本文選題：小泛素樣修飾蛋白 + 骨髓間充質(zhì)干細(xì)胞　； 參考：《天津醫(yī)科大學(xué)》2017年博士論文

【摘要】：目的:研究神經(jīng)元中小泛素樣修飾蛋白在低溫及熱應(yīng)激條件下的變化特點(diǎn)和規(guī)律,并將該規(guī)律應(yīng)用于中樞神經(jīng)系統(tǒng)疾病中,發(fā)揮其神經(jīng)保護(hù)作用,達(dá)到救治與溫度應(yīng)激相關(guān)的中樞神經(jīng)系統(tǒng)疾病的目的。方法:(1)(1)原代分離培養(yǎng)小鼠源性BMSCs,流式細(xì)胞術(shù)鑒定其細(xì)胞表面標(biāo)記蛋白的表達(dá);(2)分別將其置于37°C(正常體溫)、33°C(亞低溫)及18°C(深低溫)培養(yǎng)環(huán)境中,MTT方法檢測(cè)BMSCs細(xì)胞增殖活性,流式細(xì)胞術(shù)檢測(cè)BMSCs細(xì)胞周期變化,細(xì)胞免疫熒光方法檢測(cè)其在不同溫度條件下向神經(jīng)元和神經(jīng)膠質(zhì)細(xì)胞的分化潛能改變情況;(3)建立神經(jīng)元OGD模型,細(xì)胞原位凋亡方法檢測(cè)BMSCs的細(xì)胞凋亡情況,ELISA實(shí)驗(yàn)檢測(cè)LDH含量;western blot方法檢測(cè)共價(jià)結(jié)合狀態(tài)及游離狀態(tài)的SUMO1和SUMO2/3的蛋白表達(dá)情況;細(xì)胞免疫熒光方法檢測(cè)SUMO1和SUMO2/3在BMSCs中的細(xì)胞定位變化;(4)si RNA技術(shù)沉默BMSCs中SUMO1/2/3的基因表達(dá),利用壯觀霉素B1抑制Ubc9的基因表達(dá),并將其置于不同溫度下觀察其細(xì)胞形態(tài)、細(xì)胞增殖活性、向神經(jīng)細(xì)胞分化以及耐受OGD環(huán)境能力的變化;western blot方法檢測(cè)PCNA、Oct4、P53、HIF-1α的蛋白表達(dá)水平,分析低溫誘導(dǎo)SUMO活化保護(hù)BMSCs耐受乏氧不利環(huán)境的可能機(jī)制。(2)(1)免疫熒光雙染方法和western blot方法鑒定SUMO1/2/3基因敲除及SUMO1/2/3轉(zhuǎn)基因小鼠的基因型;(2)原代分離和培養(yǎng)小鼠胎鼠大腦皮層神經(jīng)元細(xì)胞,將其分別置于37°C(正常體溫)、42°C(高熱)及47°C(超高熱)培養(yǎng)環(huán)境中,western blot方法檢測(cè)SUMO1和SUMO2/3的蛋白表達(dá)水平,免疫熒光方法檢測(cè)SUMO1和SUMO2/3蛋白在神經(jīng)元中的細(xì)胞定位;(3)細(xì)胞原位凋亡方法檢測(cè)野生型、SUMO1/2/3基因敲除型及SUMO1/2/3轉(zhuǎn)基因型神經(jīng)元在上述溫度下的細(xì)胞凋亡情況,ELISA方法檢測(cè)上清液中LDH含量;(4)制作小鼠熱驚厥模型,五點(diǎn)量表法進(jìn)行驚厥發(fā)作評(píng)分,記錄小鼠驚厥百分率、潛伏時(shí)間和驚厥持續(xù)時(shí)間。結(jié)果:(1)(1)BMSCs高表達(dá)間充質(zhì)干細(xì)胞特異性蛋白CD71和CD105,而不表達(dá)造血干細(xì)胞特異蛋白CD34和CD4;(2)BMSCs在低溫下生長(zhǎng)緩慢,隨著溫度的降低其分化為神經(jīng)細(xì)胞的能力逐漸降低;BMSCs在OGD條件下可見(jiàn)大量細(xì)胞凋亡,伴隨著高水平的乳酸脫氫酶釋放,低溫能夠改善上述情況;(3)低溫可以誘導(dǎo)大量的蛋白質(zhì)被SUMOs修飾,表現(xiàn)為共價(jià)結(jié)合態(tài)SUMO1和SUMO2/3水平的明顯升高,而游離SUMO1和SUMO2/3水平的下降,同時(shí)伴隨著其從細(xì)胞質(zhì)向細(xì)胞核的移位;(4)沉默SUMO1/2/3基因表達(dá)后BMSCs形態(tài)開(kāi)始老化,細(xì)胞生長(zhǎng)速度明顯減慢,細(xì)胞周期停滯,并向神經(jīng)細(xì)胞發(fā)生終末分化;壯觀霉素B1能夠在一定程度上抑制Ubc9的表達(dá),進(jìn)而降低共價(jià)結(jié)合狀態(tài)的SUMO1和SUMO2/3的蛋白水平,BMSCs增殖速度減緩,低溫能夠增加BMSCs對(duì)乏氧不利環(huán)境的耐受能力;壯觀霉素B1能夠降低PCNA、Oct4、P53、HIF-1α的蛋白表達(dá)水平。(2)(1)免疫熒光雙染方法和western blot方法鑒定SUMO1/2/3基因敲除及SUMO1/2/3轉(zhuǎn)基因小鼠的基因型在轉(zhuǎn)基因小鼠神經(jīng)元中穩(wěn)定表達(dá),性狀穩(wěn)定;(2)小鼠胎鼠大腦皮層神經(jīng)元細(xì)胞置于37°C、42°C及47°C培養(yǎng)環(huán)境中時(shí)共價(jià)及游離狀態(tài)的SUMO1蛋白表達(dá)水平?jīng)]有明顯變化,但共價(jià)結(jié)合狀態(tài)的SUMO2/3的蛋白表達(dá)水平明顯升高,相應(yīng)地其游離狀態(tài)SUMO2/3的蛋白表達(dá)水平下降;免疫熒光結(jié)果顯示SUMO2/3蛋白存在由細(xì)胞漿向細(xì)胞核的移位;上述現(xiàn)象在自42°C回復(fù)到37°C后能夠得到恢復(fù),但自47°C回復(fù)到37°C后不能完成恢復(fù);(3)與野生型小鼠源性的神經(jīng)元相比較,SUMO1/2/3基因敲除神經(jīng)元在高熱應(yīng)激條件下具有更高的細(xì)胞凋亡和LDH水平,而SUMO1/2/3轉(zhuǎn)基因神經(jīng)元能夠明顯增加其對(duì)高熱應(yīng)激的耐受程度;(4)小鼠熱驚厥模型檢測(cè)結(jié)果顯示,與野生型小鼠相比較,SUMO1/2/3基因敲除小鼠的驚厥評(píng)分、驚厥發(fā)作百分率、潛伏時(shí)間和驚厥持續(xù)時(shí)間均最高,而SUMO1/2/3轉(zhuǎn)基因小鼠的驚厥評(píng)分、驚厥發(fā)作百分率、潛伏時(shí)間和驚厥持續(xù)時(shí)間均最低。結(jié)論:(1)低溫能夠抑制BMSCs的增殖能力,降低其向神經(jīng)細(xì)胞的分化潛能,同時(shí)能夠增加其對(duì)乏氧微環(huán)境的耐受程度;(2)低溫能夠增加BMSCs中大量蛋白質(zhì)的SUMO化修飾水平,并誘導(dǎo)SUMO1和SUMO2/3從細(xì)胞漿向細(xì)胞核移位;(3)SUMOs通路的活化對(duì)于BMSCs的增殖和干性維持是必不可少的;(4)壯觀霉素B1能夠通過(guò)抑制Ubc9基因表達(dá)抑制SUMOs通路,進(jìn)而降低BMSCs對(duì)乏氧微環(huán)境的耐受能力。(5)低溫能夠增加PCNA、Oct4、P53、HIF-1α蛋白的SUMO化修飾水平,上述機(jī)制共同參與BMSCs在低溫環(huán)境下的增殖能力、干性維持能力以及對(duì)乏氧不利微環(huán)境的耐受能力;(6)SUMO2/3(而非SUMO1)參與介導(dǎo)神經(jīng)元熱應(yīng)激早期反應(yīng);(7)短時(shí)間的高熱應(yīng)激(42°C)誘導(dǎo)的SUMO2/3共價(jià)修飾反應(yīng)是可逆的,而超高溫度的熱應(yīng)激(47°C)誘導(dǎo)的SUMO2/3共價(jià)修飾反應(yīng)是不可逆的;(8)增加神經(jīng)元中SUMOs過(guò)表達(dá)能夠使其耐受更高程度的熱應(yīng)激環(huán)境,降低其發(fā)生熱驚厥的幾率。
[Abstract]:Objective: To study the characteristics and rules of small ubiquitin like modified neurons in neurons under low temperature and heat stress, and to apply this rule to central nervous system disease, and to play its neuroprotective role in the treatment of central nervous system diseases related to temperature stress. Methods: (1) (1) primary isolation and culture of the mouse derived BM SCs, flow cytometry identified the expression of the cell surface marker protein; (2) in the culture environment of 37 degree C (normal body temperature), 33 degree C (mild hypothermia) and 18 degree C (deep hypothermia), MTT method was used to detect the proliferation activity of BMSCs cells. Flow cytometry was used to detect the changes of BMSCs cell cycle, and cell immunofluorescence method was used to detect its direction under different temperature conditions. The differentiation potential of neurons and glial cells was changed; (3) the neuron OGD model was established, the apoptosis of BMSCs was detected by the cell in situ apoptosis method, the LDH content was detected by ELISA test, the Western blot method was used to detect the protein expression of SUMO1 and SUMO2 /3 in the covalent binding state and free state, and the cell immunofluorescence method was used to detect SU. The cell localization of MO1 and SUMO2/3 in BMSCs; (4) the Si RNA technique silenced the gene expression of SUMO1/2/3 in BMSCs, inhibited the gene expression of Ubc9 using splendin B1, and observed the cell morphology, cell proliferation activity, the differentiation of the cells to the nerve cells and the tolerance to the OGD environment at different temperatures; Western blot method was detected. The protein expression level of PCNA, Oct4, P53, HIF-1 alpha and the possible mechanism of SUMO activation to protect BMSCs from the adverse environment of hypoxia tolerance. (2) (1) immunofluorescence double staining method and Western blot method to identify the genotype of SUMO1/2/3 knockout and SUMO1/2/3 transgenic mice; (2) primary isolation and Cultivation of cerebral cortex neurons in mouse fetal mice Cells were placed in 37 degree C (normal body temperature), 42 C (high fever) and 47 C (hyperthermia) culture environment. Western blot was used to detect the protein expression level of SUMO1 and SUMO2/3. Immunofluorescence method was used to detect the cell location of SUMO1 and SUMO2/3 protein in neurons; (3) in situ apoptosis method was used to detect the wild type and SUMO1/2/3 gene knockout type And the apoptosis of SUMO1/2/3 transgenic neurons at the above temperature, ELISA method to detect the LDH content in the supernatant; (4) the model of thermal convulsion in mice was made and the five point scale was used for the seizure score, the percentage of convulsion in mice, the latency time and the duration of convulsion were recorded. The results were (1) (1) the specificity of the high expression of mesenchymal stem cells in BMSCs. Protein CD71 and CD105, but not expression of hematopoietic stem cell specific protein CD34 and CD4; (2) BMSCs grows slowly at low temperature, and the ability to differentiate into nerve cells gradually decreases with the decrease of temperature; BMSCs can be seen in a large number of cell apoptosis under OGD conditions. With the release of high level lactate dehydrogenase, low temperature can improve the above situation; (3) hypothermia It can induce a large number of proteins to be modified by SUMOs, showing a significant increase in covalent binding state SUMO1 and SUMO2/3 levels, while the decrease of free SUMO1 and SUMO2/3 levels and the shift from the cytoplasm to the nucleus; (4) after the silence of SUMO1/2/3 gene expression, the BMSCs morphology begins to grow, the growth speed of the cells is significantly slowed and the cell cycle is slow. Stagnation and terminal differentiation to the nerve cells; splendin B1 can inhibit the expression of Ubc9 to a certain extent, and then reduce the protein level of SUMO1 and SUMO2/3 in covalent binding state, BMSCs proliferation slows, and low temperature can increase the tolerance of BMSCs to the hypoxic adverse environment; splendamycin B1 can reduce PCNA, Oct4, P53, HIF-1 alpha. (2) (2) (1) the double staining method of immunofluorescence and Western blot method identified that the genotype of SUMO1/2/3 gene knockout and SUMO1/2/3 transgenic mice were stable and stable in transgenic mice neurons. (2) the cerebral cortical neurons of mice were covalent and free when they were placed in 37 degrees C, 42 degree C and 47 degree C culture environment. There was no obvious change in the expression level of SUMO1 protein in the state, but the protein expression level of the covalent binding state of SUMO2/3 was significantly increased, and the protein expression level of the free state of SUMO2/3 decreased accordingly. The immunofluorescence results showed that the SUMO2/3 protein was shifted from the cytoplasm to the nucleus, and the above phenomenon could be obtained from 42 degree C to 37 C. The recovery could not be recovered from 47 degree C to 37 C. (3) compared with the wild type mice, the SUMO1/2/3 gene knockout neurons had higher apoptosis and LDH level under high heat stress, while SUMO1/2/3 transgenic neurons could significantly increase their tolerance to high heat stress; (4) the heat shock of mice. The convulsive score, the rate of convulsion, the latent time and the duration of convulsion were the highest in the SUMO1/2/3 gene knockout mice compared with the wild type mice. The convulsion score, the percentage of convulsions, the latent time and the duration of convulsion were the lowest in the SUMO1/2/3 transgenic mice. Conclusion: (1) low temperature can be suppressed. The proliferation ability of BMSCs, reducing its differentiation potential to neural cells, and increasing its tolerance to the hypoxia microenvironment; (2) low temperature can increase the SUMO modification level of a large number of proteins in BMSCs and induce SUMO1 and SUMO2/3 to shift from the cytoplasm to the nucleus; (3) the activation of the SUMOs pathway is for the proliferation and dry maintenance of BMSCs. It is essential: (4) granomycin B1 can inhibit the SUMOs pathway by inhibiting the expression of Ubc9 gene, and then reduce the tolerance of BMSCs to hypoxia microenvironment. (5) low temperature can increase the SUMO modification level of PCNA, Oct4, P53, HIF-1 alpha protein, and the mechanisms mentioned above jointly participate in the proliferation and dry maintenance ability of BMSCs in the low temperature environment. Tolerance to the hypoxic adverse microenvironment; (6) SUMO2/3 (rather than SUMO1) was involved in mediating early response to heat stress in neurons; (7) a short time hyperthermia (42 C) induced SUMO2/3 covalent modification was reversible, while the SUMO2/3 covalent reaction induced by hyperthermia (47 C) was irreversible; (8) increasing the SUMOs in neurons Overexpression can make them tolerate a higher degree of heat stress and reduce the risk of febrile seizures.
【學(xué)位授予單位】：天津醫(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)】：R741

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