本文選題：質(zhì)譜成像 + 脂類��； 參考：《北京協(xié)和醫(yī)學院》2015年博士論文

【摘要】：眾所周知,癌癥是世界范圍內(nèi)造成人口死亡和經(jīng)濟損失的主要原因之一。人們針對這種疾病的研究已經(jīng)持續(xù)多年,但是研究方法還局限于相對傳統(tǒng)的技術。近年來,質(zhì)譜成像(MSI)作為一種快速且原位的分析方法正在飛速發(fā)展。該技術可在無標記的情況下同時檢測樣本表面多種分子的空間分布,為我們進行腫瘤診斷及相應機理研究提供了新的手段。本研究采用基質(zhì)輔助激光解吸電離(MALDI)傅里葉變換離子回旋共振質(zhì)譜(FTICR MS)技術,研究腫瘤組織中脂類等多種代謝物的分布,旨在尋找可用于腫瘤診斷的潛在標志物并探究腫瘤微環(huán)境中代謝物的變化規(guī)律。1.組織成像結合血液分析尋找具有甲狀腺癌診斷能力的脂類標志物血液與組織中脂類的變化與腫瘤密切相關。本研究采用MALDI-FTICR MS方法分別對甲狀腺癌患者(惡性、良性)的36例組織樣本及289例血液樣本進行分析,以尋找組織和血液中協(xié)同變化的脂類分子。多因素統(tǒng)計結合質(zhì)譜成像結果發(fā)現(xiàn)甲狀腺癌(惡性、良性)患者與正常人群的組織和血液樣本中有10種脂類分子出現(xiàn)顯著差異(卵磷脂3個、磷脂酸6個和鞘磷脂1個)。診斷分析發(fā)現(xiàn)卵磷脂(PC)(34:1)、鞘磷脂(SM)(34:1)和磷脂酸(PA)(36:3)的脂類標志物組合對于甲狀腺癌惡性、良性患者及正常人群有很好的診斷能力。2.質(zhì)譜成像原位分析六種癌癥組織中脂類代謝物的變化規(guī)律乳腺癌、肺癌、結直腸癌、食管癌、胃癌和甲狀腺癌等六種癌癥在世界范圍內(nèi)具有很高的發(fā)病率和死亡率。文獻報道脂類從頭合成途徑的激活是腫瘤發(fā)生發(fā)展的早期共性事件。本研究使用質(zhì)譜成像方法結合2,5-二羥基苯甲酸(DHB)和1,8-二氨基萘(DMAN)基質(zhì)分別在正、負離子模式下大規(guī)模分析了來自六種癌癥的134例腫瘤組織樣本。多因素統(tǒng)計結合質(zhì)譜成像結果發(fā)現(xiàn)單不飽和脂肪酸和磷脂在腫瘤區(qū)顯著上調(diào),多不飽和的脂肪酸和脂類在相同區(qū)域顯著下調(diào)。免疫組化結果顯示脂肪酸合成酶(FASN)、硬脂酰去飽和酶(SCD1)以及膽堿激酶(CKa)在腫瘤區(qū)均出現(xiàn)上調(diào)。根據(jù)以上結果,六種癌癥組織中的脂類從頭合成途徑可能被激活,且該途徑在腫瘤區(qū)促進單不飽和脂類分子的合成,同時抑制多不飽和脂類的合成。3.電場輔助循環(huán)噴霧系統(tǒng)結合高分辨率質(zhì)譜研究臨床組織樣本中低分子量代謝物的分布低分子量代謝物(分子量500 Da)作為一種重要的細胞成分與腫瘤的發(fā)生發(fā)展密切相關。但是,MALDI MSI對于低分子量代謝物在組織表面的檢測存在著靈敏度不高和基質(zhì)峰干擾的問題。本研究采用電場誘導循環(huán)噴霧系統(tǒng)(EFASS)在組織表面噴涂基質(zhì),結合FTICR MS實現(xiàn)高質(zhì)量分辨質(zhì)譜成像。與空氣噴槍和真空升華等傳統(tǒng)噴基質(zhì)方法比較時發(fā)現(xiàn)EFASS能顯著提高質(zhì)譜檢測低分子量代謝物的靈敏度和檢測數(shù)量。使用該方法分析胃癌組織表面低分子量代謝物的分布,發(fā)現(xiàn)單不飽和脂肪酸(棕櫚酸、油酸)和單磷酸核苷(單磷酸尿苷、單磷酸腺苷、單磷酸尿苷)在腫瘤區(qū)顯著上調(diào),核苷(肌苷、鳥苷、尿苷)和唾液酸在相同區(qū)域顯著下調(diào)。
[Abstract]:It is well known that cancer is one of the major causes of population death and economic loss worldwide. Research on this disease has lasted for many years, but the research method is limited to relative traditional technology. In recent years, mass spectrometry (MSI) is developing rapidly as a fast and in-situ analysis method. The simultaneous detection of the spatial distribution of a variety of molecules on the surface of the sample under unmarked conditions provides a new method for our tumor diagnosis and the study of the corresponding mechanisms. This study uses the matrix assisted laser desorption ionization (MALDI) Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) to study a variety of metabolites in tumor tissues. The purpose of this study is to search for potential markers for cancer diagnosis and to explore the changes in metabolites in the tumor microenvironment.1. tissue imaging combined with blood analysis to find the lipid markers in the blood and tissue of thyroid cancer. The changes of lipids in the blood and tissues are closely related to the tumor. This study uses the MALDI-FTICR MS method to treat a tumor, respectively. 36 tissue samples and 289 blood samples were analyzed to find the lipid molecules in tissue and blood. The results of multivariate statistical combined mass spectrometry found that the thyroid cancer (malignant, benign) patients had significant differences in 10 kinds of lipid molecules in the tissues and blood samples from the normal population (the malignant, benign). Phosphatidylcholine 3, phosphatidic acid 6 and sphingomyelin 1. Diagnostic analysis found that the lipid markers of PC (34:1), sphingomyelin (SM) (34:1) and phosphatidic acid (PA) (36:3) were good for the diagnosis of malignant thyroid cancer, benign patients and normal people with a good diagnostic energy.2. mass spectrometry in situ analysis of lipid metabolites in six cancer tissues Six cancers, such as breast cancer, lung cancer, colorectal cancer, esophageal cancer, gastric cancer, and thyroid cancer, have high morbidity and mortality worldwide. It is reported that activation of lipids from ab initio pathway is an early common event in the development of tumor. This study combines 2,5- two hydroxybenzoic acid (DHB) and 1,8- two by mass spectrometry A large scale analysis of 134 tumor tissue samples from six cancers was carried out in a positive and negative ion model. The results of multi factor statistical combined mass spectrometry found that monounsaturated fatty acids and phospholipids were significantly up-regulated in the tumor area, and polyunsaturated fatty acids and lipids were significantly down in the same region. The immunohistochemical results showed that the results of DMAN were significantly reduced. The fatty acid synthetase (FASN), stearoyl desaturase (SCD1) and choline kinase (CKa) are up-regulated in the tumor areas. According to the above results, the lipo synthesis pathway in the six cancer tissues may be activated, and this pathway promotes the synthesis of monounsaturated lipid molecules in the tumor area and inhibits the synthesis of.3. electricity from polyunsaturated lipids. The distribution of low molecular weight metabolites (molecular weight 500 Da) in clinical tissue samples is closely related to the occurrence and development of tumor as an important cell component. However, MALDI MSI is sensitive to the detection of low molecular weight metabolites on the tissue surface. This study uses electric field induced circular spray system (EFASS) to spray substrate on tissue surface and combine with FTICR MS to achieve mass resolution mass spectrometry. Compared with the traditional spray matrix method, such as air spray gun and vacuum sublimation, it is found that EFASS can significantly improve the sensitivity of mass spectrometry to detect low molecular weight metabolites. This method was used to analyze the distribution of low molecular weight metabolites on the surface of gastric carcinoma. It was found that monounsaturated fatty acids (palmitic acid, oleic acid) and monophosphate (uridine monophosphate, adenosine monophosphate, uridine monophosphate) were significantly up-regulated in the tumor area, and the nucleoside (myoside, guanosine, uridine) and sialic acid were significantly down down in the same region.
【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R730.4

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