本文選題：阿爾茨海默癥 + 蛋白質(zhì)組學(xué)　； 參考：《深圳大學(xué)》2017年碩士論文

【摘要】：目的:阿爾茨海默癥(Alzheimer’s disease,AD)是一種神經(jīng)退行性疾病,病變過程較長,出現(xiàn)記憶障礙、生活不能自理等病狀,早發(fā)現(xiàn)早干預(yù)十分重要�，F(xiàn)今神經(jīng)影像學(xué)可以直觀的顯示患者海馬的受損程度,判斷病變進(jìn)程,但是,神經(jīng)影像檢測(cè)價(jià)格昂貴,且需要患者長時(shí)間靜臥不動(dòng)對(duì)海馬進(jìn)行檢測(cè),有一定難度。而生物標(biāo)志物的興起,提供了另一條診斷途徑。在生物標(biāo)志物研究方面,腦脊液檢測(cè)被認(rèn)為是“金標(biāo)準(zhǔn)”,但取樣困難,而外周血可以在一定程度上反映病情,且取樣容易,易于推廣,使用外周血來尋找阿爾茨海默癥的生物標(biāo)志物,便于疾病的診斷。本研究以健康對(duì)照組、AD組和輕度認(rèn)知功能障礙患者(mild cognitive impairment,MCI)組為研究對(duì)象,選擇適合的蛋白質(zhì)組學(xué)研究技術(shù),基于將這些技術(shù)適用性和優(yōu)缺點(diǎn),組合運(yùn)用于實(shí)驗(yàn)中,篩選出阿爾茨海默癥的候選生物標(biāo)志物,并通過多種手段進(jìn)行驗(yàn)證,致力于反復(fù)驗(yàn)證以確保結(jié)果的準(zhǔn)確性,從候選生物標(biāo)志物中鑒定出可信的生物標(biāo)志物。方法:本研究第一部分以AD和健康對(duì)照為研究對(duì)象,利用酶聯(lián)免疫檢測(cè)技術(shù)(enzyme linked immunosorbent assay,ELISA)驗(yàn)證既往文獻(xiàn)報(bào)道的AD生物標(biāo)志物,包括:Apolipoprotein A1、Haptoglobin、Alpha-1-antitrypsin、Clusterin、C-reative protein、Matrix metalloproteinase 9、Calgranulin A、Calgranulin B和Alpha-2-macroglobulin。第二部分以AD和健康對(duì)照為研究對(duì)象,運(yùn)用同位素標(biāo)記相對(duì)與絕對(duì)定量技術(shù)(isobaric tags for relative and absolute quantitation,iTRAQ)和蛋白芯片技術(shù),結(jié)合生物信息學(xué)分析,研究阿爾茨海默癥生物標(biāo)志物,同時(shí)用ELISA和免疫印跡技術(shù)(Western blot,WB)對(duì)部分差異蛋白進(jìn)行了驗(yàn)證,包括:Afamin、Platelet basic protein、Fibulin-1、Plasma protease C1inhibitor、Thrombospondin-1、Inter-alpha-trypsin inhibitor heavy chain H4、Ceruloplasmin和Fibrinogen gamma chain。第三部分以MCI和健康對(duì)照為研究對(duì)象,運(yùn)用iTRAQ技術(shù)研究兩組血液表達(dá)差異蛋白。結(jié)果:第一部分,驗(yàn)證了文獻(xiàn)中的部分生物標(biāo)記物,一共有6個(gè)蛋白的表達(dá)水平有統(tǒng)計(jì)學(xué)意義,其中Haptoglobin顯著上調(diào),Apolipoprotein A1、Alpha-1-antitrypsin、Matrix metalloproteinase 9、Calgranulin A和Calgranulin B顯著下調(diào),這6個(gè)蛋白中Apolipoprotein A1、Calgranulin A和Calgranulin B的趨勢(shì)與文獻(xiàn)報(bào)道一致。第二部分,驗(yàn)證了運(yùn)用iTRAQ和蛋白芯片技術(shù)篩選出的7個(gè)蛋白,其中Platelet basic protein、Fibulin-1和Fibrinogen gamma chain顯著上調(diào),Plasma protease C1 inhibitor、Thrombospondin-1、Afamin和Ceruloplasmin顯著下調(diào),這7個(gè)蛋白中Plasma protease C1 inhibitor的趨勢(shì)與文獻(xiàn)報(bào)道和iTRAQ結(jié)果趨勢(shì)一致,Fibulin-1和Thrombospondin-1的變化趨勢(shì)與iTRAQ結(jié)果一致,Ceruloplasmin和Fibrinogen gamma chain的變化趨勢(shì)與文獻(xiàn)報(bào)道、蛋白芯片結(jié)果和WB結(jié)果一致。第三部分,以對(duì)照組和MCI組為實(shí)驗(yàn)對(duì)象,運(yùn)用iTRAQ技術(shù)篩選出差異蛋白。結(jié)論:本研究結(jié)果表明阿爾茨海默癥的病變可能與Apolipoprotein A1、Calgranulin A、Calgranulin B、Plasma protease C1 inhibitor、Thrombospondin-1、Ceruloplasmin和Fibrinogen gamma chain的表達(dá)水平變化有關(guān),這些蛋白可能是阿爾茨海默癥的潛在生物標(biāo)記物。本研究發(fā)現(xiàn)的這些蛋白可否作為阿爾茨海默癥的生物標(biāo)記物,尚需進(jìn)一步研究。
[Abstract]:Objective: Blzheimer (Alzheimer 's disease, AD) is a neurodegenerative disease with a longer pathological process, memory disorder, and inability to take care of itself. Early detection and early intervention is very important. Neuroimaging can directly display the damage degree of the hippocampus and judge the process of the disease. However, the price of neuroimaging is used to detect the price. It is difficult to detect the hippocampus for a long time, and it is difficult to detect the hippocampus for a long time. And the rise of the biomarker provides another way of diagnosis. In the study of biomarkers, the detection of cerebrospinal fluid is considered as a "gold standard", but the sampling is difficult, and the peripheral blood can reflect the condition to a certain extent, and the sampling is easy and easy to sample. To promote the use of peripheral blood to find the biomarkers of Alzheimer's disease and facilitate the diagnosis of disease. This study was conducted in the healthy control group, the AD group and the mild cognitive dysfunction (mild cognitive impairment, MCI) group, and selected suitable proteomics research techniques based on the applicability and advantages and disadvantages of these techniques. In the experiment, the candidate biomarkers of Alzheimer's disease are screened and verified by a variety of means. They are committed to repeated validation to ensure the accuracy of the results and identify credible biomarkers from the candidate biomarkers. Methods: the first part of the study was based on AD and healthy controls, using enzyme linked immunosorbent assay. The enzyme linked immunosorbent assay (ELISA) verifies the AD biomarkers reported in the previous literature, including Apolipoprotein A1, Haptoglobin, Alpha-1-antitrypsin, Clusterin, C-reative statements, and second parts. For the study, the biomarkers of Alzheimer's disease were studied by means of isobaric tags for relative and absolute quantitation, iTRAQ and protein chip technology, combined with bioinformatics analysis, and some differential proteins were tested by ELISA and immunological trace technology (Western blot, WB). Evidence, including: Afamin, Platelet basic protein, Fibulin-1, Plasma protease C1inhibitor, Thrombospondin-1, Inter-alpha-trypsin inhibitor heavy, and healthy control as the research object, using the technique to study the two groups of blood differential proteins. Results: the first part Some of the biomarkers in the literature were verified. The expression level of 6 proteins was statistically significant, in which Haptoglobin was significantly up-regulated, Apolipoprotein A1, Alpha-1-antitrypsin, Matrix metalloproteinase 9, Calgranulin A and Calgranulin B decreased significantly. The 6 proteins were Apolipoprotein A1. The trend of B is consistent with the literature report. In the second part, 7 proteins were screened by iTRAQ and protein chip technology, of which Platelet basic protein, Fibulin-1 and Fibrinogen gamma chain were significantly up-regulated, Plasma protease C1. The trend of 1 inhibitor is consistent with the trend of literature report and iTRAQ result, the change trend of Fibulin-1 and Thrombospondin-1 is the same as that of iTRAQ. The change trend of Ceruloplasmin and Fibrinogen gamma chain is consistent with the literature report, the result of protein chip and WB results. The third part is the experiment object of the control group and the MCI group, and the iTRAQ technology is used. Conclusion: the results of this study suggest that Alzheimer's disease may be associated with the changes in the level of expression of Apolipoprotein A1, Calgranulin A, Calgranulin B, Plasma protease C1 inhibitor, Thrombospondin-1, Ceruloplasmin, and such proteins may be potential organisms for Alzheimer's disease. Markers. Whether these proteins can be used as biomarkers for Alzheimer's disease need further study.
【學(xué)位授予單位】：深圳大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R749.16

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