本文選題：蛋白質(zhì)組學(xué) + 尋常型銀屑病��； 參考：《中國科學(xué)院大學(xué)(中國科學(xué)院上海藥物研究所)》2017年碩士論文

【摘要】：銀屑病是一種長期的慢性免疫炎癥性皮膚病,易復(fù)發(fā),難根治。銀屑病分為尋常型銀屑病、膿皰型銀屑病、紅皮病型銀屑病和關(guān)節(jié)病型銀屑病四種類型,其中,尋常型銀屑病是臨床中最常見的一種類型,在銀屑病中占幾乎90%的比重。甲氨蝶呤(MTX)是1971年由美國FDA批準(zhǔn)的可用于治療嚴(yán)重的銀屑病的藥物。甲氨蝶呤對(duì)于患有嚴(yán)重銀屑病的患者起效快,但是不能防止復(fù)發(fā),部分患者用藥后無療效,并且因其抑制二氫葉酸還原酶來抑制核酸代謝而有嚴(yán)重的副作用,故需要在臨床上選擇適合的銀屑病患者人群進(jìn)行甲氨蝶呤的用藥治療。隨著質(zhì)譜技術(shù)的發(fā)展,使得高靈敏度和超高分辨率的質(zhì)譜技術(shù)和更優(yōu)化的組學(xué)方法能夠應(yīng)用于臨床樣本的研究,推動(dòng)個(gè)體化治療的進(jìn)程。本工作運(yùn)用基于化學(xué)標(biāo)記的定量蛋白質(zhì)組學(xué)方法來研究服用甲氨蝶呤后有無顯著療效患者的外周血單個(gè)核細(xì)胞(PBMC)的蛋白表達(dá)譜,結(jié)合臨床數(shù)據(jù),以期望找到與甲氨蝶呤敏感性和療效相關(guān)的生物標(biāo)志物,從而對(duì)敏感患者人群進(jìn)行區(qū)分,可用于銀屑病患者的個(gè)體化治療。我們選取4例甲氨蝶呤有效治療的患者(治療0周和8周)、4例甲氨蝶呤無效治療的患者(治療0周和8周)和4例正常對(duì)照組的共20個(gè)外周血單個(gè)核細(xì)胞樣本,采用了體外穩(wěn)定同位素化學(xué)(iTRAQ)標(biāo)記策略來進(jìn)行定量蛋白質(zhì)組學(xué)分析。一共鑒定到3397個(gè)蛋白,其中3190個(gè)蛋白具有定量信息。通過生物信息分析,我們發(fā)現(xiàn)一組蛋白在甲氨蝶呤治療效果好的患者中治療前后的表達(dá)水平發(fā)生顯著改變,且在甲氨蝶呤治療后表達(dá)恢復(fù)到正常水平。我們對(duì)其中的ANXA6進(jìn)行初步的生物學(xué)驗(yàn)證,證明甲氨蝶呤治療效果好的患者,治療前ANXA6特異性高表達(dá),并在治療后回復(fù)到正常水平。在本工作中,我們首次將藥物蛋白質(zhì)組學(xué)技術(shù)運(yùn)用到銀屑病患者PBMC細(xì)胞中,并發(fā)現(xiàn)了與甲氨蝶呤療效相關(guān)的動(dòng)態(tài)蛋白質(zhì)分子網(wǎng)絡(luò)。我們的研究結(jié)果將為甲氨蝶呤的臨床用藥予以一定的指導(dǎo),并對(duì)甲氨蝶呤治療銀屑病的藥物作用機(jī)制研究提供新的線索。
[Abstract]:Psoriasis is a chronic chronic immune inflammatory skin disease, easy to relapse, difficult to cure. Psoriasis is divided into four types: psoriasis vulgaris, pustular psoriasis, psoriasis vulgaris and psoriasis of arthropathy. Among them, psoriasis vulgaris is the most common type, accounting for almost 90% of psoriasis. Methotrexate (MTX) is a drug approved by FDA in 1971 for the treatment of severe psoriasis. Methotrexate acts quickly in patients with severe psoriasis, but does not prevent recurrence. Some patients have no effect after medication, and have serious side effects because of its inhibition of dihydrofolate reductase to inhibit nucleic acid metabolism. Therefore, it is necessary to select suitable patients with psoriasis for methotrexate therapy. With the development of mass spectrometry technology, high sensitivity and ultra-high resolution mass spectrometry technology and more optimized methods can be applied to the study of clinical samples, and promote the process of individualized treatment. In this study, a quantitative proteomics method based on chemical markers was used to study the protein expression profiles of peripheral blood mononuclear cells (PBMC) in patients with significant efficacy after methotrexate administration, and to combine with clinical data. The biomarkers related to the sensitivity and efficacy of methotrexate are expected to be found to distinguish the sensitive patients and to be used in individual treatment of psoriasis. We selected 20 peripheral blood mononuclear cell samples from 4 patients with effective methotrexate therapy (0 and 8 weeks of treatment) and 4 normal controls. A stable isotope chemochemistry in vitro iTRAQ labeling strategy was used for quantitative proteomics analysis. A total of 3397 proteins were identified, of which 3190 had quantitative information. Through bioinformatics analysis, we found that the expression of histone in patients with good methotrexate treatment changed significantly before and after treatment, and returned to normal level after methotrexate treatment. Our preliminary biological verification of ANXA6 showed that the specific expression of ANXA6 in patients with good methotrexate treatment was high before treatment and returned to normal level after treatment. In this work, we applied drug proteomics to PBMC cells of psoriatic patients for the first time, and found a dynamic protein molecular network related to the efficacy of methotrexate. Our results will provide some guidance for the clinical use of methotrexate and provide new clues for the study of the pharmacological mechanism of methotrexate in the treatment of psoriasis.
【學(xué)位授予單位】：中國科學(xué)院大學(xué)(中國科學(xué)院上海藥物研究所)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R96

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

1 丁曉嵐;王婷琳;沈佚葳;王曉艷;周城;田珊;劉盈;彭光輝;周俊娥;薛樹旗;王仁利;唐英;孟雪梅;裴廣德;白云花;劉青;李航;張建中;;中國六省市銀屑病流行病學(xué)調(diào)查[J];中國皮膚性病學(xué)雜志;2010年07期

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本文編號(hào)：1785839