本文選題：EphB4信號(hào)通路 + 神經(jīng)干細(xì)胞��； 參考：《首都醫(yī)科大學(xué)》2017年博士論文

【摘要】：目的缺血性腦卒中是一種嚴(yán)重?fù)p害神經(jīng)功能的疾病,其具有很高的發(fā)病率和死亡率。缺血性腦損傷后期的神經(jīng)再生與修復(fù)是腦卒中治療的關(guān)鍵環(huán)節(jié)。腦卒中后可以誘發(fā)內(nèi)源性神經(jīng)干細(xì)胞增殖、分化并向損傷區(qū)域遷移,其中多條信號(hào)通路參與調(diào)節(jié)神經(jīng)干細(xì)胞的活動(dòng)。通過調(diào)節(jié)特異性的分子機(jī)制,可以增強(qiáng)腦損傷誘導(dǎo)的內(nèi)源性神經(jīng)干細(xì)胞的增殖與分化過程。目前,參與調(diào)節(jié)神經(jīng)干細(xì)胞增殖與分化的經(jīng)典信號(hào)通路有四條,即Wnt信號(hào)通路、Notch信號(hào)通路、Shh(Sonic Hedgehog,Shh)信號(hào)通路與骨形態(tài)發(fā)生蛋白(bone morphogenetic protein,BMP)信號(hào)通路。在前期我們研究Wnt信號(hào)通路時(shí)發(fā)現(xiàn),β-catenin做為Wnt信號(hào)通路的關(guān)鍵調(diào)節(jié)因子,同時(shí)也是Eph信號(hào)通路的下游蛋白之一。因此,我們關(guān)注到了Eph/ephrin這條信號(hào)通路。Eph受體是具有最多成員的受體酪氨酸激酶家族,其與配體ephrin結(jié)合后可以誘發(fā)雙向傳導(dǎo)過程。近年來研究表明Eph受體與ephrin配體參與調(diào)節(jié)神經(jīng)干細(xì)胞的增殖、分化、存活與遷移活動(dòng)。但對(duì)于EphB4的研究都集中在腫瘤方面,其對(duì)神經(jīng)干細(xì)胞的調(diào)節(jié)作用卻未見報(bào)道。而腫瘤細(xì)胞中存在少部分腫瘤激活細(xì)胞,這些細(xì)胞與干細(xì)胞有著共同的特性,腫瘤可以從正常組織干細(xì)胞轉(zhuǎn)化而來。我們猜想EphB4是否在神經(jīng)干細(xì)胞的增殖與分化方面也起到重要作用。本實(shí)驗(yàn)旨在研究EphB4是否參與調(diào)節(jié)了人胚胎神經(jīng)干細(xì)胞的增殖、分化、凋亡活動(dòng),并探索其下游信號(hào)通路與調(diào)節(jié)機(jī)制,為腦卒中治療提供新的靶點(diǎn)。方法(1)人胚胎神經(jīng)干細(xì)胞的鑒定:培養(yǎng)原代人胚胎神經(jīng)干細(xì)胞,正常培養(yǎng)3天后進(jìn)行Nestin免疫熒光染色標(biāo)記巢蛋白;分化培養(yǎng)10天后進(jìn)行βⅢ-tubulin與膠質(zhì)纖維酸性蛋白(glial fibrillary acidic protein,GFAP)免疫熒光染色分別標(biāo)記神經(jīng)元與星形膠質(zhì)細(xì)胞;分化培養(yǎng)16天后進(jìn)行半乳糖腦苷脂(galactocerebroside,Galc)免疫熒光染色標(biāo)記少突膠質(zhì)細(xì)胞,進(jìn)行人胚胎神經(jīng)干細(xì)胞鑒定。(2)EphB4信號(hào)通路的機(jī)制研究:培養(yǎng)原代人胚胎神經(jīng)干細(xì)胞,使用沉默慢病毒與過表達(dá)慢病毒轉(zhuǎn)染細(xì)胞,分別下調(diào)和上調(diào)EphB4基因水平及其蛋白表達(dá)水平,分為EphB4基因沉默對(duì)照組(Scrambled-sh RNA)、EphB4基因沉默組(EphB4-sh RNA)、EphB4基因過表達(dá)對(duì)照組(EphB4-control)、EphB4基因過表達(dá)組(EphB4-OE)。然后通過實(shí)時(shí)熒光定量聚合酶鏈反應(yīng)(real-time reverse transcription-polymerase chain reaction,RT-PCR)檢測EphB4的基因表達(dá)水平,Western blot檢測EphB4的蛋白表達(dá)水平來確定沉默及過表達(dá)效率。通過克隆分析、Brd U免疫熒光染色觀察EphB4對(duì)細(xì)胞自我更新與增殖的影響;通過Dcx、βⅢ-tubulin、GFAP、NG2免疫熒光染色及RT-PCR檢測Dcx、βⅢ-tubulin、GFAP、NG2基因水平,Western blot檢測Mash1蛋白表達(dá)水平觀察EphB4對(duì)人胚胎神經(jīng)干細(xì)胞分化的影響;通過Cleaved-caspase3、caspase8免疫熒光染色,Western blot檢測活性caspase8的表達(dá)水平、AnnexinⅤ-PE/7-AAD流式試劑盒分析觀察EphB4對(duì)人胚胎神經(jīng)干細(xì)胞凋亡的影響;通過細(xì)胞周期分析及使用Cyclin D1/CDK4抑制劑FAS、Abl抑制劑Gleevec、Abl激動(dòng)劑DPH抑制和激活蛋白表達(dá)水平探索EphB4下游信號(hào)通路。結(jié)果(1)我們培養(yǎng)的人胚胎神經(jīng)干細(xì)胞,Nestin~+細(xì)胞的比例為77.37%,并且可以成功分化為βⅢ-tubulin~+神經(jīng)元、GFAP~+星形膠質(zhì)細(xì)胞與Galc~+少突膠質(zhì)細(xì)胞。(2)與對(duì)照組相比,轉(zhuǎn)染EphB4沉默慢病毒可以顯著降低EphB4的m RNA水平與蛋白表達(dá)水平,轉(zhuǎn)染EphB4過表達(dá)慢病毒可以顯著提高EphB4的m RNA水平與蛋白表達(dá)水平,人胚胎神經(jīng)干細(xì)胞EphB4基因沉默及過表達(dá)模型成功建立。(3)克隆分析與免疫熒光染色結(jié)果顯示,與對(duì)照組相比,EphB4基因沉默顯著降低了神經(jīng)球直徑、神經(jīng)球個(gè)數(shù)與Brd U陽性細(xì)胞數(shù),抑制了細(xì)胞增殖;EphB4過表達(dá)顯著增加了神經(jīng)球的直徑、神經(jīng)球個(gè)數(shù)與Brd U陽性細(xì)胞數(shù),促進(jìn)了細(xì)胞增殖。(4)免疫熒光染色、RT-PCR分析與Western blot結(jié)果顯示,與對(duì)照組相比,EphB4基因沉默顯著降低了Dcx、βⅢ-tubulin陽性細(xì)胞數(shù)及其m RNA水平、Mash1蛋白表達(dá)水平,顯著增加了GFAP、NG2陽性細(xì)胞數(shù)及其m RNA水平,抑制細(xì)胞向神經(jīng)元分化,促進(jìn)細(xì)胞向膠質(zhì)細(xì)胞分化;EphB4基因過表達(dá)顯著增加了Dcx、βⅢ-tubulin陽性細(xì)胞數(shù)及其m RNA水平、Mash1蛋白表達(dá)水平,顯著降低了GFAP、NG2陽性細(xì)胞數(shù)及其m RNA水平,促進(jìn)細(xì)胞向神經(jīng)元分化,抑制細(xì)胞向膠質(zhì)細(xì)胞分化。(5)免疫熒光染色、Western blot及細(xì)胞流式結(jié)果顯示,與對(duì)照組相比,EphB4沉默組與過表達(dá)組Cleaved-caspase3、caspase8陽性細(xì)胞數(shù)、活性caspase8蛋白表達(dá)水平及AnnexinⅤ-PE~+/7-AAD-標(biāo)記的細(xì)胞數(shù)量無顯著變化,EphB4基因沉默及過表達(dá)對(duì)細(xì)胞凋亡無影響。(6)細(xì)胞周期檢測結(jié)果顯示,與對(duì)照組相比,EphB4基因沉默可以顯著增加G0/G1期細(xì)胞數(shù)量,相對(duì)的減少S期與G2/M期的細(xì)胞數(shù)量;EphB4基因過表達(dá)可以顯著減少G0/G1期細(xì)胞數(shù)量,相對(duì)的增加S期與G2/M期的細(xì)胞數(shù)量。EphB4基因沉默及過表達(dá)可以影響G1期調(diào)節(jié)蛋白Cyclin D1、CDK4的表達(dá)水平,使用Cyclin D1/CDK4抑制劑FAS抑制蛋白活性后消除了EphB4過表達(dá)促進(jìn)細(xì)胞增殖的作用。結(jié)果表明Cyclin D1/CDK4介導(dǎo)了EphB4蛋白對(duì)人胚胎神經(jīng)干細(xì)胞增殖的調(diào)節(jié)作用。(7)Western blot結(jié)果顯示,EphB4基因沉默及過表達(dá)可以影響Abl的表達(dá)水平,使用Abl抑制劑Gleevec與激動(dòng)劑DPH抑制與激活A(yù)bl蛋白可以影響Cyclin D1、CDK4的表達(dá)水平,并且在Abl蛋白活性被抑制后可以消除EphB4過表達(dá)促進(jìn)細(xì)胞增殖的作用。結(jié)果表明,Abl作為EphB4的下游蛋白介導(dǎo)了EphB4調(diào)控Cyclin D1/CDK4影響細(xì)胞增殖的作用。(8)使用Abl抑制劑Gleevec與Cyclin D1/CDK4抑制劑FAS抑制蛋白活性并未影響EphB4過表達(dá)促進(jìn)細(xì)胞向神經(jīng)元方向分化,抑制細(xì)胞向膠質(zhì)細(xì)胞分化的作用。結(jié)果表明,Abl-Cyclin D1/CDK4信號(hào)通路并未參與調(diào)節(jié)EphB4對(duì)細(xì)胞分化的作用。結(jié)論:EphB4基因沉默后,抑制體外培養(yǎng)人胚胎神經(jīng)干細(xì)胞的增殖及細(xì)胞向神經(jīng)元分化,促進(jìn)細(xì)胞向膠質(zhì)細(xì)胞分化,對(duì)細(xì)胞凋亡無影響。EphB4基因過表達(dá)后,促進(jìn)體外培養(yǎng)人胚胎神經(jīng)干細(xì)胞的增殖及細(xì)胞向神經(jīng)元的分化,抑制細(xì)胞向膠質(zhì)細(xì)胞分化,對(duì)細(xì)胞凋亡無影響。EphB4是通過下游信號(hào)通路Abl-Cyclin D1調(diào)節(jié)細(xì)胞增殖,此信號(hào)通路不參與EphB4在細(xì)胞分化方面的調(diào)節(jié)。EphB4參與調(diào)節(jié)神經(jīng)干細(xì)胞增殖,而且是決定神經(jīng)干細(xì)胞向神經(jīng)元分化還是向膠質(zhì)細(xì)胞分化的開關(guān),其很可能成為腦損傷后神經(jīng)元修復(fù)的有效治療靶點(diǎn)。
[Abstract]:Objective ischemic stroke is a serious damage to nerve function. It has a high incidence and mortality. Neural regeneration and repair in the later stage of ischemic brain injury is the key link in the treatment of stroke. After stroke, it can induce endogenous neural stem cells to proliferate, differentiate and migrate to the injured area, including multiple signal pathways. By regulating the activity of neural stem cells, the proliferation and differentiation process of endogenous neural stem cells induced by brain damage can be enhanced by regulating specific molecular mechanisms. There are four classical signaling pathways involved in regulating the proliferation and differentiation of neural stem cells, namely, Wnt signal pathway, Notch signaling pathway, and Shh (Sonic Hedgehog, Shh) signal The pathway and the bone morphogenetic protein (BMP) signaling pathway. In our earlier study of the Wnt signaling pathway, we found that beta -catenin is a key regulator of the Wnt signaling pathway, and is also one of the downstream proteins of the Eph signaling pathway. Therefore, we have noticed that Eph/ephrin, a signal pathway, is the most important of the.Eph receptors. Many members of the receptor tyrosine kinase family, which bind to the ligand ephrin, can induce two-way conduction process. In recent years, studies have shown that Eph receptors and ephrin ligands are involved in regulating the proliferation, differentiation, survival and migration of neural stem cells. However, the study of EphB4 is concentrated in the swelling of the tumor and its regulation on neural stem cells is not There are few tumor activated cells in the tumor cells. These cells have a common characteristic with the stem cells, and the tumor can be transformed from normal tissue stem cells. We guess whether EphB4 plays an important role in the proliferation and differentiation of neural stem cells. This test is to investigate whether EphB4 participates in the regulation of human embryos. The proliferation, differentiation and apoptosis of fetal neural stem cells, and explore the downstream signal pathway and regulation mechanism to provide new targets for the treatment of stroke. Method (1) identification of human embryonic neural stem cells: culture of human embryonic neural stem cells, Nestin immunofluorescence staining for 3 days after normal culture and 10 days after differentiation and culture. The neurons and astrocytes were labeled with beta III -tubulin and glial fibrillary acidic protein (glial fibrillary acidic protein, GFAP), and 16 days after differentiation and culture, galactosida (galactocerebroside, Galc) immunofluorescence staining was used to mark oligodendrocytes, and human embryonic neural stem cells were identified. (2) EphB4 The mechanism of signal pathway: the culture of human embryonic neural stem cells, the use of silent lentivirus and overexpression of lentivirus transfected cells, down and up regulation of EphB4 gene level and protein expression level, divided into EphB4 gene silencing control group (Scrambled-sh RNA), EphB4 gene silencing group (EphB4-sh RNA), EphB4 gene overexpression control group ( EphB4-control), EphB4 gene overexpression group (EphB4-OE). Then the gene expression level of EphB4 was detected by real-time quantitative polymerase chain reaction (real-time reverse transcription-polymerase chain reaction, RT-PCR). Western blot detected the protein expression to determine the silencing and overexpression efficiency. Immunofluorescence staining was used to observe the effect of EphB4 on cell self renewal and proliferation. The effects of Dcx, beta III -tubulin, GFAP, NG2 immunofluorescence staining and RT-PCR on the detection of Dcx, beta III -tubulin, GFAP, NG2 gene level, and Western blot test protein expression level on the differentiation of human embryonic neural stem cells were observed. The expression level of active caspase8 was detected by immunofluorescence staining and Western blot. The effect of EphB4 on the apoptosis of human embryonic neural stem cells was analyzed by Annexin V -PE/7-AAD flow reagent box, and the expression level of Cyclin D1/CDK4 inhibitor FAS, Abl inhibitor Gleevec, Abl agonist inhibition and activation protein expression level were explored. 4 downstream signal pathway. Results (1) we cultured human embryonic neural stem cells, the proportion of Nestin~+ cells is 77.37%, and can successfully differentiate into beta III -tubulin~+ neurons, GFAP~+ astrocytes and Galc~+ oligodendrocytes. (2) compared with the control group, EphB4 silencing lentivirus can significantly reduce the m RNA level of EphB4 and eggs. In white expression level, transfection of EphB4 over expression of lentivirus could significantly increase the level of M RNA and protein expression of EphB4, and the EphB4 gene silencing and overexpression model of human embryonic neural stem cells were successfully established. (3) cloning analysis and immunofluorescence staining showed that the EphB4 gene silencing significantly reduced the diameter of the nerve bulb compared with the control group. The number of balls and the number of Brd U positive cells inhibited the proliferation of cells; EphB4 overexpression significantly increased the diameter of the nerve bulb, the number of nerve spheres and the number of Brd U positive cells, and promoted the cell proliferation. (4) immunofluorescence staining, RT-PCR analysis and Western blot results showed that the EphB4 gene silencing significantly decreased Dcx, beta III -tubulin Yang compared with the control group. The number of sex cells, the level of M RNA and the expression level of Mash1 protein significantly increased the number of GFAP, the number of NG2 positive cells and the level of M RNA, inhibited the differentiation of cells into neurons and promoted the differentiation of cells into glial cells, and the overexpression of EphB4 gene significantly increased the Dcx, the number of positive cells of beta III -tubulin and the m RNA level, and the level of protein expression decreased significantly. GFAP, NG2 positive cells and their m RNA levels, promote cells to differentiate into neurons and inhibit cell differentiation to glia. (5) immunofluorescence staining, Western blot and cell flow results showed that compared with the control group, EphB4 silencing group and overexpressed group Cleaved-caspase3, the number of caspase8 positive cells, active caspase8 protein expression level and Annexin There was no significant change in the number of cells labeled by V -PE~+/7-AAD-, and the silence and overexpression of EphB4 gene had no effect on cell apoptosis. (6) cell cycle detection showed that EphB4 gene silencing could significantly increase the number of G0/G1 cells and decrease the number of cells in the S phase and G2/M phase compared with the control group, and the EphB4 gene overexpression could significantly reduce G. The number of cells in phase 0/G1, the relative increase of the number of S and G2/M phase.EphB4 gene silencing and overexpression can affect the expression level of Cyclin D1, CDK4, and the use of Cyclin D1/CDK4 inhibitor FAS inhibitory protein activity to eliminate the effect of EphB4 over expression to promote cell proliferation. The regulation of protein on the proliferation of human embryonic neural stem cells. (7) Western blot results show that the silence and overexpression of EphB4 gene can affect the expression level of Abl. The inhibition and activation of Abl protein with the Abl inhibitor Gleevec and activator DPH can affect Cyclin D1, CDK4 expression is flat, and can be eliminated after the activity of Abl protein is inhibited. HB4 overexpression promotes cell proliferation. The results show that Abl as a downstream protein of EphB4 mediates the effect of EphB4 regulating Cyclin D1/CDK4 on cell proliferation. (8) the use of Abl inhibitor Gleevec and Cyclin D1/CDK4 inhibitor FAS inhibitory protein activity does not affect the proliferation of cells to neurons and inhibit cell direction. The effect of glial cell differentiation. The results showed that Abl-Cyclin D1/CDK4 signaling pathway did not regulate the effect of EphB4 on cell differentiation. Conclusion: after the silence of EphB4 gene, the proliferation of human embryonic neural stem cells and the differentiation of cells into neurons in vitro, and the differentiation of cells into glial cells, and no effect of.EphB4 gene on the apoptosis of the cells. After expression, it promotes the proliferation of human embryonic neural stem cells and the differentiation of cells into neurons, inhibits the differentiation of cells into glial cells, and does not affect cell apoptosis by regulating cell proliferation through the downstream signal pathway Abl-Cyclin D1. This signaling pathway does not participate in the regulation of EphB4 in cell differentiation by regulating.EphB4 to regulate the nerve. Stem cells proliferate, and they are the switches that determine whether neural stem cells differentiate into neurons or differentiate into glial cells. It is likely to be an effective target for the repair of neurons after brain damage.

【學(xué)位授予單位】：首都醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R743.3

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