(shí)干預(yù)效果并不理想。結(jié)合以上結(jié)果,篩選出經(jīng)后增殖方含藥血清抑制卵巢顆粒細(xì)胞凋亡的最佳作用時(shí)間為24小時(shí),最佳作用濃度為高劑量。2.2經(jīng)后增殖方含藥血清對(duì)COH大鼠COCs和CCs中GDF9和Bim表達(dá)的調(diào)節(jié)2.2.1經(jīng)后增殖方含藥血清能提高COH大鼠COCs和CCs中GDF9基因和蛋白的表達(dá)COCs-含藥血清組GDF9基因相對(duì)表達(dá)量明顯高于COCs-空白血清組和COCs-含藥血清+GDF9受體阻斷劑組(均為P0.05),CCs-含藥血清組GDF9基因相對(duì)表達(dá)量明顯高于CCs-空白血清組和CCs-含藥血清+GDF9受體阻斷劑組(均為P0.05),說明經(jīng)后增殖方含藥血清能提高COH大鼠COCs和CCs中GDF9基因的表達(dá)。COCs-含藥血清組GDF9蛋白相對(duì)表達(dá)量明顯高于COCs-空白血清組(P0.05),高于COCs-含藥血清+GDF9受體阻斷劑組,但差異無(wú)統(tǒng)計(jì)學(xué)意義(P0.05);CCs-含藥血清組GDF9蛋白相對(duì)表達(dá)量明顯高于CCs-空白血清組和CCs-含藥血清+GDF9受體阻斷劑組(均為P0.05),說明經(jīng)后增殖方含藥血清能提高COH大鼠COCs和CCs中GDF9蛋白的表達(dá)。COCs-含藥血清組GDF9基因相對(duì)表達(dá)量明顯高于CCs-含藥血清組(P0.05),說明COCs較去除卵母細(xì)胞的CCs更有利于GDF9的表達(dá)。2.2.2經(jīng)后增殖方含藥血清能抑制COH大鼠COCs和CCs中Bim基因的表達(dá)COCs-含藥血清組和COCs-含藥血清+GDF9受體阻斷劑組Bim基因相對(duì)表達(dá)量均明顯低于COCs-空白血清組(均為PO.05),CCs-含藥血清組和CCs-含藥血清+GDF9受體阻斷劑組Bim基因相對(duì)表達(dá)量均明顯低于CCs-空白血清組(均為P0.05),說明經(jīng)后增殖方含藥血清能抑制COH大鼠COCs和CCs中Bim基因的表達(dá)。COCs-含藥血清組Bim基因相對(duì)表達(dá)量低于COCs-含藥血清+GDF9受體阻斷劑組,但差異無(wú)統(tǒng)計(jì)學(xué)意義(P0.05),CCs-含藥血清組Bim基因相對(duì)表達(dá)量明顯低于CCs-含藥血清+GDF9受體阻斷劑組(P0.05),說明由于受GDF9受體阻斷劑作用,GDF9的表達(dá)明顯降低,從而無(wú)法維持Bim表達(dá)的低水平,驗(yàn)證了 GDF9有維持CCs中Bim表達(dá)的低水平的作用。2.3經(jīng)后增殖方含藥血清對(duì)COH大鼠COCs中GDF9和Bim表達(dá)的調(diào)節(jié)是通過p38MAPK和NF-κB通路介導(dǎo)的含藥血清+PI3K inhibitors組、含藥血清+PKA inhibitors組、和含藥血清+SMAD inhibitors組GDF9基因和蛋白的相對(duì)表達(dá)量均明顯高于空白血清組(均為P0.05),與含藥血清組比較,差異均無(wú)統(tǒng)計(jì)學(xué)意義(均為P0.05);含藥血清+p38MAPK inhibitors組和含藥血清+NF-κ B inhibitors組GDF9基因和蛋白的相對(duì)表達(dá)量均明顯低于含藥血清組(均為P0.05),與空白血清組比較,差異均無(wú)統(tǒng)計(jì)學(xué)意義(均為P0.05)。說明經(jīng)后增殖方含藥血清能提高COH大鼠COCs中GDF9基因和蛋白的表達(dá)水平,該作用是通過p38MAPK和NF-κ B通路介導(dǎo)的。含藥血清+PI3K inhibitors組、含藥血清+PKA inhibitors組和含藥血清+SMAD inhibitors組Bim基因相對(duì)表達(dá)量明顯低于空白血清組(均為P0.05),與含藥血清組比較,差異無(wú)統(tǒng)計(jì)學(xué)意義(均為P0.05);含藥血清+p38MAPK inhibitors組和含藥血清+NF-κ B inhibitors組Bim基因相對(duì)表達(dá)量明顯高于含藥血清組(均為P0.05),與空白血清組比較,差異無(wú)統(tǒng)計(jì)學(xué)意義(均為P0.05)。說明經(jīng)后增殖方含藥血清能降低COH大鼠COCs中Bim基因的表達(dá)水平,該作用可能是通過p38MAPK信號(hào)通路和NF-κ B信號(hào)通路介導(dǎo)的。結(jié)論:①益氣血法經(jīng)后增殖方能通過促進(jìn)COH大鼠卵巢COCs中卵母細(xì)胞分泌GDF9,而GDF9通過旁分泌作用周圍的CCs,維持CCs的低凋亡率而改善COCs的功能,從而提高卵細(xì)胞質(zhì)量;②益氣血法經(jīng)后增殖方能通過多途徑抑制COH大鼠卵巢COCs和CCs中Bim的表達(dá)水平,途徑之一是通過促進(jìn)GDF9的分泌以維持Bim表達(dá)的低水平,從而抑制CCs凋亡;③益氣血法經(jīng)后增殖方對(duì)COH大鼠卵巢COCs和CCs中GDF9和Bim表達(dá)的調(diào)節(jié)是通過p38MAPK和NF-κB信號(hào)轉(zhuǎn)導(dǎo)通路介導(dǎo)的。
[Abstract]:Controlled ovary hyperstimulation (COH) is an important part of the cycle of in vitro fertilization and embryo transfer (In vitro fertilization and embryo transfer, IVF-ET). It has been proved that COH may destroy the structure of chromosomes in the egg cells, affect the function of the chromophore, and lead to the defects in the expression of some genes in the cells, The development of the egg cell has a negative effect on the quality of the embryo and its implantation ability. Therefore, COH can lead to a lower level of embryo implantation rate and pregnancy rate. The effect of TCM Intervention on IVF-ET cycle is remarkable. The effect of post proliferation on the apoptosis of COH ovarian cumulus cells (cumulus cells, CCs). Human CCs has a close relationship with oocyte. CCs can directly influence the development and maturation of oocyte, affect the quality of embryo, and oocyte can also secrete the secretory factor of oocyte (oocyte secreted factors, OSFs), and regulate by the role of paracrine. The growth and differentiation of the surrounding CCs. During the maturation of oocytes, the two are mutually beneficial, and the growth differentiation factor 9 (growth differentiation factor 9, GDF9) is an important member of the transforming growth factor beta (transforming growth factor beta, TGF beta) superfamily, as the cytokine secreted by oocyte, GDF9 and egg thin. Cell development and development are closely related to the development of follicle development. The GDF9 in follicular fluid is an important indicator. The prediction of the quality of oocyte and embryo.Bim (Bcl-2 interacting mediator of cell death) is a member of the Bcl-2 family, which is subordinate to the BH3-only subfamily.Bim in the body. Species, including different levels of expression in germ cells, plays an important role in initiating apoptosis and regulating apoptosis. It is an important apoptosis regulating protein. This paper mainly discusses the mechanism of inhibiting the apoptosis of COH ovarian CCs by regulating the GDF9 secretion and Bim expression by the beneficial Qi and blood method, and the possible signaling pathway. To provide the basis of molecular theory for its extensive clinical application. We hope to find a way to improve the quality and development potential of oocyte in IVF-ET, and to further improve the implantation rate and pregnancy rate of IVF-ET clinical embryo. Objective: To observe the effect of the recipe of Supplementing Qi and blood on the secretion of GDF9 and Bim in the egg nests of COH rats, and to explore the post proliferative side. The mechanism of inhibiting the apoptosis of COH ovarian CCs and its possible signal pathways were verified. Methods: 1 animal experiments were conducted by establishing a COH rat model and using the post proliferation prescription to intervene with the natural ovulation rats as the blank control, and the COH rats were used as the positive control, and the TUNEL and qPCR techniques were used to detect the different doses of the rats. The apoptosis rate of ovarian granulosa cells and the expression level of Bim gene in the ovarian tissue of COH rats with the intervention of the posterior proliferative prescription (.2 cells) experimental study 2.1 by preparing the serum containing different concentrations of the post proliferating prescription, the expression level of Bim gene in the granulosa cells of the COH rats was detected by qPCR technique. The optimal concentration and time of the drug containing serum were used to establish the COH rat model in the follow-up experiment.2.2, and the ovarian COCs and CCs were cultured in vitro. The serum and GDF9 receptor blockers were used to intervene. The qPCR and Westernblot techniques were used to detect the expression level of GDF9 genes and proteins and Bim genes in COCs and CCs. OH rat model was used to obtain ovarian COCs for culture in vitro. The serum and PI3K, PKA, p38MAPK, SMAD and NF- kappa B pathway blockers were intervened by the post proliferation prescription, and the expression level of GDF9 genes and proteins in COCs was detected by qPCR and Westernblot techniques. The effect of Bim gene expression in ovarian tissue 1.1 can reduce the apoptosis rate of ovarian granulosa cells in COH rats lower than that of the positive control group (all P0.05), and there is no significant difference between the high dose group and the blank control group (all P0.05), indicating that the high, middle, and low dose of the post proliferative side can reduce the COH big. The apoptosis rate of rat ovarian granulosa cells, and the high dose of after proliferation can make the apoptosis rate of ovarian granulosa cells in COH rats reach the level of the rats with natural ovulation. The apoptosis rate of ovarian granulosa cells in the low, middle and high dose groups gradually decreased, and there were significant differences between each dose group (P0.01), indicating that the apoptosis rate of ovarian granulosa cells in COH rats withered. The negative correlation between the death rate and the volume of the post proliferating agent.1.2 could reduce the expression of the Bim gene in the ovarian tissue of COH rats, and the high dose group was significantly higher than that of the blank control group (all PM0.05), which was significantly lower than the positive control group (all P0.05), indicating that the high, middle and low dose of the post proliferative side could reduce the Bim base in the ovarian tissue of COH rats. The relative expression level of Bim mRNA decreased gradually in low, medium and high dose groups, but there was no significant difference (all P0.05). The effect of high, medium and low doses on the expression level of Bim gene in the ovarian tissue of COH rats was equivalent to the regulation of.2 and Bi by the p38MAPK and NF- kappa B pathway in the serum containing.2 after the proliferation. M expression inhibits the apoptosis of CCs in the ovary of COH rats 2.1 to inhibit the optimal concentration of Bim gene expression in the ovarian granulosa cells of COH rats and the time 24 hours of Chinese medicine low, and the high dose group is significantly lower than that of the blank sera group (P0.01), indicating that the high, middle, low dose of the Bim gene after the intervention of the serum containing drug serum after 24 hours. The expression level of BimmRNA decreased significantly, and the relative expression level of the low, middle and high dose groups decreased gradually, and there were significant differences between each group (all P0.01). The results showed that the effect of reducing the expression level of Bim gene in the post proliferating prescription serum was positively correlated with the concentration of Bim gene. The best effect of high dose.48 hours was low, middle and high dose group Bim mRNA. The relative expression level decreased gradually. The high dose group of traditional Chinese medicine was significantly lower than the other 3 groups (all P0.05), and there was no significant difference between the other 3 groups (all P0.05). It indicated that the low dose of the serum containing the high dose of the posterior proliferative side still maintained the low level of Bim gene expression in the 48 hour intervention, and the intervention effect of the serum containing the low dose of the post proliferation prescription was 48 hours. Not ideal. Combined with the above results, the best action time of inhibiting the apoptosis of ovarian granulosa cells was 24 hours. The optimum concentration was the regulation of the expression of GDF9 and Bim in COCs and CCs of COH rats by the high dose.2.2 serum containing serum of the proliferating prescription of the proliferative prescription of 2.2.1 and the COCs and CCs of COH rats could be improved. The expression of GDF9 gene and protein in COCs- containing serum group GDF9 gene was significantly higher than that of COCs- blank sera group and COCs- containing serum +GDF9 receptor blocker group (P0.05). The relative expression of GDF9 gene in CCs- containing serum group was significantly higher than that of CCs- blank sera group and CCs- drug serum +GDF9 blocker group. The expression of serum containing GDF9 in COH rats after Ming Jing can improve the expression of GDF9 gene in COH rats, and the relative expression of GDF9 protein in serum group of.COCs- was higher than that of COCs- blank sera group (P0.05), which was higher than that of COCs- containing serum +GDF9 receptor blocker group, but the difference was not statistically significant (P0.05). Higher than CCs- blank sera group and CCs- containing serum +GDF9 receptor blocker group (all P0.05), the expression of serum containing GDF9 protein in COCs and CCs in COH rats was significantly higher than that of CCs- drug serum group (P0.05) in COH rats. The expression of DF9 expression.2.2.2 can inhibit the expression of Bim gene in COCs and CCs of COH rats, COCs- containing serum group and COCs- containing serum +GDF9 receptor blocker group, the relative expression of Bim gene in the +GDF9 receptor blocker group is significantly lower than that of COCs- blank sera group (all PO.05). The relative expression was significantly lower than that of the CCs- blank sera group (P0.05), indicating the expression of Bim gene in COCs and CCs in COH rats could inhibit the expression of Bim gene in the serum of COH rats. The relative expression of Bim gene in the serum group of.COCs- was lower than that of the COCs- containing serum +GDF9 receptor blocker group, but the difference was not statistically significant (P0.05). The relative expression of the gene was significantly lower than that of the +GDF9 receptor blocker group (P0.05), which indicated that the expression of GDF9 was obviously reduced because of the effect of the GDF9 receptor blocker. Thus, the low level of Bim expression could not be maintained. It was proved that the GDF9 has a low level of Bim expression in the CCs, and the serum containing the.2.3 via the proliferating side of the.2.3 is used in COH rat COCs. The expression of 9 and Bim was mediated by p38MAPK and NF- kappa B pathway in the drug serum +PI3K inhibitors group. The relative expression of GDF9 gene and protein in the serum containing +PKA inhibitors and the serum +SMAD inhibitors group of the drug serum were significantly higher than that in the blank sera group (all P0.05), and the difference was not statistically significant compared with the drug serum group. P0.05): the relative expression of the GDF9 gene and protein in the serum +p38MAPK inhibitors group and the serum containing +NF- kappa B inhibitors group were significantly lower than that in the drug containing serum group (all P0.05), and the difference was not statistically significant (all P0.05) compared with the blank sera group (all P0.05). The expression level of white was mediated by the p38MAPK and NF- kappa B pathway. The drug serum +PI3K inhibitors group, the relative expression of the Bim gene in the serum +PKA inhibitors group and the serum containing +SMAD inhibitors group was significantly lower than that in the blank sera group (all P0.05), and the difference was not statistically significant (all P0.05), compared with the drug serum group. The relative expression of the Bim gene in the drug serum +p38MAPK inhibitors group and the drug serum +NF- kappa B inhibitors group was significantly higher than that in the drug serum group (all P0.05). The difference was not statistically significant (all P0.05) compared with the blank sera group (all P0.05). It was suggested that the serum level of the posterior proliferative prescription could reduce the expression level of Bim gene in COCs of COH rats, which may be the effect of this effect. Through the p38MAPK signaling pathway and the NF- kappa B signaling pathway. Conclusion: (1) the supplementing qi and blood method can improve the function of COCs by promoting the secretion of GDF9 in the oocytes of COCs in the ovarian COCs of COH rats, while GDF9 passes the paracrine CCs around the paracrine, and improves the function of COCs so as to improve the quality of the egg cell. One way is to inhibit the expression level of Bim in the COCs and CCs of COH rats by multiple pathways. One way is to maintain the low level of Bim expression by promoting the secretion of GDF9, and thus inhibit the apoptosis of CCs. Guide.

【學(xué)位授予單位】：廣州中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R285.5

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