本文選題：分子克隆 + 慢病毒　； 參考：《蘇州大學(xué)》2016年博士論文

【摘要】：第一部分IL-1α表達(dá)系統(tǒng)的構(gòu)建目的:IL-1α基因的N端含有核定位序列,能夠進(jìn)入細(xì)胞核,但入核型IL-1α具體功能機(jī)制并不清楚。研究表明白血病細(xì)胞中IL-1α水平異常升高。為了探尋入核型IL-1αpropiece在白血病細(xì)胞中的生物學(xué)功能以及可能的調(diào)控機(jī)制,為IL-1α的入核功能的研究提供實(shí)驗(yàn)基礎(chǔ)。方法:利用PCR方法克隆IL-1αpropiece基因,經(jīng)過(guò)測(cè)序驗(yàn)證之后連接到慢病毒載體。其中包含帶有FLAG標(biāo)簽與strep標(biāo)簽的IL-1αpropiece,用于對(duì)propiece進(jìn)行定位與純化。非標(biāo)簽IL-1αpropiece用于減少標(biāo)簽蛋白對(duì)蛋白功能最少程的影響。度包裝慢病毒顆粒對(duì)jurkat細(xì)胞進(jìn)行感染,利用流式細(xì)胞儀技術(shù)分選出高表達(dá)IL-1αpropiece的細(xì)胞。分離細(xì)胞漿蛋白與細(xì)胞核蛋白,使用免疫印跡的方法對(duì)不同組分中標(biāo)簽蛋白進(jìn)行檢測(cè),從而對(duì)IL-1αpropiece的表達(dá)空間進(jìn)行質(zhì)控。免疫熒光也被用來(lái)對(duì)IL-1αpropiece的核定位進(jìn)行質(zhì)控。細(xì)胞核被分離出來(lái),經(jīng)過(guò)免疫熒光染色使用流式細(xì)胞儀進(jìn)行檢測(cè)。對(duì)整個(gè)細(xì)胞進(jìn)行免疫熒光染色后,共聚焦檢測(cè)標(biāo)簽蛋白在細(xì)胞中的定位。結(jié)果:入核型IL-1α克隆至慢病毒表達(dá)載體,成功包裝出病毒顆粒,流式分選感染慢病毒后高表達(dá)GFP的細(xì)胞。細(xì)胞胞漿蛋白與核蛋白中對(duì)標(biāo)簽蛋白的免疫印跡表明IL-1αpropiece存在于細(xì)胞核組份中。共聚焦檢測(cè)發(fā)現(xiàn)IL-1αpropiece與DAPI的信號(hào)出現(xiàn)共定位。而在對(duì)染色后的細(xì)胞核流式染色中,發(fā)現(xiàn)IL-1αpropiece組的平均熒光強(qiáng)度高于對(duì)照組。結(jié)論:成功制備高表達(dá)IL-1αpropiece的jurkat細(xì)胞。免疫印跡實(shí)驗(yàn)、共聚焦顯微鏡及細(xì)胞核的流式染色均表明propiece定位表達(dá)于細(xì)胞核中。IL-1αpropiece真核過(guò)表達(dá)平臺(tái)構(gòu)建成功。第二部分IL-1α在急性淋巴細(xì)胞白血病細(xì)胞系中的生物學(xué)功能目的:研究在急性淋巴細(xì)胞白血病細(xì)胞系過(guò)表達(dá)IL-1αpropiece對(duì)細(xì)胞增殖、細(xì)胞周期、細(xì)胞凋亡的影響。研究低血清生存壓力脅迫下及抗腫瘤藥物順鉑毒性下,過(guò)表達(dá)IL-1αpropiece在急性淋巴白血病細(xì)胞中的生物學(xué)作用。方法:在過(guò)表達(dá)IL-1αpropiece的急性淋巴白血病細(xì)胞系中MTT法檢測(cè)24、48,72小時(shí)細(xì)胞增殖情況,并檢測(cè)低血清生存脅迫與順鉑藥物毒性下的細(xì)胞增殖情況。Annexin V與7AAD雙染檢測(cè)IL-1αpropiece過(guò)表達(dá)對(duì)細(xì)胞凋亡的影響。PI染色檢測(cè)低血清生存壓力脅迫與順鉑藥物毒性下過(guò)表達(dá)IL-1αpropiece對(duì)細(xì)胞周期的影響。結(jié)果:IL-1αpropiece過(guò)表達(dá)能夠促進(jìn)jurkat細(xì)胞與P388細(xì)胞增殖,增加G2/M期細(xì)胞百分比,并在順鉑毒性及低血清脅迫實(shí)驗(yàn)中降低細(xì)胞凋亡水平。結(jié)論:IL-1αpropiece過(guò)表達(dá)能夠促進(jìn)急性淋巴白血病細(xì)胞增殖,抑制細(xì)胞凋亡以及增加G2/M期細(xì)胞。第三部分IL-1αpropiece過(guò)表達(dá)生物芯片檢測(cè)與數(shù)據(jù)挖掘目的:探尋IL-1αpropiece在急性淋巴白血病細(xì)胞中的作用機(jī)制,生物芯片檢測(cè)過(guò)表達(dá)IL-1αpropiece引起的差異表達(dá)基因,并對(duì)信號(hào)通路、信號(hào)網(wǎng)絡(luò)、分子功能的影響進(jìn)行數(shù)據(jù)挖掘。方法:在過(guò)表達(dá)IL-1αpropiece急性淋巴細(xì)胞白血病細(xì)胞中使用Agilent Human4x44K gene expression array對(duì)基因表達(dá)譜的變化進(jìn)行檢測(cè)。聚類分析差異表達(dá)基因。選取Gene Go與GO(Gene Ontology)數(shù)據(jù)庫(kù)找出與差異基因相關(guān)的通路與生物學(xué)過(guò)程。通過(guò)I-TASSER對(duì)propiece的空間結(jié)構(gòu)進(jìn)行預(yù)測(cè),結(jié)合DBD-Hunter數(shù)據(jù)庫(kù),Bind N數(shù)據(jù)庫(kù),DISPLAR數(shù)據(jù)庫(kù)與i DBPs server數(shù)據(jù)庫(kù)的結(jié)果對(duì)propiece與DNA的結(jié)合能力進(jìn)行分析。利用PRIMA算法富集了差異表達(dá)基因的共同啟動(dòng)子。結(jié)果:芯片信息通過(guò)聚類分析可以發(fā)現(xiàn)MT家族基因與NF-κB靶基因均上調(diào)�；贕ene Go數(shù)據(jù)庫(kù)的分析中,通過(guò)對(duì)比110個(gè)已經(jīng)注釋過(guò)的信號(hào)動(dòng)態(tài)網(wǎng)絡(luò),推測(cè)propiece可能通過(guò)從血管新生,炎癥,抗凋亡,神經(jīng)新生等方面對(duì)疾病進(jìn)行調(diào)控。I-TASSER數(shù)據(jù)庫(kù)分析出的空間結(jié)構(gòu)也具有與DNA結(jié)合的可能性,并且PRIMA算法富集得到Sp1啟動(dòng)子為下調(diào)基因的共同啟動(dòng)子區(qū)域。結(jié)論:IL-1αpropiece能夠?qū)?dòng)態(tài)神經(jīng)網(wǎng)絡(luò)的進(jìn)行調(diào)節(jié),并且預(yù)測(cè)具有核酸結(jié)合的結(jié)合區(qū)域�？赡芡ㄟ^(guò)調(diào)控Sp1啟動(dòng)子區(qū)域達(dá)到生物學(xué)功能。第四部分IL-1αpropiece對(duì)信號(hào)通路的調(diào)控及其核酸結(jié)合片段的篩選目的:對(duì)本課題前期通過(guò)生物信息取得的預(yù)測(cè)結(jié)果進(jìn)行驗(yàn)證。構(gòu)建Sp1 mini promoter文庫(kù)尋找能與IL-1αpropiece發(fā)生相互作用的DNA序列信息。方法:使用免疫印跡對(duì)信號(hào)通路中發(fā)生改變的關(guān)鍵節(jié)點(diǎn)基因檢測(cè),對(duì)利用差異表達(dá)基因數(shù)據(jù)挖掘產(chǎn)生的信號(hào)網(wǎng)絡(luò)進(jìn)行驗(yàn)證。獲得重組IL-1αpropiece蛋白,與Sp1 promoter deletion assay混合,經(jīng)過(guò)SELEX方法篩選,經(jīng)過(guò)四輪進(jìn)化篩選。最終親和力高的文庫(kù)片段被連入T載體。測(cè)序后根據(jù)結(jié)果對(duì)每個(gè)區(qū)域計(jì)數(shù)統(tǒng)計(jì),獲得IL-1αpropiece的高親和力區(qū)域。并且分析其結(jié)合DNA motifs。使用豐度更高的商品化文庫(kù)與IL-1αpropiece進(jìn)行SELEX實(shí)驗(yàn),提高IL-1αpropiece結(jié)合DNA序列的分辨率。結(jié)果:IL-1αpropiece能激活NF-κB,AKT與p38 MAPK通路,降低外源性凋亡,上調(diào)抗凋亡基因。IL-1αpropiece能與Sp1啟動(dòng)子部分DNA發(fā)生相互作用。結(jié)論:IL-1αpropiece通過(guò)調(diào)控NF-κB通路,AKT通路與p38 MAPK通路協(xié)同作用發(fā)揮細(xì)胞促進(jìn)增殖,抑制凋亡的功能。SELEX的方法篩選與IL-1αpropiece結(jié)合的DNA序列,DNA序列具有CG含量高的特點(diǎn)。
[Abstract]:The first part of the construction of the IL-1 alpha expression system: the N end of the IL-1 alpha gene contains a nuclear location sequence, which can enter the nucleus, but the specific functional mechanism of the nuclear type IL-1 alpha is not clear. The study shows that the level of IL-1 alpha in the leukemia cells is abnormal. In order to explore the biological function and possibility of the nucleate IL-1 alpha propiece in leukemia cells. The regulatory mechanism provides an experimental basis for the study of IL-1 alpha nucleation function. Methods: the IL-1 alpha propiece gene was cloned by PCR method. After sequencing, it was connected to the lentivirus vector, including the IL-1 alpha propiece with the FLAG tag and strep label, which was used to locate and purify propiece. The non label IL-1 alpha propiece was used to reduce it. The effect of the less labelling protein on the function of the protein function at least. The Jurkat cells were infected by the lentivirus, and the cells with high expression of IL-1 alpha propiece were separated by flow cytometry. The cytoplasmic protein and nuclear protein were separated and the labelling proteins in different components were detected by immunoblotting, thus the IL-1 alpha prop was detected. The expression space of iece is controlled. Immunofluorescence is also used to control the nuclear location of IL-1 alpha propiece. The nucleus is separated and detected by immunofluorescence staining with flow cytometry. After immunofluorescence, the location of the confocal labeling protein in the cell is detected. Results: nucleate IL-1 alpha grams The virus particles were successfully packaged, and the cells with high expression of GFP after the infection of the lentivirus were successfully packed. The immunoblotting of cytoplasmic protein and the nuclear protein showed that the IL-1 alpha propiece existed in the nuclear components. Confocal detection found that the signals of IL-1 alpha propiece and DAPI were Co located. In the post color nuclear flow staining, the average fluorescence intensity of IL-1 alpha propiece group was higher than that of the control group. Conclusion: the Jurkat cells with high expression of IL-1 alpha propiece were successfully prepared. The immunoblot test, confocal microscopy and the flow staining of the nucleus showed that the propiece localization was expressed in the eukaryotic expression platform of.IL-1 alpha propiece in the nucleus. Second part of the biological function of IL-1 alpha in acute lymphoblastic leukemia cell lines: To study the effect of IL-1 alpha propiece on cell proliferation, cell cycle and apoptosis in acute lymphoblastic leukemia cell lines. Study the expression of IL-1 alpha under the low serum pressure stress and the toxicity of antitumor drug cisplatin. Biological effects of propiece in acute lymphoblastic leukemia cells. Methods: in the acute lymphoblastic leukemia cell lines that overexpressed IL-1 alpha propiece, MTT assay was used to detect the proliferation of 24,48,72 hours cells, and the cell proliferation under low serum stress and cisplatin toxicity was detected by.Annexin V and 7AAD double staining for the detection of IL-1 alpha propiece The effect of.PI staining on the survival pressure of low serum and the overexpression of IL-1 alpha propiece on the cell cycle of cisplatin. Results: the overexpression of IL-1 alpha propiece can promote the proliferation of Jurkat cells and P388 cells, increase the percentage of G2/M phase cells, and reduce the detail in the toxicity of cisplatin and the low serum stress test. Conclusion: IL-1 alpha propiece overexpression can promote the proliferation of acute lymphoblastic leukemia cells, inhibit cell apoptosis and increase G2/M phase cells. Third part IL-1 alpha propiece overexpression biochip detection and data mining aim to explore the mechanism of IL-1 alpha propiece in acute lymphoblastic leukemia cells, biochip detection Overexpression of differentially expressed genes caused by IL-1 alpha propiece and data mining on the effects of signal pathways, signal networks, and molecular functions. Methods: detection of the changes in gene expression profiles using Agilent Human4x44K gene expression array in IL-1 alpha propiece acute lymphoblastic leukemia cells. Cluster analysis differential table Gene Go and GO (Gene Ontology) database were selected to identify the pathways and biological processes related to differential genes. The spatial structure of propiece was predicted by I-TASSER, and the combining ability of DBD-Hunter database, Bind N database, DISPLAR database and I database were analyzed. PRIMA algorithm is used to enrich the common promoter of differentially expressed genes. Results: the MT family gene and the target gene of NF- kappa B can be found by cluster analysis. Based on the analysis of the Gene Go database, by comparing 110 signal dynamic networks that have already been annotated, the propiece may be measured from the angiogenesis, inflammation, and resistance to withering. The spatial structure of the.I-TASSER database analyzed by the.I-TASSER database also has the possibility of combining with DNA, and the PRIMA algorithm enriching the Sp1 promoter as the co promoter region of the down regulated gene. Conclusion: IL-1 alpha propiece can regulate the dynamic neural network and predict the binding of nucleic acid. The combination area. Maybe by regulating the Sp1 promoter region to achieve biological function. Fourth part IL-1 alpha propiece regulation of the signal pathway and the screening of nucleic acid binding fragments: to verify the prediction results obtained by biological information in the early stage of this project. The construction of Sp1 Mini promoter library can be found to occur with IL-1 alpha propiece. DNA sequence information of interaction. Method: using immunoblotting to detect the key node genes that change in the signal pathway, verify the signal network produced by the differential expression gene data mining. The recombinant IL-1 alpha propiece protein is obtained and mixed with Sp1 promoter deletion assay. Through SELEX method, four rounds of evolution sieve are screened by SELEX method. Selection. The final affinity high library fragments were connected to the T carrier. After sequencing, the high affinity regions of IL-1 alpha propiece were obtained according to the results. And the higher abundance commercial library of DNA motifs. and IL-1 alpha propiece were used to carry out SELEX experiments, and the resolution of IL-1 alpha propiece combined with DNA sequence was raised. Fruit: IL-1 alpha propiece activates NF- kappa B, AKT and p38 MAPK pathway, reduces exogenous apoptosis and up-regulates the DNA interaction of the anti apoptotic gene.IL-1 alpha propiece and Sp1 promoter part. Methods DNA sequences were screened with IL-1 alpha propiece, and the DNA sequence was characterized by high CG content.

【學(xué)位授予單位】：蘇州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R392

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