疾病代谢物的色谱—质谱分析方法研究
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摘要
近年来,随着人类基因组测序工作的完成,人们对生命过程的理解有了很大的提高;人类越来越关注自身的健康状况以及生命质量。在科学领域,研究的热点也由此转移到基因的功能和几个“组学”研究,包括研究核糖核酸(RNA)转录过程的转录组学、研究某个过程中所有蛋白及其功能的蛋白组学、研究代谢产物的变化及代谢途径的代谢组学。
代谢组学是继“基因组学”、“转录组学”、“蛋白组学”之后新兴的又一门“组学”研究。代谢物组中,有一类异常新陈代谢物与疾病息息相关。正如大自然中生物个体之间和生物体内部的化学联系是一个普遍规律,人体内部也时刻通过生物化学信号物质进行联系。当人体发生疾病时,新陈代谢相应出现异常,血液、尿液、组织以及呼吸气体中会相应出现异常代谢物,而疾病化学标志物顾名思义就是可以作为指针与疾病各个病理阶段相关联。分析这些疾病相关的化学信号物质已经成为临床诊断疾病的一种重要手段。生物医学研究结合分析化学、生命科学、医学等学科进行人类重大疾病的筛查、诊断、治疗已成为当前研究的热点。发展色谱质谱新技术新方法发现并分析人体生物化学信号物质对重大疾病进行筛查和预警已经成为其重要的方向之一。
本论文以重大疾病(糖尿病、肺癌、新生儿遗传代谢疾病等)血液和组织中疾病化学标志物分离和鉴定为研究内容。该研究有十分重要的理论和现实意义。对肺癌病人的血液进行固相微萃取GC-MS顶空分析,发现并论证肺癌标记物分子,为肺癌开辟了一条新的、能够用于早期诊断的途径;并进一步发展了液滴衍生微萃取技术与GC-MS联用技术,分析癌症以及新生儿遗传代谢疾病病人血液、尿液中小分子代谢物,首次发现了癌症潜在早期标志物——己醛和庚醛;通过肝病不同阶段的病理模型以及随访跟踪病人,运用该方法进一步论证了己醛和庚醛作为癌症早期预警信号物质的作用。而对于新生儿遗传性有机酸尿症,我国儿童医学在新生儿筛查此类病症方面一直处于空白,我们运用了液滴微萃取技术与GC-MS联用,应用于几类典型的新生儿有机酸尿症研究,结果表明该方法快速简便,定量准确,是潜在的临床早期筛查手段。
本论文共分四章。主要内容摘要如下:
第一章论述了代谢组学的定义、研究范畴以及在药学、微生物学、毒理学、临床学等各方面的广泛应用与重要性。阐述了人体疾病信号物质研究对于重大疾病早期诊断和预警的理论和实际意义。此外还综述了疾病化学信号物质的分析方法,复杂体系样品前处理的方法以及建立合适动态模型的重要性和必要性。提出了本论文的研究目标和选题意义。
第二章的工作中,首先发展了色谱质谱技术分析重大癌症以及肝病的生物标志物,初步建立了早期筛查与预警癌症与肝病的简单、可靠的方法。发展了顶空固相微萃取方法分析病人血样中挥发性小分子代谢物;针对小分子羰基化合物,比较多种衍生试剂,进一步发展了定量分析小分子醛酮化合物的原位衍生化固相微萃取GC-MS方法,首次发现了癌症病人血液中己醛与庚醛含量异常,为正常人血液中含量的10倍以上,我们认为己醛与庚醛为癌症病人体内代谢异常的标志指针。我们通过建立不同阶段肝病病症的病人模型,动态跟踪随访病人,分析病人血液中小分子醛酮的含量,进而验证了己醛及庚醛与癌症的相关性。衍生固相微萃取与GC-MS方法联用,具有快速、无害、简单、准确的优点,解决了传统方法难以准确定量分析挥发性强的小分子羰基化合物的问题。
第三章在第二章原位衍生固相微萃取技术的基础上,进一步发展了液滴衍生微萃取技术与GC-MS联用分析重大疾病血样中小分子羰基化合物。论文首先综述了近年来液液(微)萃取技术的发展与应用,设计了简便的液滴微萃取设备并与固相微萃取技术进行比较,两者各有其优缺点。固相微萃取无需有机溶剂、对环境友好,但缺点是成本较高、萃取头容易损坏、进样易残留;液滴微萃取技术与其相比优点是成本低廉、毒性溶剂仅使用微升级别可忽略不计,集萃取、衍生、进样于一步骤,缺点则是与固相微萃取相比操作需要训练,该方法适用于大量样本筛查,大大降低成本。本章发展了一系列液滴萃取方法:(1)液滴微萃取溶液内衍生化-GC/MS分析癌症病人血液中羰基化合物,试验结果与固相微萃取技术可较好吻合,检测限略高,但足够满足血样中实际浓度分析。(2)液滴内衍生微萃取-GC/MS分析癌症病人羰基化合物标志物,将衍生试剂先溶入萃取试剂,使得衍生反应在液滴溶剂内发生,试验结果论证该方法的重现性、回收率更加良好。(3)静态顶空液滴微萃取与动态顶空液滴微萃取分析技术比较,理论预测动态萃取方法的相相接触更为完全,萃取效率更好,但是试验论证由于操作的难度较大,动态过程中液滴溶剂容易损失,该方法检测限确实降低,但是重现性比较差。总体而言,对于重大疾病的生物标志物分析,固相微萃取和液滴微萃取都可以很好的达到分析目的,可根据实际情况进行选择。
第四章主要针对几类重要的新生儿有机酸尿症的信号物质进行研究分析。由于我国目前医疗水平还未达到发达国家水平,新生儿有机酸尿症的胎检以及出生筛查基本属于空白。然而遗传性有机酸尿症在早期基本没有明显病症,患者在生长过程中会伴随着发育缓慢、脑发育不健全、神经性疾病等一系列复杂病症,因而对于有机酸尿症研究发展适合新生儿筛查的新技术新方法势在必行。本章通过寻找合适的衍生试剂,对于几类典型有机酸尿症的标志物——短链有机酸利用固相微萃取以及液滴微萃取技术进行分析,并应用此方法检测实际新生儿尿样。研究结果表明使用该方法能快速准确的定量分析新生儿尿样中几个重要锻炼酸指标,从而进行新生儿有机酸尿症的初步筛查。
本论文围绕疾病化学信号物质这个主题,发展建立了一系列前处理新方法新技术与气相色谱-质谱联用,分析了与几类重大疾病相关的疾病化学信号物质。为重大疾病的筛查和预警提供了新颖有效的研究手段和方法。
Since the completion of the first whole-genome sequence of a free-living organism,we began to realize the paucity of our knowledge with respect to the existence,let alone the function,of the novel genes thereby uncovered.More recently,completion of the human genome sequence has accelerated further the demand for determining the biochemical function of orphan genes and for validating them as molecular targets for therapeutic intervention.
The search for biomarkers that can serve as indicators of disease progression or response to therapeutic intervention has also increased. Functional studies have thus emphasized analyses at the level of gene expression (transcriptomics),protein translation(proteomics) including post-translational modifications,and the metabolic network(metabolomics),with a view to a 'systems biology' approach of defining the phenotype and bridging the genotype-to-phenotype gap.There is active debate in the research community over the exact definition of the 'metabolome',but it was first defined by Oliver et al.as the quantitative complement of all of the low molecular weight molecules present in cells in a particular physiological or developmental state.
Metabolomics is gaining increasing interest in drug discovery and disease diagnostics and treatment.The concept was recently introduced as the global analysis of all metabolites in a sample(metabolomics) and the analysis of metabolic responses to drugs or diseases(metabonomics).Metabolomics has proven to be very rapid and superior to any other post-genomics technology for pattern-recognition analyses of biological samples.Changing steady state concentrations and fluctuations of metabolites that occur within milliseconds are a result of biochemical processes such as signaling cascades:metabolomic techniques are instrumental in measuring these changes rapidly and sensitively. Metabolite data can be complemented by protein,transcript and external (environmental) data,thereby leading to the identification of multiple physiological biomarkers embedded in correlative molecular networks that are not approachable with targeted studies.
In view of the chemical and physical diversity of small biological molecules, the challenge remains of developing protocols to gather the whole 'metabolome'. No single technique is suitable for the analysis of different types of molecules, which is why a mixture of techniques has to be used.
GC-MS is a combined system where volatile and thermally stable compounds are first separated by GC and then eluting compounds are detected traditionally by electron-impact mass spectrometers.In metabolomics,GC-MS has been described as the gold standard,although it is biased against non-volatile, high-MW metabolites.Volatile,low-MW metabolites can be sampled and subsequently analyzed directly,including breath and plant volatiles.However, the majority of metabolites analyses require chemical derivatisation at room or elevated temperatures to provide volatility and thermal stability prior to analysis.
In this thesis,we focused on the development of series of novel techniques and methods to analyze the low-molecular weight molecules in the biological fluids and tissues and find the potential biomarkers of fatal diseases such as cancers,diabetes and inborn errors of metabolism.This dissertation is divided into four parts.
In Chapter 1,advances in metabolomics research,current analytical platforms and methodologies,applications of f metabolomics research techniques in the field of biomarkers research,drug discovery,and clinical diagnostics and so on were summarized in details.The intention and meaning of this dissertation were explained.
In chapter 2,GC-MS and solid-phase microextrction with on-fiber derivatization was developed for analysis of acetone in human plasma and breath.It is demonstrated that breath analysis could be applied to diagnosis of diabetes.In the study of lung cancer biomarkers,we developed headspace solid-phase microextraction for determination of volatile compounds in blood. Using this method,for the first time,we found two aldehyde biomarkers (hexanal and heptanal) in lung cancer blood.Further,headspace solid-phase microextrction with on-fiber derivatization technique was developed for determination of aldehydes in blood.The results proved that hexanal and heptanal might be biomarkers of lung cancer.
In chapter 3,we developed two new approaches to the analysis of the lung cancer biomarkers,hexanal and heptanal in human blood that was based on headspace single-drop microextraction(HS-SDME) with(droplet) derivatization, followed by gas chromatography-mass spectrometry(GC-MS).Aldehydes in blood were headspace extracted,concentrated,and derivatized by a suspended microdrop solvent containing the derivatization agent O-(2,3,4,5,6-pentaXuorobenzyi)hydroxylamine hydrochloride.The aldehyde oximes formed in the microdrop solvent were analyzed by GC-MS.the proposed method was applied to the quantiWcation of hexanal and heptanal in cancer blood and normal blood.Due to sample extraction,concentration,and derivatization being performed in a single step,the method provided a simple, rapid,low-cost,and efficient approach to analysis of aldehydes in blood samples.
In chapter 4,a novel technique of aqueous-phase derivatization followed by headspace solid-phase microextraction and gas chromatography-mass spectrometry was developed for the determination of organic acids in urine.The analytical procedure involves derivatization of organic acids to their ethyl esters with diethyl sulfate,headspace sampling,and GC/MS analysis.The proposed method was applied to the determination of methylmalonic acid and glutaric acid in urine.The experimental parameters and method validation were studied. Consequently,in-situ derivatization/HS-SPME/GC/MS is an alternative and powerful method for determination of organic acids as biomarkers in biological fluids.
In summary,the main contributes of this dissertation is that we initially developed a series of novel techniques and methods to quick and quantitative measure the low-molecular weight metabolites in biological fluids and tissues. We established HS-SPME/GC/MS and HS-SDME/GC/MS to analyze the aldehydes and short chain fatty acids in blood and urine to find the biomarkers of feral diseases.We aimed at exploring and finding out new techniques in sample preparation,derivatization and enrichment of metabolome research fields,so that more breakthroughs can be obtained in the metabolome research study.
代谢组学是继“基因组学”、“转录组学”、“蛋白组学”之后新兴的又一门“组学”研究。代谢物组中,有一类异常新陈代谢物与疾病息息相关。正如大自然中生物个体之间和生物体内部的化学联系是一个普遍规律,人体内部也时刻通过生物化学信号物质进行联系。当人体发生疾病时,新陈代谢相应出现异常,血液、尿液、组织以及呼吸气体中会相应出现异常代谢物,而疾病化学标志物顾名思义就是可以作为指针与疾病各个病理阶段相关联。分析这些疾病相关的化学信号物质已经成为临床诊断疾病的一种重要手段。生物医学研究结合分析化学、生命科学、医学等学科进行人类重大疾病的筛查、诊断、治疗已成为当前研究的热点。发展色谱质谱新技术新方法发现并分析人体生物化学信号物质对重大疾病进行筛查和预警已经成为其重要的方向之一。
本论文以重大疾病(糖尿病、肺癌、新生儿遗传代谢疾病等)血液和组织中疾病化学标志物分离和鉴定为研究内容。该研究有十分重要的理论和现实意义。对肺癌病人的血液进行固相微萃取GC-MS顶空分析,发现并论证肺癌标记物分子,为肺癌开辟了一条新的、能够用于早期诊断的途径;并进一步发展了液滴衍生微萃取技术与GC-MS联用技术,分析癌症以及新生儿遗传代谢疾病病人血液、尿液中小分子代谢物,首次发现了癌症潜在早期标志物——己醛和庚醛;通过肝病不同阶段的病理模型以及随访跟踪病人,运用该方法进一步论证了己醛和庚醛作为癌症早期预警信号物质的作用。而对于新生儿遗传性有机酸尿症,我国儿童医学在新生儿筛查此类病症方面一直处于空白,我们运用了液滴微萃取技术与GC-MS联用,应用于几类典型的新生儿有机酸尿症研究,结果表明该方法快速简便,定量准确,是潜在的临床早期筛查手段。
本论文共分四章。主要内容摘要如下:
第一章论述了代谢组学的定义、研究范畴以及在药学、微生物学、毒理学、临床学等各方面的广泛应用与重要性。阐述了人体疾病信号物质研究对于重大疾病早期诊断和预警的理论和实际意义。此外还综述了疾病化学信号物质的分析方法,复杂体系样品前处理的方法以及建立合适动态模型的重要性和必要性。提出了本论文的研究目标和选题意义。
第二章的工作中,首先发展了色谱质谱技术分析重大癌症以及肝病的生物标志物,初步建立了早期筛查与预警癌症与肝病的简单、可靠的方法。发展了顶空固相微萃取方法分析病人血样中挥发性小分子代谢物;针对小分子羰基化合物,比较多种衍生试剂,进一步发展了定量分析小分子醛酮化合物的原位衍生化固相微萃取GC-MS方法,首次发现了癌症病人血液中己醛与庚醛含量异常,为正常人血液中含量的10倍以上,我们认为己醛与庚醛为癌症病人体内代谢异常的标志指针。我们通过建立不同阶段肝病病症的病人模型,动态跟踪随访病人,分析病人血液中小分子醛酮的含量,进而验证了己醛及庚醛与癌症的相关性。衍生固相微萃取与GC-MS方法联用,具有快速、无害、简单、准确的优点,解决了传统方法难以准确定量分析挥发性强的小分子羰基化合物的问题。
第三章在第二章原位衍生固相微萃取技术的基础上,进一步发展了液滴衍生微萃取技术与GC-MS联用分析重大疾病血样中小分子羰基化合物。论文首先综述了近年来液液(微)萃取技术的发展与应用,设计了简便的液滴微萃取设备并与固相微萃取技术进行比较,两者各有其优缺点。固相微萃取无需有机溶剂、对环境友好,但缺点是成本较高、萃取头容易损坏、进样易残留;液滴微萃取技术与其相比优点是成本低廉、毒性溶剂仅使用微升级别可忽略不计,集萃取、衍生、进样于一步骤,缺点则是与固相微萃取相比操作需要训练,该方法适用于大量样本筛查,大大降低成本。本章发展了一系列液滴萃取方法:(1)液滴微萃取溶液内衍生化-GC/MS分析癌症病人血液中羰基化合物,试验结果与固相微萃取技术可较好吻合,检测限略高,但足够满足血样中实际浓度分析。(2)液滴内衍生微萃取-GC/MS分析癌症病人羰基化合物标志物,将衍生试剂先溶入萃取试剂,使得衍生反应在液滴溶剂内发生,试验结果论证该方法的重现性、回收率更加良好。(3)静态顶空液滴微萃取与动态顶空液滴微萃取分析技术比较,理论预测动态萃取方法的相相接触更为完全,萃取效率更好,但是试验论证由于操作的难度较大,动态过程中液滴溶剂容易损失,该方法检测限确实降低,但是重现性比较差。总体而言,对于重大疾病的生物标志物分析,固相微萃取和液滴微萃取都可以很好的达到分析目的,可根据实际情况进行选择。
第四章主要针对几类重要的新生儿有机酸尿症的信号物质进行研究分析。由于我国目前医疗水平还未达到发达国家水平,新生儿有机酸尿症的胎检以及出生筛查基本属于空白。然而遗传性有机酸尿症在早期基本没有明显病症,患者在生长过程中会伴随着发育缓慢、脑发育不健全、神经性疾病等一系列复杂病症,因而对于有机酸尿症研究发展适合新生儿筛查的新技术新方法势在必行。本章通过寻找合适的衍生试剂,对于几类典型有机酸尿症的标志物——短链有机酸利用固相微萃取以及液滴微萃取技术进行分析,并应用此方法检测实际新生儿尿样。研究结果表明使用该方法能快速准确的定量分析新生儿尿样中几个重要锻炼酸指标,从而进行新生儿有机酸尿症的初步筛查。
本论文围绕疾病化学信号物质这个主题,发展建立了一系列前处理新方法新技术与气相色谱-质谱联用,分析了与几类重大疾病相关的疾病化学信号物质。为重大疾病的筛查和预警提供了新颖有效的研究手段和方法。
Since the completion of the first whole-genome sequence of a free-living organism,we began to realize the paucity of our knowledge with respect to the existence,let alone the function,of the novel genes thereby uncovered.More recently,completion of the human genome sequence has accelerated further the demand for determining the biochemical function of orphan genes and for validating them as molecular targets for therapeutic intervention.
The search for biomarkers that can serve as indicators of disease progression or response to therapeutic intervention has also increased. Functional studies have thus emphasized analyses at the level of gene expression (transcriptomics),protein translation(proteomics) including post-translational modifications,and the metabolic network(metabolomics),with a view to a 'systems biology' approach of defining the phenotype and bridging the genotype-to-phenotype gap.There is active debate in the research community over the exact definition of the 'metabolome',but it was first defined by Oliver et al.as the quantitative complement of all of the low molecular weight molecules present in cells in a particular physiological or developmental state.
Metabolomics is gaining increasing interest in drug discovery and disease diagnostics and treatment.The concept was recently introduced as the global analysis of all metabolites in a sample(metabolomics) and the analysis of metabolic responses to drugs or diseases(metabonomics).Metabolomics has proven to be very rapid and superior to any other post-genomics technology for pattern-recognition analyses of biological samples.Changing steady state concentrations and fluctuations of metabolites that occur within milliseconds are a result of biochemical processes such as signaling cascades:metabolomic techniques are instrumental in measuring these changes rapidly and sensitively. Metabolite data can be complemented by protein,transcript and external (environmental) data,thereby leading to the identification of multiple physiological biomarkers embedded in correlative molecular networks that are not approachable with targeted studies.
In view of the chemical and physical diversity of small biological molecules, the challenge remains of developing protocols to gather the whole 'metabolome'. No single technique is suitable for the analysis of different types of molecules, which is why a mixture of techniques has to be used.
GC-MS is a combined system where volatile and thermally stable compounds are first separated by GC and then eluting compounds are detected traditionally by electron-impact mass spectrometers.In metabolomics,GC-MS has been described as the gold standard,although it is biased against non-volatile, high-MW metabolites.Volatile,low-MW metabolites can be sampled and subsequently analyzed directly,including breath and plant volatiles.However, the majority of metabolites analyses require chemical derivatisation at room or elevated temperatures to provide volatility and thermal stability prior to analysis.
In this thesis,we focused on the development of series of novel techniques and methods to analyze the low-molecular weight molecules in the biological fluids and tissues and find the potential biomarkers of fatal diseases such as cancers,diabetes and inborn errors of metabolism.This dissertation is divided into four parts.
In Chapter 1,advances in metabolomics research,current analytical platforms and methodologies,applications of f metabolomics research techniques in the field of biomarkers research,drug discovery,and clinical diagnostics and so on were summarized in details.The intention and meaning of this dissertation were explained.
In chapter 2,GC-MS and solid-phase microextrction with on-fiber derivatization was developed for analysis of acetone in human plasma and breath.It is demonstrated that breath analysis could be applied to diagnosis of diabetes.In the study of lung cancer biomarkers,we developed headspace solid-phase microextraction for determination of volatile compounds in blood. Using this method,for the first time,we found two aldehyde biomarkers (hexanal and heptanal) in lung cancer blood.Further,headspace solid-phase microextrction with on-fiber derivatization technique was developed for determination of aldehydes in blood.The results proved that hexanal and heptanal might be biomarkers of lung cancer.
In chapter 3,we developed two new approaches to the analysis of the lung cancer biomarkers,hexanal and heptanal in human blood that was based on headspace single-drop microextraction(HS-SDME) with(droplet) derivatization, followed by gas chromatography-mass spectrometry(GC-MS).Aldehydes in blood were headspace extracted,concentrated,and derivatized by a suspended microdrop solvent containing the derivatization agent O-(2,3,4,5,6-pentaXuorobenzyi)hydroxylamine hydrochloride.The aldehyde oximes formed in the microdrop solvent were analyzed by GC-MS.the proposed method was applied to the quantiWcation of hexanal and heptanal in cancer blood and normal blood.Due to sample extraction,concentration,and derivatization being performed in a single step,the method provided a simple, rapid,low-cost,and efficient approach to analysis of aldehydes in blood samples.
In chapter 4,a novel technique of aqueous-phase derivatization followed by headspace solid-phase microextraction and gas chromatography-mass spectrometry was developed for the determination of organic acids in urine.The analytical procedure involves derivatization of organic acids to their ethyl esters with diethyl sulfate,headspace sampling,and GC/MS analysis.The proposed method was applied to the determination of methylmalonic acid and glutaric acid in urine.The experimental parameters and method validation were studied. Consequently,in-situ derivatization/HS-SPME/GC/MS is an alternative and powerful method for determination of organic acids as biomarkers in biological fluids.
In summary,the main contributes of this dissertation is that we initially developed a series of novel techniques and methods to quick and quantitative measure the low-molecular weight metabolites in biological fluids and tissues. We established HS-SPME/GC/MS and HS-SDME/GC/MS to analyze the aldehydes and short chain fatty acids in blood and urine to find the biomarkers of feral diseases.We aimed at exploring and finding out new techniques in sample preparation,derivatization and enrichment of metabolome research fields,so that more breakthroughs can be obtained in the metabolome research study.
引文
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