“寒淫”致病及转归的转录组与代谢组实验研究
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摘要
背景
随着后基因组和系统生物学的理论与技术不断发展,为中医证候研究搭建了现代分子生物学研究的平台,组学研究复杂的中医证候重大问题成为了可能,也成为了现在中医证候研究的新突破口。但是整合组学研究重大中医证候问题还有待深入。因此,“寒淫”致病及中药干预的转录组与代谢组整合研究,利用现有的技术和方法学平台,有力的为解决目前寒证研究面临的困难,进行了积极的有意义的探索。
目的
1、“寒淫”致病的代谢谱和转录谱共性特征
2、热药干预“寒淫”致病的代谢与转录的修复网络
方法
1、模拟寒淫：实验大鼠随机分为3组,即正常组(n=10)、寒淫组(n=10)和给药组(n=10),正常组大鼠常规室温下喂养,同时于实验第二天开始每日给予常温蒸馏水2ml灌胃；模型组的大鼠在10±2℃冷柜常规喂养,每天4-6小时,同时于实验第二天开始每日给予常温蒸馏水2ml灌胃；给药组大鼠在-10±2℃冷柜常规喂养,每天4-6小时；同时从实验第二天开始每日给予中药汤剂2ml灌胃,实验持续3周。每组结束时,抽取静脉血12ml,其中8ml入抗凝离心管中,离心提取白细胞,冻藏于-20℃冰箱,以备检测；其余4ml分离取得血浆样本,冻藏于-70℃冰箱,以备检测。
2、生物信息方法：一个生物学功能很少会是完全归功于一个单独细胞分子的作用,大部分生物学特性是来自于细胞内无数组分间的相互复杂作用。网络构建是当代生物信息学技术中解决该问题的主要手段,可以较为完整、全面的揭示各组分间是如何协同作用,共同完成一种生物学行为的。代谢组的实验数据分析采用线性模式识别技术。利用SIMCA-P11.5进行主成分分析,观察各组样品聚集、离散和离群点,然后再采用偏最小二乘判别分析观察引起聚集和离散的关键差异变量。
结果
1、“寒淫”致病通过构建共表达基因网络反映出有4个生物过程关系甚为密切,它们分别是细胞因子受体相互作用、内吞作用、粘着斑和胞外基质受体相互作用,其涉及到的关键基因主要是Gnaq、Plcb1、Ptk2、Pik3r3、Pdgfra、Erbb2、 Vegfa、IL-6、Jun、Mmp2、Ptga2、Itga1、Itgb6、LOC684555和Sdc2,共15个基因。另外还有抗原加工提呈、P53信号通路和细胞周期,涉及到的关键基因有Cxcr6、Ccr5、Ccr1、 Cd8a和Klrc2共5个基因。
2、“寒淫”造模后,采用辛热中药附子对其进行干预,通过对共表达基因网络构建,分析可以看到5个生物过程存在着明显的关系,他们分别是吞噬体、细胞黏附分子、外源性物质的细胞色素P450代谢、钙信号通路和细胞因子相互作用,出现的关键基因有Itga6、Itgb3、Ptk2、Pdgfra、Pik3r3、Src、Rac1、Gna14、 Plcb1、Calm3、 Gnaq、Pla2g3、Pla2g12a、Mylpf和Jakl共15个基因。
3、为了反映辛热中药附子对“寒淫”的干预变化情况,本实验比较分析了给药组和模型组的PCA和PLS-DA模式。分析过程中为了降低给药组和模型组的组间和组内差异出现的偏差,得到更加真实和可靠的实验数据结果,主要关注两组间贡献大的,表达有区别的物质,将其作为“寒淫”致病与中药干预的代谢物变化的有效结果。我们可以看出两组关键差异表达代谢物,这些代谢物主要涉及到31个代谢途径。
结论
1、模拟外寒侵袭肌表,郁遏或损伤人体卫阳,探索轻度寒淫影响机体的能量代谢变化。对于寒淫致病的研究结果初步发现,氧化磷酸化通路活跃,ATP6V0D1表达活跃；寒淫侵袭,诱发机体免疫应答,调动机体卫阳进行抵抗和防御,免疫应答可能是机体卫阳防御与抵抗的表达形式。动物实验研究结果提示细胞因子介导信号通路和抗原处理和提呈通路可能成为“寒淫”致病的分子机制研究的一个突破方向。两者提示了模拟“寒淫”致病实验条件和研究方向。
2、“寒淫”致病关键生物学过程是细胞因子受体相互作用、内吞作用、粘着斑和胞外基质受体相互作用、抗原加工提呈、P53信号通路和细胞周期。其涉及到的关键基因20个。参与到了“寒淫”致病当中,但是由于样本量较小,抗原加工提呈、P53信号通路和细胞周期3个生物过程没有在网络图中与另外的4个生物过程发生关联性,这有待以后在扩充样本量的基础上有所发现。
3、“寒淫”造模后,采用辛热中药附子对其进行干预,关键生物学过程是吞噬体、细胞黏附分子、钙信号通路、细胞因子相互作用、抗原加工提呈和IgA产生的肠道免疫网络,这反映出辛热中药作用在于调节免疫系统,通过对免疫相关通路,如吞噬体、细胞黏附分子、外源性物质的细胞色素P450代谢、细胞因子相互作用等进行调节达到影响“寒淫”致病中药干预的目的,出现的关键基因15个。其中抗原加工提呈和IgA产生的肠道免疫网络与其他生物学过程未发生关联,出现这种情况是与样本量多少有较大关系,所以有待以后在扩充样本量的基础上有所发现。
4、“寒淫”致病及中药干预的实验研究结果分析发现,“寒淫”致病主要是由于寒淫刺激机体免疫系统后,引起机体发生免疫应答,主要是Th2细胞的参与体液免疫,打破了Th1和Th2细胞之间的相互平衡,引发疾病。实验结果中IL-6、IL-10以及IL-10家族成员,还有大量的趋化因子和受体的表达活跃都提示了“寒淫”致病可能的主要作用机制即在于此。
5、“寒淫”致病的中药干预,采用辛热中药“附子”后,积极的调动起了机体的免疫机能,促进激素、血管活性物质和神经递质的分泌,增强细胞之间,以及细胞与外基质之间的信号传导,引导细胞识别,促进细胞的增殖和分化,趋势细胞移动,活跃第二信使信号传导通路,激活激酶系统的相关激酶,如磷脂酶C、磷酸化酶和蛋白激酶。在“寒淫”刺激作用下,调节肌动蛋白依赖的细胞活动和提升黏附蛋白诱导的趋化作用,最终加强效应细胞的具体功能,这样一系列的效应干预疾病状态。
Background
With the theory and technology development of the post-genome and system biology, it establishes research platform on the modern molecular biology for syndrome of TCM. Omics becomes possible and new breakthrough to the research significant problems on syndrome of TCM. But omics integration need be further to the research significant problems on syndrome of TCM. So, Transcriptome and metabolome integration on pathopoiesia and outcome of "cold pathogen" utilize existing technology and methodology platform to actively meaningfully explore on research difficulty of cold syndrome now.
Objective
1. Common features of metabolism and transcription on pathopoiesia of "cold pathogen"
2. Repair network of metabolism and transcription on hot medicine intervention "cold pathogen"
Methods
1. Animal model:Experimental rats were randomly divided into three groups, Normal rats fed in conventional temperature room, Rats gave2ml of distilled water irrigation stomach from the second day of molding everyday; Model rats fed in10±2℃from4to6hours every day, Rats gave2ml of distilled water irrigation stomach from the second day of molding everyday; Dosed rats fed in10±2℃from4to6hours every day, Rats gave2ml of herbal soup irrigation stomach from the second day of molding every day. The experiment continued for3weeks.12ml venous blood of rats in experiment collected,8ml blood was conserved in-20℃for the test,4ml serum was conserved in-70℃for the test.
2. Biological information method:A biological function seldom due to a single cell and molecular role, most of the biological characteristics come from complex interaction in numerous cells. Net-Work construction is contemporary bioinformatics technology to solve the problem of the main method. Net-Work construction can completely and roundly reveal how various components commonly achieve a kind of biological behavior. Data on metabolism is analyzed by PCA and PLS-DA. Data is analyzed PCA by SIMCA-P11.5, and then observe the samples gathered together, discrete and outliers, then using PLS-DA observation and discrete key cause gathered difference variables.
Results
1. Gene expression of cwas constructed a network. The network reflects close relationship four signal pathway, they were Cytokine-cytokine receptor interaction, Endocytosis and Focal adhesion and ECM-receptor interaction, and key genes involved Gnaq、 Plcb1、Ptk2、Pik3r3、Pdgfra、Erbb2、Vegfa、IL-6、Jun、 Mmp2、 Ptga2、Itga1、Itgb6、LOC684555and Sdc2. In addition, there were antigen processing and presentation,P53signaling pathway and Cell cycle, and key genes involved Cxcr6、 Ccr5、Ccr1、Cd8a and Klrc.
2. After "cold pathogen" stimulation, model rats were interposed by radix aconiti carmichaeli of the traditional Chinese medicine. Gene expression of outcome of "cold pathogen" was constructed a network. The network reflects close relationship five signal pathway, they were Phagosome, Cell adhesion molecules, Calcium signaling pathway, Cytokine-cytokine receptor interaction and Metabolism of xenobiotics by cytochrome P450, and key genes involved Itga6、tgb3、Ptk2、Pdgfra、Pik3r3、Src、 Rac1、Gna14、Plcb1、Calm3、 Gnaq、Pla2g3、Pla2gl2a、Mylpf and Jakl.
3. Data of metabolism on dosed rats and model rats were analyzed by PCA and PLS-DA to reflect radix aconiti carmichaeli intervention model rats. We pay close attention to the big contribution and difference expression in two groups in order to reduce differences between the dosed group and the model and get more real and reliable results, as effective results on radix aconiti carmichaeli intervention model rats.
Conclusion
1."Cold Pathogen" make inroads on skin and damage defensive Qi in human body. The early experiment simulated to explore energy metabolism changes in organism. The research result found oxidative phosphorylation pathways active and ATP6V0D1express active; animal experiment found antigen processing and presentation and cytokine who maybe a breakthrough direction on molecular mechanism of pathopoiesia and outcome of "cold pathogen".
2. The key pathways on pathopoiesia of "cold pathogen" were Cytokine-cytokine receptor interaction, Endocytosis, Focal adhesion and ECM-receptor interaction, antigen processing and presentation, P53signaling pathway and Cell cycle, and there were20key genes. But antigen processing and presentation, P53signaling pathway and Cell cycle were not connected with Cytokine-cytokine receptor interaction, Endocytosis, Focal adhesion and ECM-receptor interaction, these awaited to find after expanded sample size.
3. After "cold pathogen" stimulation, model rats were interposed by radix aconiti carmichaeli of the traditional Chinese medicine. Gene expression of outcome of "cold pathogen" was constructed a network. The network reflects close relationship five signal pathway, they were Phagosome, Cell adhesion molecules, Calcium signaling pathway, Cytokine-cytokine receptor interaction and Metabolism of xenobiotics by cytochrome P450, and key genes had15. Intestinal immune network for IgA production and antigen processing and presentation were not connected with Phagosome, Cell adhesion molecules, Calcium signaling pathway, Cytokine-cytokine receptor interaction and Metabolism of xenobiotics by cytochrome P450these awaited to find after expanded sample size.
4."Cold pathogen" pathopoiesia main can participate in humoral immune on Th2cell. The "cold pathogen" breaks balance between Thland Th2and trigger disease. IL-6, IL-10JL-10family, chemotactic factor, FC receptor both are very active. Pathogenic mechanism of "cold pathogen" is these description.
5. After "cold pathogen" stimulation, model rats were interposed by radix aconiti carmichaeli of the traditional Chinese medicine. Herb can stimulate immune function, promote hormone, vessel activated substances and the neurotransmitter secretion, strengthen signal transmission between cells and cells, cells and ECM, guide cell recognition, promote cell proliferation, differentiation and move, stimulate second messenger signaling pathways, activate the kinase system, such as phospholipase C, phosphorylating enzymes and protein kinase. And then regulate actin dependent cellular activities and improve adhesion protein induction chemotaxis to specific function of effector cell, this intervene disease development through a series of effect, and recover the body's health.
随着后基因组和系统生物学的理论与技术不断发展,为中医证候研究搭建了现代分子生物学研究的平台,组学研究复杂的中医证候重大问题成为了可能,也成为了现在中医证候研究的新突破口。但是整合组学研究重大中医证候问题还有待深入。因此,“寒淫”致病及中药干预的转录组与代谢组整合研究,利用现有的技术和方法学平台,有力的为解决目前寒证研究面临的困难,进行了积极的有意义的探索。
目的
1、“寒淫”致病的代谢谱和转录谱共性特征
2、热药干预“寒淫”致病的代谢与转录的修复网络
方法
1、模拟寒淫：实验大鼠随机分为3组,即正常组(n=10)、寒淫组(n=10)和给药组(n=10),正常组大鼠常规室温下喂养,同时于实验第二天开始每日给予常温蒸馏水2ml灌胃；模型组的大鼠在10±2℃冷柜常规喂养,每天4-6小时,同时于实验第二天开始每日给予常温蒸馏水2ml灌胃；给药组大鼠在-10±2℃冷柜常规喂养,每天4-6小时；同时从实验第二天开始每日给予中药汤剂2ml灌胃,实验持续3周。每组结束时,抽取静脉血12ml,其中8ml入抗凝离心管中,离心提取白细胞,冻藏于-20℃冰箱,以备检测；其余4ml分离取得血浆样本,冻藏于-70℃冰箱,以备检测。
2、生物信息方法：一个生物学功能很少会是完全归功于一个单独细胞分子的作用,大部分生物学特性是来自于细胞内无数组分间的相互复杂作用。网络构建是当代生物信息学技术中解决该问题的主要手段,可以较为完整、全面的揭示各组分间是如何协同作用,共同完成一种生物学行为的。代谢组的实验数据分析采用线性模式识别技术。利用SIMCA-P11.5进行主成分分析,观察各组样品聚集、离散和离群点,然后再采用偏最小二乘判别分析观察引起聚集和离散的关键差异变量。
结果
1、“寒淫”致病通过构建共表达基因网络反映出有4个生物过程关系甚为密切,它们分别是细胞因子受体相互作用、内吞作用、粘着斑和胞外基质受体相互作用,其涉及到的关键基因主要是Gnaq、Plcb1、Ptk2、Pik3r3、Pdgfra、Erbb2、 Vegfa、IL-6、Jun、Mmp2、Ptga2、Itga1、Itgb6、LOC684555和Sdc2,共15个基因。另外还有抗原加工提呈、P53信号通路和细胞周期,涉及到的关键基因有Cxcr6、Ccr5、Ccr1、 Cd8a和Klrc2共5个基因。
2、“寒淫”造模后,采用辛热中药附子对其进行干预,通过对共表达基因网络构建,分析可以看到5个生物过程存在着明显的关系,他们分别是吞噬体、细胞黏附分子、外源性物质的细胞色素P450代谢、钙信号通路和细胞因子相互作用,出现的关键基因有Itga6、Itgb3、Ptk2、Pdgfra、Pik3r3、Src、Rac1、Gna14、 Plcb1、Calm3、 Gnaq、Pla2g3、Pla2g12a、Mylpf和Jakl共15个基因。
3、为了反映辛热中药附子对“寒淫”的干预变化情况,本实验比较分析了给药组和模型组的PCA和PLS-DA模式。分析过程中为了降低给药组和模型组的组间和组内差异出现的偏差,得到更加真实和可靠的实验数据结果,主要关注两组间贡献大的,表达有区别的物质,将其作为“寒淫”致病与中药干预的代谢物变化的有效结果。我们可以看出两组关键差异表达代谢物,这些代谢物主要涉及到31个代谢途径。
结论
1、模拟外寒侵袭肌表,郁遏或损伤人体卫阳,探索轻度寒淫影响机体的能量代谢变化。对于寒淫致病的研究结果初步发现,氧化磷酸化通路活跃,ATP6V0D1表达活跃；寒淫侵袭,诱发机体免疫应答,调动机体卫阳进行抵抗和防御,免疫应答可能是机体卫阳防御与抵抗的表达形式。动物实验研究结果提示细胞因子介导信号通路和抗原处理和提呈通路可能成为“寒淫”致病的分子机制研究的一个突破方向。两者提示了模拟“寒淫”致病实验条件和研究方向。
2、“寒淫”致病关键生物学过程是细胞因子受体相互作用、内吞作用、粘着斑和胞外基质受体相互作用、抗原加工提呈、P53信号通路和细胞周期。其涉及到的关键基因20个。参与到了“寒淫”致病当中,但是由于样本量较小,抗原加工提呈、P53信号通路和细胞周期3个生物过程没有在网络图中与另外的4个生物过程发生关联性,这有待以后在扩充样本量的基础上有所发现。
3、“寒淫”造模后,采用辛热中药附子对其进行干预,关键生物学过程是吞噬体、细胞黏附分子、钙信号通路、细胞因子相互作用、抗原加工提呈和IgA产生的肠道免疫网络,这反映出辛热中药作用在于调节免疫系统,通过对免疫相关通路,如吞噬体、细胞黏附分子、外源性物质的细胞色素P450代谢、细胞因子相互作用等进行调节达到影响“寒淫”致病中药干预的目的,出现的关键基因15个。其中抗原加工提呈和IgA产生的肠道免疫网络与其他生物学过程未发生关联,出现这种情况是与样本量多少有较大关系,所以有待以后在扩充样本量的基础上有所发现。
4、“寒淫”致病及中药干预的实验研究结果分析发现,“寒淫”致病主要是由于寒淫刺激机体免疫系统后,引起机体发生免疫应答,主要是Th2细胞的参与体液免疫,打破了Th1和Th2细胞之间的相互平衡,引发疾病。实验结果中IL-6、IL-10以及IL-10家族成员,还有大量的趋化因子和受体的表达活跃都提示了“寒淫”致病可能的主要作用机制即在于此。
5、“寒淫”致病的中药干预,采用辛热中药“附子”后,积极的调动起了机体的免疫机能,促进激素、血管活性物质和神经递质的分泌,增强细胞之间,以及细胞与外基质之间的信号传导,引导细胞识别,促进细胞的增殖和分化,趋势细胞移动,活跃第二信使信号传导通路,激活激酶系统的相关激酶,如磷脂酶C、磷酸化酶和蛋白激酶。在“寒淫”刺激作用下,调节肌动蛋白依赖的细胞活动和提升黏附蛋白诱导的趋化作用,最终加强效应细胞的具体功能,这样一系列的效应干预疾病状态。
Background
With the theory and technology development of the post-genome and system biology, it establishes research platform on the modern molecular biology for syndrome of TCM. Omics becomes possible and new breakthrough to the research significant problems on syndrome of TCM. But omics integration need be further to the research significant problems on syndrome of TCM. So, Transcriptome and metabolome integration on pathopoiesia and outcome of "cold pathogen" utilize existing technology and methodology platform to actively meaningfully explore on research difficulty of cold syndrome now.
Objective
1. Common features of metabolism and transcription on pathopoiesia of "cold pathogen"
2. Repair network of metabolism and transcription on hot medicine intervention "cold pathogen"
Methods
1. Animal model:Experimental rats were randomly divided into three groups, Normal rats fed in conventional temperature room, Rats gave2ml of distilled water irrigation stomach from the second day of molding everyday; Model rats fed in10±2℃from4to6hours every day, Rats gave2ml of distilled water irrigation stomach from the second day of molding everyday; Dosed rats fed in10±2℃from4to6hours every day, Rats gave2ml of herbal soup irrigation stomach from the second day of molding every day. The experiment continued for3weeks.12ml venous blood of rats in experiment collected,8ml blood was conserved in-20℃for the test,4ml serum was conserved in-70℃for the test.
2. Biological information method:A biological function seldom due to a single cell and molecular role, most of the biological characteristics come from complex interaction in numerous cells. Net-Work construction is contemporary bioinformatics technology to solve the problem of the main method. Net-Work construction can completely and roundly reveal how various components commonly achieve a kind of biological behavior. Data on metabolism is analyzed by PCA and PLS-DA. Data is analyzed PCA by SIMCA-P11.5, and then observe the samples gathered together, discrete and outliers, then using PLS-DA observation and discrete key cause gathered difference variables.
Results
1. Gene expression of cwas constructed a network. The network reflects close relationship four signal pathway, they were Cytokine-cytokine receptor interaction, Endocytosis and Focal adhesion and ECM-receptor interaction, and key genes involved Gnaq、 Plcb1、Ptk2、Pik3r3、Pdgfra、Erbb2、Vegfa、IL-6、Jun、 Mmp2、 Ptga2、Itga1、Itgb6、LOC684555and Sdc2. In addition, there were antigen processing and presentation,P53signaling pathway and Cell cycle, and key genes involved Cxcr6、 Ccr5、Ccr1、Cd8a and Klrc.
2. After "cold pathogen" stimulation, model rats were interposed by radix aconiti carmichaeli of the traditional Chinese medicine. Gene expression of outcome of "cold pathogen" was constructed a network. The network reflects close relationship five signal pathway, they were Phagosome, Cell adhesion molecules, Calcium signaling pathway, Cytokine-cytokine receptor interaction and Metabolism of xenobiotics by cytochrome P450, and key genes involved Itga6、tgb3、Ptk2、Pdgfra、Pik3r3、Src、 Rac1、Gna14、Plcb1、Calm3、 Gnaq、Pla2g3、Pla2gl2a、Mylpf and Jakl.
3. Data of metabolism on dosed rats and model rats were analyzed by PCA and PLS-DA to reflect radix aconiti carmichaeli intervention model rats. We pay close attention to the big contribution and difference expression in two groups in order to reduce differences between the dosed group and the model and get more real and reliable results, as effective results on radix aconiti carmichaeli intervention model rats.
Conclusion
1."Cold Pathogen" make inroads on skin and damage defensive Qi in human body. The early experiment simulated to explore energy metabolism changes in organism. The research result found oxidative phosphorylation pathways active and ATP6V0D1express active; animal experiment found antigen processing and presentation and cytokine who maybe a breakthrough direction on molecular mechanism of pathopoiesia and outcome of "cold pathogen".
2. The key pathways on pathopoiesia of "cold pathogen" were Cytokine-cytokine receptor interaction, Endocytosis, Focal adhesion and ECM-receptor interaction, antigen processing and presentation, P53signaling pathway and Cell cycle, and there were20key genes. But antigen processing and presentation, P53signaling pathway and Cell cycle were not connected with Cytokine-cytokine receptor interaction, Endocytosis, Focal adhesion and ECM-receptor interaction, these awaited to find after expanded sample size.
3. After "cold pathogen" stimulation, model rats were interposed by radix aconiti carmichaeli of the traditional Chinese medicine. Gene expression of outcome of "cold pathogen" was constructed a network. The network reflects close relationship five signal pathway, they were Phagosome, Cell adhesion molecules, Calcium signaling pathway, Cytokine-cytokine receptor interaction and Metabolism of xenobiotics by cytochrome P450, and key genes had15. Intestinal immune network for IgA production and antigen processing and presentation were not connected with Phagosome, Cell adhesion molecules, Calcium signaling pathway, Cytokine-cytokine receptor interaction and Metabolism of xenobiotics by cytochrome P450these awaited to find after expanded sample size.
4."Cold pathogen" pathopoiesia main can participate in humoral immune on Th2cell. The "cold pathogen" breaks balance between Thland Th2and trigger disease. IL-6, IL-10JL-10family, chemotactic factor, FC receptor both are very active. Pathogenic mechanism of "cold pathogen" is these description.
5. After "cold pathogen" stimulation, model rats were interposed by radix aconiti carmichaeli of the traditional Chinese medicine. Herb can stimulate immune function, promote hormone, vessel activated substances and the neurotransmitter secretion, strengthen signal transmission between cells and cells, cells and ECM, guide cell recognition, promote cell proliferation, differentiation and move, stimulate second messenger signaling pathways, activate the kinase system, such as phospholipase C, phosphorylating enzymes and protein kinase. And then regulate actin dependent cellular activities and improve adhesion protein induction chemotaxis to specific function of effector cell, this intervene disease development through a series of effect, and recover the body's health.
引文
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