本文選題：COPD + 蛋白質(zhì)組學(xué)�。� 參考：《復(fù)旦大學(xué)》2012年博士論文

【摘要】：第一部分慢性阻塞性肺病蛋白質(zhì)組學(xué)相關(guān)文獻(xiàn)回顧 目的：蛋白質(zhì)組學(xué)方法用于研究細(xì)胞、活檢組織、體液中的蛋白組分,廣泛用于深入探索人類疾病機(jī)制,尋找用于診斷、治療、預(yù)后的特異性的新型生物標(biāo)志物,以及研發(fā)藥物靶位等方面。本文第一部分研究意在通過回顧以往慢性阻塞性肺病(chronic obstructive pulmonary disease, COPD)的蛋白質(zhì)組學(xué)報道,從中總結(jié)已有的候選生物標(biāo)志物。 方法：利用文獻(xiàn)檢索,回顧以往基于蛋白質(zhì)組學(xué)方法的COPD報道。歸納總結(jié)這些報道涉及的研究對象、研究方法、候選生物標(biāo)志物等內(nèi)容。同時比較部分候選生物標(biāo)志物在其他慢性肺部疾病的變化。 結(jié)果：通過文獻(xiàn)檢索,得到符合納入標(biāo)準(zhǔn)的文獻(xiàn)共8篇。所涉及的研究對象,除COPD外,還包括正常非吸煙人群,健康吸煙者,α1胰蛋白酶缺陷者,支氣管哮喘,肺囊性纖維化,特發(fā)性肺間質(zhì)纖維化,支氣管擴(kuò)張等。所選用的研究標(biāo)本來源于肺組織活檢標(biāo)本,支氣管肺泡灌洗液,痰液或血液。使用的蛋白質(zhì)組學(xué)實驗手段包括雙向電泳,反向高效液相色譜,串聯(lián)質(zhì)譜法,基質(zhì)輔助激光解離質(zhì)譜法,表面增強(qiáng)激光解吸電離質(zhì)譜法等。在不同標(biāo)本中發(fā)現(xiàn)的大量候選生物標(biāo)志物可歸屬于氧化-抗氧化系統(tǒng),蛋白酶-抗蛋白酶系統(tǒng),炎癥介質(zhì)以及肺部特異性蛋白等。 結(jié)論：單一蛋白難以作為生物標(biāo)志物,而由多個蛋白組成的生物標(biāo)志物組群則可更好的反映復(fù)雜疾病的狀態(tài)。蛋白質(zhì)組學(xué)在COPD研究中,特別是挖掘生物標(biāo)志物方面獨具優(yōu)勢,但仍需建立標(biāo)準(zhǔn)化體系,規(guī)范組學(xué)研究,并最大限度的聯(lián)系臨床資料；利用生物信息學(xué)工具將臨床資料和蛋白質(zhì)組學(xué)結(jié)果相聯(lián)系,以期建立數(shù)字化模式監(jiān)測COPD的進(jìn)程和預(yù)后。 第二部分COPD及急性加重期病例血漿炎性生物標(biāo)志物組群的定性研究 目的：COPD不斷增長的死亡率與癥狀急性加重(chronic obstructive pulmonary disease in acute exacerbatioins, AECOPD)的頻率和嚴(yán)重程度有關(guān)。系統(tǒng)性炎癥在COPD/AECOPD中發(fā)揮重要作用。在第一部分研究中發(fā)現(xiàn),目前蛋白質(zhì)組學(xué)中存在的問題之一是如何將組學(xué)的結(jié)果與臨床信息相結(jié)合。因而本文第二部分研究意在通過蛋白質(zhì)組學(xué)方法檢測多種炎性介質(zhì),并利用新方法將組學(xué)結(jié)果和臨床信息結(jié)合,以期從新角度發(fā)現(xiàn)候選生物標(biāo)志物組群。 方法：收集健康正常人、COPD以及AECOPD患者的血液標(biāo)本,利用抗體芯片,定性檢測507個血漿炎癥因子。設(shè)計一套用于評價COPD及AECOPD病例病情的臨床評分系統(tǒng)(DESS),包括主要癥狀、體征、實驗室檢查等臨床信息,用于評估患者疾病的嚴(yán)重程度。將芯片檢測的差異蛋白與DESS評分結(jié)合進(jìn)行相關(guān)性分析。 結(jié)果：20個炎癥因子在3組人群間存在顯著差異(p0.05)。其中Cerberus1, Growth Hormone R, IL-1F6, IL-17B R, IL-17D, IL-19, Lymphotoxin β,MMP-10, Thrombopoietin和TLR4與患者DESS評分相關(guān)(p0.05)。在AECOPD患者中存在系統(tǒng)性炎癥的下調(diào)反應(yīng)。 結(jié)論：20個炎癥因子可能組成檢測COPD/AECOPD的候選生物標(biāo)志物組群。將臨床信息量化并與組學(xué)結(jié)果結(jié)合的方法,為篩選疾病特異性和疾病階段特異性的生物標(biāo)志物提供了新的研究模式。 第三部分COPD及急性加重期病例血漿趨化因子組群動態(tài)變化的研究 目的：第三部分意在利用蛋白質(zhì)組學(xué)方法定量檢測COPD/AECOPD循環(huán)中趨化因子的動態(tài)變化。并繼續(xù)使用第二部分中的評分系統(tǒng),對AECOPD患者進(jìn)行動態(tài)評分,以期發(fā)現(xiàn)與AECOPD病程進(jìn)展相關(guān)的候選生物標(biāo)志物組群。 方法：收集健康正常人、COPD以及AECOPD患者的血液標(biāo)本。AECOPD患者分別在確診時、治療中及癥狀好轉(zhuǎn)后采集血液標(biāo)本。利用多重趨化因子抗體芯片,定量檢測血漿中40個趨化因子。將芯片檢測的差異蛋白與DESS評分結(jié)合進(jìn)行相關(guān)性分析。 結(jié)果：在40個趨化因子中,30個在COPD和健康正常人間存在統(tǒng)計學(xué)差異(p0.05),16個在AECOPD和健康正常人間存在統(tǒng)計學(xué)差異(p0.05)。13個趨化因子,包括BTC,IL-9, IL-18Bpa, CCL22, CCL23, CCL25, CCL28, CTACK, LIGHT, MSPa, MCP-3, MCP-4和OPN,在三組間均存在差異。部分趨化因子的表達(dá)量與DESS評分間存在關(guān)聯(lián)(p0.05)。 結(jié)論：13個趨化因子可能組成監(jiān)測AECOPD發(fā)生和治療進(jìn)展的候選生物標(biāo)志物組群。第二部分中的研究方法,為篩選疾病特異性和疾病階段特異性的生物標(biāo)志物提供了新的研究模式。
[Abstract]:Literature Review on the Proteomics of Chronic Obstructive Pulmonary Disease in Part I

Objective : Proteomics method is used to study the protein components of cells , biopsy tissues and body fluids . It is widely used to probe into the mechanism of human diseases , to find novel biomarkers for diagnosis , treatment and prognosis , as well as to research and develop drug targets . The first part of this paper is to summarize the existing candidate biomarkers by reviewing the proteomic report of chronic obstructive pulmonary disease ( COPD ) .

Methods : Literature search was used to review the previous COPD reports based on proteomic methods . The subjects , methods and candidate biomarkers of these reports were summarized . At the same time , the changes of some candidate biomarkers in other chronic lung diseases were compared .

Results : A total of 8 articles conforming to the standard were obtained by literature search . In addition to COPD , there were normal non - smokers , healthy smokers , 偽 1 trypsin deficiency , bronchial asthma , pulmonary cystic fibrosis , idiopathic pulmonary fibrosis , bronchiectasis , etc . The selected study samples were derived from lung tissue biopsy specimens , bronchoalveolar lavage fluid , sputum or blood . The methods used in the study included two - dimensional electrophoresis , reverse high performance liquid chromatography , tandem mass spectrometry , matrix assisted laser desorption mass spectrometry , surface enhanced laser desorption ionization mass spectrometry , etc . The large number of candidate biomarkers found in different specimens could be attributed to oxidation - oxidation resistant systems , protease - antiprotease systems , inflammatory mediators , and lung - specific proteins .

Conclusion : Single protein is difficult to be used as biomarker , and biomarker group composed of multiple proteins can better reflect the state of complex disease . Proteomics has unique advantages in the study of COPD , especially in mining biomarkers , but it is still necessary to establish a standardized system , standardize the study of group and maximize the clinical data ;
A bioinformatic tool is used to link clinical data and proteomic results with a view to establishing a digital pattern to monitor the progression and prognosis of COPD .

Qualitative study of plasma inflammatory biomarkers in patients with COPD and acute exacerbation

Objective : To investigate the frequency and severity of chronic obstructive pulmonary disease in COPD / AECOPD . Systemic inflammation plays an important role in COPD / AECOPD .

Methods : Blood samples from healthy individuals , COPD and AECOPD patients were collected . 507 plasma inflammatory factors were qualitatively detected by using antibody chip . A set of clinical scoring system ( DESS ) was designed to evaluate the condition of COPD and AECOPD .

Results : There was a significant difference among the 20 inflammatory factors among the 3 groups ( p < 0.05 ) . Among them , Cerberus 1 , Growth Hormone R , IL - 1F6 , IL - 17B R , IL - 17 , IL - 19 , lymphotoxin 尾 , MMP - 10 , Thrombopoietin and TLR were correlated with the DESS score of the patients ( p < 0.05 ) . There was a down - regulation reaction of systemic inflammation in patients with AECOPD .

Conclusion : 20 inflammatory factors may constitute a candidate biomarker group for COPD / AECOPD . The clinical information is quantified and combined with the results of group learning to provide a new research mode for screening biomarkers specific to disease specificity and disease stage .

Study on the Dynamic Changes of Plasma Chemokine Cluster in the Third Part of COPD and Acute Aggravated Period

Objective : The third part is to quantitatively detect the dynamic changes of chemokine in COPD / AECOPD by proteomic method , and continue to use the scoring system in the second part to dynamically score AECOPD patients with a view to finding the candidate biomarker group associated with the progression of AECOPD .

Methods : Blood samples from healthy subjects , COPD and AECOPD patients were collected . Blood samples were collected from the patients with AECOPD .

Results : There were statistically significant differences ( p . 05 ) between 30 COPD patients and healthy controls ( p . 05 ) . There were 13 chemokine ( p . 05 ) in AECOPD and normal controls . There was a difference between the three groups . There was a correlation between the expression of partial chemokine and DESS score ( p < 0 . 05 ) .

Conclusion : 13 chemokine may constitute a candidate biomarker group for monitoring the development and progression of AECOPD . In the second part , a new research mode is provided for screening biomarkers specific to disease - specific and disease - stage .

【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2012
【分類號】：R563.9

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

1 蔡珊,陳平,朱應(yīng)群,彭紅,鄭東元,劉志軍,蔣惜念,劉友文;慢性阻塞性肺疾病氣道炎癥與肺泡巨噬細(xì)胞炎癥蛋白1α、明膠酶B活性的研究[J];中華結(jié)核和呼吸雜志;2001年07期

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本文編號：1776793