MALDI质谱新方法与新技术及其在蛋白质组学中的应用研究
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摘要
本博士学位论文工作的主要集中于基于基质辅助激光解析飞行时间质谱(MALDI-TOFMS)的新方法新技术新发展及其在在蛋白质组学领域中的应用研究。在痕量多肽富集除盐的研究方面取得了创新性的进展,利用嵌段共聚物成功实现了样品高效靶上原位除盐与富集后直接用于MALDI-TOFMS分析,并成功应用到实际样品小鼠肝脏的蛋白质组学研究中。在蛋白质直接靶上酶解技术方面,发展了以树枝状聚合物-碳纳米管为基体,将胰蛋白酶固定在树枝状聚合物的表面得到可溶性的固定化酶,成功实现了蛋白质在靶板上快速酶解后直接用于MALDI-TOFMS分析,特别适用于低丰度蛋白质的高效酶解和质谱鉴定。在基质方面开展了针对磷酸化多肽、寡聚糖和磷脂离子化效率低等问题的研究工作,对基质体系进行研究,大大提高了上述三类分子的离子化效率,为质谱高灵敏度检测提供了解决方案。在MALDI-TOFMS用于非小细胞组织切片直接分析开展了研究工作,建立了用组织成像的方法寻找非小细胞癌生物标志物的方法,发现在非小细胞肺鳞癌中发现有别于癌旁组织的m/z 3000-3500的簇峰;发现非小细胞2种亚型肺鳞癌和肺腺癌相比,有各自特征性的磷脂分子峰出现;发现癌组织中heme b(m/z 616.2)表达量远低于癌旁组织,成为区别非小细胞肺癌和癌旁组织的生物标志物。
随着人类基因组序列“全书”的绘制完成,首次在分子层面上为人类揭示生命奥秘提供了一份生命“解剖图”。此后,人类对生命“密码”的解读大大加快了,进入了后基因组时代中。蛋白质组学(Proteomics)研究正是生命科学进入后基因组时代的标志之一。蛋白质组学以蛋白质组(Proteome)为研究对象。蛋白质组最初是指“由一个细胞或一个组织的基因组所表达的全部相应的蛋白质”。测定一个有机体的基因组所表达的全部蛋白质的设想,萌发在1975年双向凝胶电泳发明之时。1994年Williams正式提出了这个问题,而“蛋白质组”的名词则是由Wilkins创造的,它是由蛋白质的“Protein”和基因组的“Ome”字母拼接而成,发表在1995年7月的Electrophoresis杂志上。现在这一概念得到了扩展,指有机体全部基因表达的全部蛋白质及其存在方式,或者说是一种细胞、组织或完整生物体在特定时空上所拥有的全套蛋白质,以及蛋白质表达后的修饰,蛋白质之间的相互作用,蛋白质的空间结构和更高级的复合物等。
蛋白质分离技术、蛋白质鉴定技术、蛋白质相互作用分析及生物信息学数据处理技术被称为蛋白质组研究的四大基本支撑技术。其中,在蛋白质鉴定方面,质谱技术是目前在鉴定蛋白质的多种方法中发展最快、应用最广泛、最具发展潜力的技术。自约翰.芬恩(JohnB.Ferm)和田中耕一(Koichi.Tanaka)分别发明了两种重要的软电离方式“电喷雾离子化(ESI)”和“基质辅助激光解析离子化(MALDI)”技术,建立对生物大分子进行确认和结构分析的方法以来,质谱目前已经成为生命科学领域最活跃的前沿研究领域之一。蛋白质组学的科学研究之所以能够取得蓬勃的发展,主要依赖于质谱技术的飞速发展以及高通量分离和分析技术的突破性进步。然而,由于蛋白质的可变性和多样性等特点,蛋白质组研究在分析技术和分析仪器上还有很多瓶颈问题有待解决。如蛋白质的表达水平差异大,动态范围宽,现有的分离技术还不足以将一个生物体内所有的蛋白质分离开来:现有分析仪器的灵敏度还很难将体内微量的蛋白质精确分析,而这种微量蛋白在生命过程中起到关键性作用。随着蛋白质组学研究的进一步深入,传统的生物质谱技术平台已不足以应对蛋白质组学中高灵敏度高通量高准确度等的检测要求,所以研究和发展基于生物质谱的新技术与新方法对于促进蛋白质组学的研究显得意义重大。
本论文以发展MALDI质谱分析相关的新技术新方法为切入点,开展了相关研究工作。本论文共分为五章,主要内容摘要如下:
第一章主要综述了蛋白质组学研究发展概况,包括蛋白质组学的研究目的、意义、主要研究方法以及蛋白质组学在人类疾病研究中的应用。质谱仪器作为蛋白质组学研究领域中一个重要的技术支撑,本章节对质谱仪器的发展状况进行了简单的综述,包括其核心部件离子源、质量分析器和检测器技术的发展状况。着重对蛋白质组学中应用广泛的两种质谱仪器基质辅助激光解析质谱和电喷雾质谱的原理和应用进行了小结。本章还对蛋白质组学分析时面临的挑战进行了归纳,对MALDI技术研究的重要性和面临的挑战进行分析,并在此基础上提出了本课题工作的研究方向。
第二章研究工作主要为嵌段共聚物PSF-b-PEO用于痕量多肽靶上除盐和富集后直接MALDI-TOFMS分析的新方法研究。我们选择微观相分离结构的嵌段共聚物PSF-b-PEO作为MALDI靶涂层,然后利用制作的聚合物涂层进行痕量多肽的靶上除盐和富集工作。嵌段共聚物结构中具有亲水和疏水的两端,在点覆样品溶液后,由于疏水端不溶解在样品溶剂中,保持嵌段聚合物在金属上的膜稳定性;亲水端则可以溶解在样品溶剂中并对盐和一些污染物具有强的吸附作用,因而在样品溶剂挥发的过程中,盐和其它污染物被牢牢地包裹在聚合物内部。点覆基质溶液后,由于盐被包裹在聚合物内部,不再进入到基质的溶剂中,而肽段会再次溶解在基质中并和基质形成结晶。并且,由于聚合物膜的疏水性使得样品会收缩在一个很小的靶点区域内,使样品在靶上得到了富集。因此无需额外清洗除盐,富集除盐后的样品就可以直接进行MALDI-TOFMS分析。
第三章的研究工作主要为以树枝状聚合物-碳纳米管为基体,将胰蛋白酶固定在树枝状聚合物的表面得到可溶性的固定化酶,成功实现了痕量蛋白质在靶板上快速酶解后直接用于MALDI-TOFMS分析。我们首先在混合酸中对碳纳米管进行酸化处理在表面形成大量羧基并通过酸化处理截短碳纳米管以及去除杂质。然后将聚酰胺-胺型树枝状聚合物(dendrimers)通过共价结合的方式结合在碳纳米管表面,并将胰蛋白酶通过戊二醛交联反应固定在聚合物的氨基端。碳纳米管表面修饰了dendrimers后,极大地增强了碳纳米管的可溶性。因此,以树枝状聚合物-碳纳米管为基体的固定化酶既具有固定化酶的稳定性高的优点又具有可溶性酶活性高的优点,并且由于它的可溶性,酶解后不需要将碳纳米管从溶液中分离即可进行质谱鉴定。以树枝状聚合物-碳纳米管为基体的固定化胰蛋白酶进行靶上酶解,效率高、速度快、酶自降解峰少,酶解完成后可以直接进行质谱检测,特别适合痕量蛋白质的酶解和鉴定。
第四章研究工作主要为针对提高磷酸化多肽、寡聚糖及磷脂离子化效率开展的MALDI基质体系研究。通过在基质溶液中添加磷酸铵盐提高磷酸化肽的离子化效率;合成了新型离子基质2,3,4-三羟基苯乙酮/N,N-二甲基苯胺(2,3,4-THAP/DMA),2,3,4-三羟基苯乙酮/吡啶(2,3,4-THAP/Py),2,4,6-三羟基苯乙酮/N,N-二甲基苯胺(2,4,6-THAP/DMA)和2,4,6-三羟基苯乙酮/吡啶(2,4,6-THAP/Py)提高寡聚糖离子化效率;此外,还扩展了非极性基质[2E-3-(4-叔-丁基苯基)-2-甲基丙-2-亚烯基]丙二腈(DCTB)的应用范围,发现其在提高磷脂离子化效率方面有着重要的贡献。大大提高了上述三类分子的离子化效率,为质谱高灵敏度检测提供了解决方案
第五章研究工作主要为MALDI质谱成像技术用于非小细胞肺癌组织切片分析的研究。MALDI质谱成像技术用于直接分析组织切片已在基础与临床医学研究中迅速发展。通过对冰冻组织切片表面的质谱扫描可以快速直观地得到组织中的分子如蛋白,多肽等的分布信息。我们采用质谱成像技术对人的非小细胞肺癌组织切片及癌旁组织切片进行了研究,对质谱直接组织表面分析的方法进行了优化,初步建立了以质谱成像法寻找非小细胞肺癌中的生物标志物的方法。结果表明,肺鳞癌组织中有m/z3000-3500范围内的特征性簇峰出现;发现非小细胞2种亚型肺鳞癌和肺腺癌相比,有各自特征性的磷脂分子峰出现;以及在肺癌组织中heme b表达量远低于癌旁组织。质谱用于直接组织切片分析技术能够直观地在分子水平上反映出癌组织和正常组织间的差异,有望进一步提高肺癌临床诊断的准确度。
The main contribution of this doctoral dissertation is the development of new methods and techniques of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) and their application for proteomics research. Carrying out discoveries and inventions of the enrichment and desalting of low-abundance peptides using block copolymer and combined with MALDI-TOFMS analysis, which were then successfully applied in real sample analysis; Development of novel on-plate high speed proteolysis method with water-soluble immobilized trypsin on dendrimers-modified-carbonnanotubes (dCNTs) followed with MALDI-TOFMS analysis, which is especially helpful for low-abundance proteins digestion and identification; Investigation of new matrices system for high ionization of molecules includes phosphopeptides, oligosaccharides and phosphatidylcholines, their ionization efficiency were in a large extent enhanced with these novel matrices systems; Using MALDI-TOFMS for directly tissue section profiling analysis of non-small cell lung cancer(NSCLC). Results indicated that cluster peaks appears in the m/z ranges from 3000 to 3500 corresponding to squamous cell carcinoma tissues; The phospholipids profiles from different subtypes of NSCLC were investigated, and there were obvious differences between squamous cell carcinoma tissues and adenocarcinoma tissues; Also, results showed m/z 616.2 corresponding to heme b showed low ion intensity in cancerous regions compared with paracancerous.
As the human genome sequence "encyclopedia" completed, it ushered a new epoch of deciphering the mystery of life and afforded "anatomic map"of human life at the molecular level for the first time. It fueled the deciphering of "life codes", and made the genomics entering the post-genomics era since then. "Proteomics", as a new frontier in life science, has become one of the landmarks for the post-genomics period. Proteomics studied with the proteome as its research object. The term "proteome" was first coined to describe "the set of proteins encoded by the genome from a given cell or tissue". Determination of all the proteins from an organism was firstly germinated in 1975 at the time invention of two-dimensional gel electrophoresis. In 1994, Willams proposed this question formally, but the term "Proteome" was created by Wilkins, it comes from the term "Protein" and the term "genome". Nowadays, the concept of "Proteome" is expanded, it refers to not only all the proteins in any given cell, but also the set of all protein isoforms and modifications, the interactions between them, the structural description of proteins and their higher-order complexes etc.
Protein separation, protein identification, protein interaction analysis and bioinformatics data processing are four basic support techniques in proteomic study. As for protein identification, mass spectrometry technology is the fastest developing, the most extensive application and the most promising technology in the various protein identification methods currently. From the invention of two important soft ionization methods "electrospray ionization"(ESI) and "matrix-assisted laser desorption ionization"(MALDI) technology by JohnB.Fenn and Koichi.Tanaka respectively, as well as the establishment of biological macromolecules identification and structure analysis method, mass spectrometry(MS) has now become the most active frontier research field in life sciences. The vigorously development of proteomics mainly rely on development of mass spectrometry technology and progress of rapid protein separation and analysis technique with high-throughput. However, because of the diversity and variability of protein, proteomics studies are far more complex and much more difficult than genomics studies, especially bottlenecks will arise in analytical techniques and instruments. For example, the separation capability of existing technology is not enough to isolate all of the proteins in a given biological because of the wide dynamic range of the protein expression level; the sensitivity of the existing analysis instrument is hard to obtain traces of proteins, even though the precise analysis of trace protein plays an important role in life process. With the further in-depth study of proteomics, traditional biomass spectrometry platform is not enough to cope with detection requirements with high sensitivity, high accuracy, and high throughput. Therefore, the development of new methods and new techniques of biomass spectrometry is of great significance for promoting proteomics research.
This thesis focused on the development of new methods and new techniques of mass spectrometry analysis. The whole doctoral dissertation consists of five chapters and the contents are summarized as follows:
The first chapter summarized the development situation of proteomics research, including its research purpose, scientific significance, main research methods, and its application in human diseases research. As an important technical support platform of proteomics research fields, the development of mass spectrometry instrument, including its core components like ion source, quality analyzer and detector technology were reviewed in this chapter. Especially, it focused on the introduction of the principle and application of the most two widely used mass spectrometry (MALDI-MS and ESI-MS) in proteomics. At last, we introduced the challenges that proteomics analysis still faced. Based on that, the investigation direction and purpose of this dissertation was put forward.
The research work describe in chapter two focused on describing a novel method of on-plate desalting and enriching of trace peptides with block copolymer PSF-b-PEO and combined with MALDI-TOFMS analysis. We choose the block copolymer PSF-b-PEO with microscopic phase separation structure as the MALDI target coating materials, and then made use of the polymer film for on-plate desalting and enriching of trace peptides. There are hydrophilic and hydrophobic domains in its structure, after the sample solution added on the polymer film, because hydrophobic domain could maintain the polymer do not dissolve in the sample solution thus keeping the stability of the polymer film. The hydrophilic domains could dissolve in samples solutions and had strong effect on adsorption of salts or other contaminates, thus with the evaporation of sample solvent, salts and other contaminates were firmly wrapped inside the polymer. After added the matrix solution, salts no longer entered into the matrix solution due to the adsorption of polymer, whereas peptides redissolved in the matrix solution and form crystals with the matrix. In addition, the sample shrunk in a small target area on the hydrophobic surface of the polymer film, thereby, the sample was enriched on-target. Therefore, after the simultaneous desalting and enriching process, the sample could be directly analyzed by MALDI-TOFMS without any additional washing process.
The research work describe in chapter three focused on describing a novel method on-plate proteolysis with immobilized trypsin on dendrimers-modified-carbon nanotubes followed with MALDI-TOFMS analysis. Firstly, we treated the carbon nanotubes in mixed acid reagent to form large amount carboxyl group on its surface, and cut short of the carbon nanotubes as well as removed impurities through the acidification treatment. Then the polyamide-amine dendrimers was covalent modified on the carbon nanotubes surface. After that, trypsin was immobilized onto the dendrimers-modified carbon nanotubes(dCNTs) through the reaction of the aldehyde groups with the amine groups on the end of dendrimers. The dendrimers modification in a large extent enhanced the water-solubility of the carbon nanotubes. Therefore, the trypsin-linked dCNTs represents innovative properties that possess the advantages of both good stability of immobilized enzymes and high activity of soluble enzymes. Moreover, because of its good water-solubility, after the completion of proteolysis it can be used for directly mass spectrometric analysis without any need to remove the carbon nanotubes. It afforded many benefits using the trypsin-linked dCNTs for on-plate proteolysis, such as high digestion efficiency, high digestion speed, less enzymatic autolysis and can be directly used for MS analysis after the completion of digestion, making it especially suitable for proteolysis and identification of trace protein.
The research work describe in chapter four focused on describing some novel matrices systems for enhanced the ionization of phosphopeptides, oligosaccharides or phosphatidylcholines. Added ammonium phosphate salts in matrix solution to improve the ionization efficiency of phosphopeptide; Synthesized novel ionic matrices 2,3,4-THAP/DMA, 2,3,4-THAP/Py, 2,4,6-THAP/DMA and 2,4,6-THAP/Py to improve the ionization efficiency of oligosaccharides; Expanded the application of nonpolar matrix T-2-(3-(4-t-Butyl-phenyl)-2-methyl-2-propenylidene)malononitrile(DCTB) to improve the ionization efficiency of phosphatidylcholines.
The research work describe in chapter five described the method using MALD1-T0FMS for directly profiling of non-small cell lung cancer(NSCLC) tissues. MALDI-MS profiling for tissue section analysis is rapidly developed among foundation and clinical medical research. Through scanning on the frozen tissue slices, distribution information of molecules such as protein and peptides from a certain tissue are directly obtained in little time by Profiling MS technology. Based on the Profiling MS technology, human being's NSCLC tissues and paracancerous tissue slices were investigated, a profiling MS method analysis of NSCLC for biomarkers has been established after optimization the related methods. Results indicated that cluster peaks appears in the m/z ranges from 3000 to 3500 corresponding to corresponding to squamous cell carcinoma tissues; The phospholipids profiles from different subtypes of NSCLC were investigated, and there were obvious differences between squamous cell carcinoma tissues and adenocarcinoma tissues; Also, result showed m/z 616.2 corresponding to heme b showed low ion intensity in a cancerous regions compared with paracancerous. The profiling MS technique can present the differences between cancerous with paracancerous areas at molecular level, which is hoped to help improving the clinical diagnosis accuracy of NSCLC.
随着人类基因组序列“全书”的绘制完成,首次在分子层面上为人类揭示生命奥秘提供了一份生命“解剖图”。此后,人类对生命“密码”的解读大大加快了,进入了后基因组时代中。蛋白质组学(Proteomics)研究正是生命科学进入后基因组时代的标志之一。蛋白质组学以蛋白质组(Proteome)为研究对象。蛋白质组最初是指“由一个细胞或一个组织的基因组所表达的全部相应的蛋白质”。测定一个有机体的基因组所表达的全部蛋白质的设想,萌发在1975年双向凝胶电泳发明之时。1994年Williams正式提出了这个问题,而“蛋白质组”的名词则是由Wilkins创造的,它是由蛋白质的“Protein”和基因组的“Ome”字母拼接而成,发表在1995年7月的Electrophoresis杂志上。现在这一概念得到了扩展,指有机体全部基因表达的全部蛋白质及其存在方式,或者说是一种细胞、组织或完整生物体在特定时空上所拥有的全套蛋白质,以及蛋白质表达后的修饰,蛋白质之间的相互作用,蛋白质的空间结构和更高级的复合物等。
蛋白质分离技术、蛋白质鉴定技术、蛋白质相互作用分析及生物信息学数据处理技术被称为蛋白质组研究的四大基本支撑技术。其中,在蛋白质鉴定方面,质谱技术是目前在鉴定蛋白质的多种方法中发展最快、应用最广泛、最具发展潜力的技术。自约翰.芬恩(JohnB.Ferm)和田中耕一(Koichi.Tanaka)分别发明了两种重要的软电离方式“电喷雾离子化(ESI)”和“基质辅助激光解析离子化(MALDI)”技术,建立对生物大分子进行确认和结构分析的方法以来,质谱目前已经成为生命科学领域最活跃的前沿研究领域之一。蛋白质组学的科学研究之所以能够取得蓬勃的发展,主要依赖于质谱技术的飞速发展以及高通量分离和分析技术的突破性进步。然而,由于蛋白质的可变性和多样性等特点,蛋白质组研究在分析技术和分析仪器上还有很多瓶颈问题有待解决。如蛋白质的表达水平差异大,动态范围宽,现有的分离技术还不足以将一个生物体内所有的蛋白质分离开来:现有分析仪器的灵敏度还很难将体内微量的蛋白质精确分析,而这种微量蛋白在生命过程中起到关键性作用。随着蛋白质组学研究的进一步深入,传统的生物质谱技术平台已不足以应对蛋白质组学中高灵敏度高通量高准确度等的检测要求,所以研究和发展基于生物质谱的新技术与新方法对于促进蛋白质组学的研究显得意义重大。
本论文以发展MALDI质谱分析相关的新技术新方法为切入点,开展了相关研究工作。本论文共分为五章,主要内容摘要如下:
第一章主要综述了蛋白质组学研究发展概况,包括蛋白质组学的研究目的、意义、主要研究方法以及蛋白质组学在人类疾病研究中的应用。质谱仪器作为蛋白质组学研究领域中一个重要的技术支撑,本章节对质谱仪器的发展状况进行了简单的综述,包括其核心部件离子源、质量分析器和检测器技术的发展状况。着重对蛋白质组学中应用广泛的两种质谱仪器基质辅助激光解析质谱和电喷雾质谱的原理和应用进行了小结。本章还对蛋白质组学分析时面临的挑战进行了归纳,对MALDI技术研究的重要性和面临的挑战进行分析,并在此基础上提出了本课题工作的研究方向。
第二章研究工作主要为嵌段共聚物PSF-b-PEO用于痕量多肽靶上除盐和富集后直接MALDI-TOFMS分析的新方法研究。我们选择微观相分离结构的嵌段共聚物PSF-b-PEO作为MALDI靶涂层,然后利用制作的聚合物涂层进行痕量多肽的靶上除盐和富集工作。嵌段共聚物结构中具有亲水和疏水的两端,在点覆样品溶液后,由于疏水端不溶解在样品溶剂中,保持嵌段聚合物在金属上的膜稳定性;亲水端则可以溶解在样品溶剂中并对盐和一些污染物具有强的吸附作用,因而在样品溶剂挥发的过程中,盐和其它污染物被牢牢地包裹在聚合物内部。点覆基质溶液后,由于盐被包裹在聚合物内部,不再进入到基质的溶剂中,而肽段会再次溶解在基质中并和基质形成结晶。并且,由于聚合物膜的疏水性使得样品会收缩在一个很小的靶点区域内,使样品在靶上得到了富集。因此无需额外清洗除盐,富集除盐后的样品就可以直接进行MALDI-TOFMS分析。
第三章的研究工作主要为以树枝状聚合物-碳纳米管为基体,将胰蛋白酶固定在树枝状聚合物的表面得到可溶性的固定化酶,成功实现了痕量蛋白质在靶板上快速酶解后直接用于MALDI-TOFMS分析。我们首先在混合酸中对碳纳米管进行酸化处理在表面形成大量羧基并通过酸化处理截短碳纳米管以及去除杂质。然后将聚酰胺-胺型树枝状聚合物(dendrimers)通过共价结合的方式结合在碳纳米管表面,并将胰蛋白酶通过戊二醛交联反应固定在聚合物的氨基端。碳纳米管表面修饰了dendrimers后,极大地增强了碳纳米管的可溶性。因此,以树枝状聚合物-碳纳米管为基体的固定化酶既具有固定化酶的稳定性高的优点又具有可溶性酶活性高的优点,并且由于它的可溶性,酶解后不需要将碳纳米管从溶液中分离即可进行质谱鉴定。以树枝状聚合物-碳纳米管为基体的固定化胰蛋白酶进行靶上酶解,效率高、速度快、酶自降解峰少,酶解完成后可以直接进行质谱检测,特别适合痕量蛋白质的酶解和鉴定。
第四章研究工作主要为针对提高磷酸化多肽、寡聚糖及磷脂离子化效率开展的MALDI基质体系研究。通过在基质溶液中添加磷酸铵盐提高磷酸化肽的离子化效率;合成了新型离子基质2,3,4-三羟基苯乙酮/N,N-二甲基苯胺(2,3,4-THAP/DMA),2,3,4-三羟基苯乙酮/吡啶(2,3,4-THAP/Py),2,4,6-三羟基苯乙酮/N,N-二甲基苯胺(2,4,6-THAP/DMA)和2,4,6-三羟基苯乙酮/吡啶(2,4,6-THAP/Py)提高寡聚糖离子化效率;此外,还扩展了非极性基质[2E-3-(4-叔-丁基苯基)-2-甲基丙-2-亚烯基]丙二腈(DCTB)的应用范围,发现其在提高磷脂离子化效率方面有着重要的贡献。大大提高了上述三类分子的离子化效率,为质谱高灵敏度检测提供了解决方案
第五章研究工作主要为MALDI质谱成像技术用于非小细胞肺癌组织切片分析的研究。MALDI质谱成像技术用于直接分析组织切片已在基础与临床医学研究中迅速发展。通过对冰冻组织切片表面的质谱扫描可以快速直观地得到组织中的分子如蛋白,多肽等的分布信息。我们采用质谱成像技术对人的非小细胞肺癌组织切片及癌旁组织切片进行了研究,对质谱直接组织表面分析的方法进行了优化,初步建立了以质谱成像法寻找非小细胞肺癌中的生物标志物的方法。结果表明,肺鳞癌组织中有m/z3000-3500范围内的特征性簇峰出现;发现非小细胞2种亚型肺鳞癌和肺腺癌相比,有各自特征性的磷脂分子峰出现;以及在肺癌组织中heme b表达量远低于癌旁组织。质谱用于直接组织切片分析技术能够直观地在分子水平上反映出癌组织和正常组织间的差异,有望进一步提高肺癌临床诊断的准确度。
The main contribution of this doctoral dissertation is the development of new methods and techniques of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) and their application for proteomics research. Carrying out discoveries and inventions of the enrichment and desalting of low-abundance peptides using block copolymer and combined with MALDI-TOFMS analysis, which were then successfully applied in real sample analysis; Development of novel on-plate high speed proteolysis method with water-soluble immobilized trypsin on dendrimers-modified-carbonnanotubes (dCNTs) followed with MALDI-TOFMS analysis, which is especially helpful for low-abundance proteins digestion and identification; Investigation of new matrices system for high ionization of molecules includes phosphopeptides, oligosaccharides and phosphatidylcholines, their ionization efficiency were in a large extent enhanced with these novel matrices systems; Using MALDI-TOFMS for directly tissue section profiling analysis of non-small cell lung cancer(NSCLC). Results indicated that cluster peaks appears in the m/z ranges from 3000 to 3500 corresponding to squamous cell carcinoma tissues; The phospholipids profiles from different subtypes of NSCLC were investigated, and there were obvious differences between squamous cell carcinoma tissues and adenocarcinoma tissues; Also, results showed m/z 616.2 corresponding to heme b showed low ion intensity in cancerous regions compared with paracancerous.
As the human genome sequence "encyclopedia" completed, it ushered a new epoch of deciphering the mystery of life and afforded "anatomic map"of human life at the molecular level for the first time. It fueled the deciphering of "life codes", and made the genomics entering the post-genomics era since then. "Proteomics", as a new frontier in life science, has become one of the landmarks for the post-genomics period. Proteomics studied with the proteome as its research object. The term "proteome" was first coined to describe "the set of proteins encoded by the genome from a given cell or tissue". Determination of all the proteins from an organism was firstly germinated in 1975 at the time invention of two-dimensional gel electrophoresis. In 1994, Willams proposed this question formally, but the term "Proteome" was created by Wilkins, it comes from the term "Protein" and the term "genome". Nowadays, the concept of "Proteome" is expanded, it refers to not only all the proteins in any given cell, but also the set of all protein isoforms and modifications, the interactions between them, the structural description of proteins and their higher-order complexes etc.
Protein separation, protein identification, protein interaction analysis and bioinformatics data processing are four basic support techniques in proteomic study. As for protein identification, mass spectrometry technology is the fastest developing, the most extensive application and the most promising technology in the various protein identification methods currently. From the invention of two important soft ionization methods "electrospray ionization"(ESI) and "matrix-assisted laser desorption ionization"(MALDI) technology by JohnB.Fenn and Koichi.Tanaka respectively, as well as the establishment of biological macromolecules identification and structure analysis method, mass spectrometry(MS) has now become the most active frontier research field in life sciences. The vigorously development of proteomics mainly rely on development of mass spectrometry technology and progress of rapid protein separation and analysis technique with high-throughput. However, because of the diversity and variability of protein, proteomics studies are far more complex and much more difficult than genomics studies, especially bottlenecks will arise in analytical techniques and instruments. For example, the separation capability of existing technology is not enough to isolate all of the proteins in a given biological because of the wide dynamic range of the protein expression level; the sensitivity of the existing analysis instrument is hard to obtain traces of proteins, even though the precise analysis of trace protein plays an important role in life process. With the further in-depth study of proteomics, traditional biomass spectrometry platform is not enough to cope with detection requirements with high sensitivity, high accuracy, and high throughput. Therefore, the development of new methods and new techniques of biomass spectrometry is of great significance for promoting proteomics research.
This thesis focused on the development of new methods and new techniques of mass spectrometry analysis. The whole doctoral dissertation consists of five chapters and the contents are summarized as follows:
The first chapter summarized the development situation of proteomics research, including its research purpose, scientific significance, main research methods, and its application in human diseases research. As an important technical support platform of proteomics research fields, the development of mass spectrometry instrument, including its core components like ion source, quality analyzer and detector technology were reviewed in this chapter. Especially, it focused on the introduction of the principle and application of the most two widely used mass spectrometry (MALDI-MS and ESI-MS) in proteomics. At last, we introduced the challenges that proteomics analysis still faced. Based on that, the investigation direction and purpose of this dissertation was put forward.
The research work describe in chapter two focused on describing a novel method of on-plate desalting and enriching of trace peptides with block copolymer PSF-b-PEO and combined with MALDI-TOFMS analysis. We choose the block copolymer PSF-b-PEO with microscopic phase separation structure as the MALDI target coating materials, and then made use of the polymer film for on-plate desalting and enriching of trace peptides. There are hydrophilic and hydrophobic domains in its structure, after the sample solution added on the polymer film, because hydrophobic domain could maintain the polymer do not dissolve in the sample solution thus keeping the stability of the polymer film. The hydrophilic domains could dissolve in samples solutions and had strong effect on adsorption of salts or other contaminates, thus with the evaporation of sample solvent, salts and other contaminates were firmly wrapped inside the polymer. After added the matrix solution, salts no longer entered into the matrix solution due to the adsorption of polymer, whereas peptides redissolved in the matrix solution and form crystals with the matrix. In addition, the sample shrunk in a small target area on the hydrophobic surface of the polymer film, thereby, the sample was enriched on-target. Therefore, after the simultaneous desalting and enriching process, the sample could be directly analyzed by MALDI-TOFMS without any additional washing process.
The research work describe in chapter three focused on describing a novel method on-plate proteolysis with immobilized trypsin on dendrimers-modified-carbon nanotubes followed with MALDI-TOFMS analysis. Firstly, we treated the carbon nanotubes in mixed acid reagent to form large amount carboxyl group on its surface, and cut short of the carbon nanotubes as well as removed impurities through the acidification treatment. Then the polyamide-amine dendrimers was covalent modified on the carbon nanotubes surface. After that, trypsin was immobilized onto the dendrimers-modified carbon nanotubes(dCNTs) through the reaction of the aldehyde groups with the amine groups on the end of dendrimers. The dendrimers modification in a large extent enhanced the water-solubility of the carbon nanotubes. Therefore, the trypsin-linked dCNTs represents innovative properties that possess the advantages of both good stability of immobilized enzymes and high activity of soluble enzymes. Moreover, because of its good water-solubility, after the completion of proteolysis it can be used for directly mass spectrometric analysis without any need to remove the carbon nanotubes. It afforded many benefits using the trypsin-linked dCNTs for on-plate proteolysis, such as high digestion efficiency, high digestion speed, less enzymatic autolysis and can be directly used for MS analysis after the completion of digestion, making it especially suitable for proteolysis and identification of trace protein.
The research work describe in chapter four focused on describing some novel matrices systems for enhanced the ionization of phosphopeptides, oligosaccharides or phosphatidylcholines. Added ammonium phosphate salts in matrix solution to improve the ionization efficiency of phosphopeptide; Synthesized novel ionic matrices 2,3,4-THAP/DMA, 2,3,4-THAP/Py, 2,4,6-THAP/DMA and 2,4,6-THAP/Py to improve the ionization efficiency of oligosaccharides; Expanded the application of nonpolar matrix T-2-(3-(4-t-Butyl-phenyl)-2-methyl-2-propenylidene)malononitrile(DCTB) to improve the ionization efficiency of phosphatidylcholines.
The research work describe in chapter five described the method using MALD1-T0FMS for directly profiling of non-small cell lung cancer(NSCLC) tissues. MALDI-MS profiling for tissue section analysis is rapidly developed among foundation and clinical medical research. Through scanning on the frozen tissue slices, distribution information of molecules such as protein and peptides from a certain tissue are directly obtained in little time by Profiling MS technology. Based on the Profiling MS technology, human being's NSCLC tissues and paracancerous tissue slices were investigated, a profiling MS method analysis of NSCLC for biomarkers has been established after optimization the related methods. Results indicated that cluster peaks appears in the m/z ranges from 3000 to 3500 corresponding to corresponding to squamous cell carcinoma tissues; The phospholipids profiles from different subtypes of NSCLC were investigated, and there were obvious differences between squamous cell carcinoma tissues and adenocarcinoma tissues; Also, result showed m/z 616.2 corresponding to heme b showed low ion intensity in a cancerous regions compared with paracancerous. The profiling MS technique can present the differences between cancerous with paracancerous areas at molecular level, which is hoped to help improving the clinical diagnosis accuracy of NSCLC.
引文
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