动物组织中微量糖链结构分析方法的建立及应用
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摘要
本论文以C57BL/6J小鼠肝脏、肾脏及心脏为研究对象，运用多种现代提取分离与分析技术，建立了一种系统分析微量组织中神经节苷脂(ganglioside, GLS)、N-糖链及糖胺聚糖(glycosaminoglycan, GAGs)的分析方法，并将所建立的方法首次应用于人宫颈癌细胞(HeLa)中N-糖链和2型糖尿病小鼠(db/db)肾脏中GAGs组成及其精细结构差异性研究。在此基础上，以所得内源性糖链和外源性海洋糖链为原料，利用糖生物芯片技术，首次研究了GLS及海洋拟寡糖脂(NGLs)与甲型流感病毒(influenza A virus, H1N1)神经氨酸酶(neuraminidase,NA)的结合作用，探讨和分析了内源性GAGs和海洋酸性多糖与结缔组织生长因子(connective tissue growth factor, CTGF)的结合特性。得出的主要结论如下：
(1).利用高效薄层色谱(HPTLC)和电喷雾质谱(ESI-MS)联用技术，建立了一种可适用于不同组织中微量GLS组成的快速分析方法。以C57BL/6J小鼠肝脏、肾脏和心脏组织为研究对象，首次对其组织中GLS进行比较分析。结果表明，不同组织来源的GLS的种类及组成存在较大差异。C57BL/6J小鼠肝脏中以GM1和GM2为主，心脏中主要含GM1、GM2和GT1a，而肾脏中5种GLS(GM3、GM2、GM1、GD1a和GT1a)含量差异不大。肝脏中GLS的种类和含量最多，与其作为脂类代谢的主要器官有关。
(2).以C57BL/6J小鼠肾脏为研究对象，建立了一种从同一组织中分步释放微量N-糖链和GAGs的方法。研究表明，C57BL/6J小鼠肾脏中主要是硫酸乙酰肝素(heparan sulfate, HS)。N-糖链轮廓分析表明，小鼠肾脏有60种复杂多样的N-糖链，其中高甘露糖型所占比例较大，多数N-糖链含有乙酰神经氨酸(NeuAc)和岩藻糖(Fuc)。利用所建立的N-糖链分析方法，首次全面分析了HeLa细胞膜表面N-糖链的结构。在获得的34种N-糖链中，除存在高甘露糖型N-糖链，二天线、三天线、四天线和五天线等复杂型N-糖链外，还发现了与肿瘤发生和转移相关的平分型和Lewis糖链结构。
(3).建立了一种适用于动物组织中微量GAGs精细结构分析方法，并将其应用于2型糖尿病小鼠肾脏组织中GAGs的精细结构差异性分析。采用2-氨基吖啶酮(2-aminoacridone,2-AMAC)荧光标记柱前衍生高效液相色谱法，比较分析了C57BL/6J正常组小鼠，db/db糖尿病模型组小鼠和海洋寡糖药物HS203给药组小鼠肾脏中GAGs的种类及二糖组成结构差异性。首次发现db/db糖尿病组小鼠肾脏中HS较正常组N-硫酸化程度降低，而海洋寡糖药物HS203可显著提高病变组肾脏中HS硫酸化程度，表明HS203具有治疗糖尿病肾病作用。
(4).利用寡糖芯片技术，首次比较分析了6种内源性GLS及36种海洋红藻来源拟寡糖脂与甲型流感病毒NA的特异性结合作用。结果表明，36种海洋来源的不同类型的卡拉胶寡糖及琼胶寡糖与NA蛋白的结合强度绝大多数都强于内源性GLS，且这种结合强度与寡糖硫酸根的有无、糖残基种类、连接方式及聚合度大小等相关。
(5).利用多糖芯片技术，首次探讨了内源性GAGs和海洋酸性多糖与2型糖尿病肾病相关因子CTGF的结合作用，并发现硫酸化程度和糖醛酸含量是影响CTGF与硫酸乙酰肝素类多糖识别的关键因素。
综上，通过动物组织中GLS、N-糖链及GAGs快速分析方法的建立及该方法的成功应用，一方面可为糖组学研究提供了可靠方法，有利于寻找新的疾病标志物，并为疾病的早期诊断治疗提供新的途径；另一方面，将有利于从GAGs细微结构的改变上评价药物的有效性，并有利于阐释糖链在相关疾病发生发展的生物学作用，并为以此开发相关糖类药物提供方法学基础。
In the thesis, by using modern multiple extraction, separation and diverseanalysis techniques, a system method for structural analysis of ganglioside (GLS),N-glycans and glycosaminoglycan (GAGs) with small amount animal tissues wasestablished by using the liver, kidney and heart tissue of C57BL/6J mouse asmaterials. The method was firstly applied on studying the structural difference ofN-glycans from human cervical cancer cells (HeLa) and GAGs from kidneys of db/dbdiabetic mouse, respectively. Based on the method established, series endogenous andexogenous glycans were used as materials, the interaction of endogenous GLS andmarine neoglycolipids (NGLs) with (Neuraminidase, NA) of influenza A virus (H1N1)was firstly investigated by oligosaccharide chips method. Meanwhile, the interactionof endogenous GAGs and marine acidic polysaccharides with connective tissuegrowth factor (CTGF) was also firstly studied by polysaccharide chips method.The major conclusions were listed below:
(1). A rapid analytical method of composition and structural characteristic of traceamount of GLS from animal tissues was established by high-performance thinlayer chromatography (HPTLC) and electrospray ionization mass spectrometry(ESI-MS) techniques. The method was firstly applied on the structural analysis ofGLS in the liver, kidney and heart tissue from C57BL/6J mice, respectively. It wasshown that the compositions of GLS from different tissues were significantlydifferent. The mice liver mainly contained GM1and GM2and the mice heartmainly contained GM1, GM2and GT1a. The content of GM3, GM2, GM1, GD1aand GT1a from mice kidney had little difference. The GLS content from liver washighest in the three tissues, and this maybe associate with it to be the major organof lipid metabolization.
(2). A method of continuous release of trace amount of N-glycans and GAGssfrom the same tissue was established. The method was applied on N-glycans andGAGss extraction from the kidney of C57BL/6J mice. The result showed that thekidney mainly contained heparan sulfate (HS) and small amount of dermatan sulfate. Sixty kinds of glycans were detected according to the MALDI-TOF-MSprofiling, including high mannose types with relative high amount and mostN-glycans contained acetylneuraminic acid (NeuAc) and Fucose (Fuc). Theestablished N-glycan analysis method was firstly applied to the structure of HeLacells glycoprotein N-glycans profiling. The34types of N-glycans obtained fromHeLa cells included both high-mannose and complex (bi-, tri-, tetra-, andpenta-antennary) types, some of the latter containing bisecting and Lewisdeterminants, which were relevant to tumor metastasis in same way.
(3). A microanalysis method of fine structural difference of trace amount of GAGsin animal tissues was established and applied on the disaccharides analysis ofGAGs from the kidney tissue of type2diabetic mice. By pre-columnderivatization of disaccharides with2-aminoacridone (2-AMAC) and followed byreverse-phase HPLC analysis, and compared with the normal C57BL/6J mouse,the N-sulfation degree of HS was obviously decreased in the kidney of db/dbdiabetes mice. It was notable that the marine-derived oligosaccharide drug (HS203)could enhance the sulfation degree of HS from the abnormal kidney tissue, thisresult suggest HS203could be a potential drug for treatment of diabeticnephropathy.
(4). The interaction of6kinds of endogenous GLS and36kinds of NGLs preparedfrom marine red alga with H1N1neuraminidase (NA) was firstly analyzed byoligosaccharides chip method. It was shown that all36kinds of marine-derivedoligosaccharides showed a higher binding ability to NA proteins than theendogenous GLS, and the binding strength was related to sorts of residue, linkages,sulfation degree and position, and the degree of polymerization ofoligosaccharides.
(5). The interaction of endogenous GAGs and marine acidic polysaccharide withtype2diabetic nephropathy related factor-CTGF was first analyzed bypolysaccharides chip method. The results showed that the sulfation degree and theuronic acid content of the polysaccharides significantly affected the bondingstrength to CTGF.
In conclusion, the method of the system analysis of trace amount of GLS,N-glycans and GAGs in animal tissues was established, and this could be a reliablemethod for the glycomics study. It was also useful for new markers development fromtissues and new treatment for the early diagnosis of diseases. Meanwhile, it was beneficial to the validity of drug evaluation by analysis the fine structural differenceof GAGss. Furthermore, it could provide methodological foundation for further revealthe biological function of glycans in the occurrence and development of relateddiseases and new drugs development.
(1).利用高效薄层色谱(HPTLC)和电喷雾质谱(ESI-MS)联用技术，建立了一种可适用于不同组织中微量GLS组成的快速分析方法。以C57BL/6J小鼠肝脏、肾脏和心脏组织为研究对象，首次对其组织中GLS进行比较分析。结果表明，不同组织来源的GLS的种类及组成存在较大差异。C57BL/6J小鼠肝脏中以GM1和GM2为主，心脏中主要含GM1、GM2和GT1a，而肾脏中5种GLS(GM3、GM2、GM1、GD1a和GT1a)含量差异不大。肝脏中GLS的种类和含量最多，与其作为脂类代谢的主要器官有关。
(2).以C57BL/6J小鼠肾脏为研究对象，建立了一种从同一组织中分步释放微量N-糖链和GAGs的方法。研究表明，C57BL/6J小鼠肾脏中主要是硫酸乙酰肝素(heparan sulfate, HS)。N-糖链轮廓分析表明，小鼠肾脏有60种复杂多样的N-糖链，其中高甘露糖型所占比例较大，多数N-糖链含有乙酰神经氨酸(NeuAc)和岩藻糖(Fuc)。利用所建立的N-糖链分析方法，首次全面分析了HeLa细胞膜表面N-糖链的结构。在获得的34种N-糖链中，除存在高甘露糖型N-糖链，二天线、三天线、四天线和五天线等复杂型N-糖链外，还发现了与肿瘤发生和转移相关的平分型和Lewis糖链结构。
(3).建立了一种适用于动物组织中微量GAGs精细结构分析方法，并将其应用于2型糖尿病小鼠肾脏组织中GAGs的精细结构差异性分析。采用2-氨基吖啶酮(2-aminoacridone,2-AMAC)荧光标记柱前衍生高效液相色谱法，比较分析了C57BL/6J正常组小鼠，db/db糖尿病模型组小鼠和海洋寡糖药物HS203给药组小鼠肾脏中GAGs的种类及二糖组成结构差异性。首次发现db/db糖尿病组小鼠肾脏中HS较正常组N-硫酸化程度降低，而海洋寡糖药物HS203可显著提高病变组肾脏中HS硫酸化程度，表明HS203具有治疗糖尿病肾病作用。
(4).利用寡糖芯片技术，首次比较分析了6种内源性GLS及36种海洋红藻来源拟寡糖脂与甲型流感病毒NA的特异性结合作用。结果表明，36种海洋来源的不同类型的卡拉胶寡糖及琼胶寡糖与NA蛋白的结合强度绝大多数都强于内源性GLS，且这种结合强度与寡糖硫酸根的有无、糖残基种类、连接方式及聚合度大小等相关。
(5).利用多糖芯片技术，首次探讨了内源性GAGs和海洋酸性多糖与2型糖尿病肾病相关因子CTGF的结合作用，并发现硫酸化程度和糖醛酸含量是影响CTGF与硫酸乙酰肝素类多糖识别的关键因素。
综上，通过动物组织中GLS、N-糖链及GAGs快速分析方法的建立及该方法的成功应用，一方面可为糖组学研究提供了可靠方法，有利于寻找新的疾病标志物，并为疾病的早期诊断治疗提供新的途径；另一方面，将有利于从GAGs细微结构的改变上评价药物的有效性，并有利于阐释糖链在相关疾病发生发展的生物学作用，并为以此开发相关糖类药物提供方法学基础。
In the thesis, by using modern multiple extraction, separation and diverseanalysis techniques, a system method for structural analysis of ganglioside (GLS),N-glycans and glycosaminoglycan (GAGs) with small amount animal tissues wasestablished by using the liver, kidney and heart tissue of C57BL/6J mouse asmaterials. The method was firstly applied on studying the structural difference ofN-glycans from human cervical cancer cells (HeLa) and GAGs from kidneys of db/dbdiabetic mouse, respectively. Based on the method established, series endogenous andexogenous glycans were used as materials, the interaction of endogenous GLS andmarine neoglycolipids (NGLs) with (Neuraminidase, NA) of influenza A virus (H1N1)was firstly investigated by oligosaccharide chips method. Meanwhile, the interactionof endogenous GAGs and marine acidic polysaccharides with connective tissuegrowth factor (CTGF) was also firstly studied by polysaccharide chips method.The major conclusions were listed below:
(1). A rapid analytical method of composition and structural characteristic of traceamount of GLS from animal tissues was established by high-performance thinlayer chromatography (HPTLC) and electrospray ionization mass spectrometry(ESI-MS) techniques. The method was firstly applied on the structural analysis ofGLS in the liver, kidney and heart tissue from C57BL/6J mice, respectively. It wasshown that the compositions of GLS from different tissues were significantlydifferent. The mice liver mainly contained GM1and GM2and the mice heartmainly contained GM1, GM2and GT1a. The content of GM3, GM2, GM1, GD1aand GT1a from mice kidney had little difference. The GLS content from liver washighest in the three tissues, and this maybe associate with it to be the major organof lipid metabolization.
(2). A method of continuous release of trace amount of N-glycans and GAGssfrom the same tissue was established. The method was applied on N-glycans andGAGss extraction from the kidney of C57BL/6J mice. The result showed that thekidney mainly contained heparan sulfate (HS) and small amount of dermatan sulfate. Sixty kinds of glycans were detected according to the MALDI-TOF-MSprofiling, including high mannose types with relative high amount and mostN-glycans contained acetylneuraminic acid (NeuAc) and Fucose (Fuc). Theestablished N-glycan analysis method was firstly applied to the structure of HeLacells glycoprotein N-glycans profiling. The34types of N-glycans obtained fromHeLa cells included both high-mannose and complex (bi-, tri-, tetra-, andpenta-antennary) types, some of the latter containing bisecting and Lewisdeterminants, which were relevant to tumor metastasis in same way.
(3). A microanalysis method of fine structural difference of trace amount of GAGsin animal tissues was established and applied on the disaccharides analysis ofGAGs from the kidney tissue of type2diabetic mice. By pre-columnderivatization of disaccharides with2-aminoacridone (2-AMAC) and followed byreverse-phase HPLC analysis, and compared with the normal C57BL/6J mouse,the N-sulfation degree of HS was obviously decreased in the kidney of db/dbdiabetes mice. It was notable that the marine-derived oligosaccharide drug (HS203)could enhance the sulfation degree of HS from the abnormal kidney tissue, thisresult suggest HS203could be a potential drug for treatment of diabeticnephropathy.
(4). The interaction of6kinds of endogenous GLS and36kinds of NGLs preparedfrom marine red alga with H1N1neuraminidase (NA) was firstly analyzed byoligosaccharides chip method. It was shown that all36kinds of marine-derivedoligosaccharides showed a higher binding ability to NA proteins than theendogenous GLS, and the binding strength was related to sorts of residue, linkages,sulfation degree and position, and the degree of polymerization ofoligosaccharides.
(5). The interaction of endogenous GAGs and marine acidic polysaccharide withtype2diabetic nephropathy related factor-CTGF was first analyzed bypolysaccharides chip method. The results showed that the sulfation degree and theuronic acid content of the polysaccharides significantly affected the bondingstrength to CTGF.
In conclusion, the method of the system analysis of trace amount of GLS,N-glycans and GAGs in animal tissues was established, and this could be a reliablemethod for the glycomics study. It was also useful for new markers development fromtissues and new treatment for the early diagnosis of diseases. Meanwhile, it was beneficial to the validity of drug evaluation by analysis the fine structural differenceof GAGss. Furthermore, it could provide methodological foundation for further revealthe biological function of glycans in the occurrence and development of relateddiseases and new drugs development.
引文
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