阳痿肾阳虚证症状规律及其转录组特征研究
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摘要
研究目的：(1)借助于现代数据挖掘有关技术,对所查找文献与临床范围内的所有记载阳痿肾阳虚证的症状进行统计分析,以期全面客观地总结阳痿肾阳虚证症状特点及规律,为阳痿肾阳虚证的临床诊断及科学研究提供理论依据。(2)基于基因芯片技术,筛选阳痿肾阳虚证患者的转录组学特征,探讨阳痿肾阳虚证的分子生物学基础。
研究方法：(1)文献临床研究：以《中华医典》中所有有关的阳痿肾阳虚证的文献记载资料,中国学术期刊全文数据库中有明确描述有关阳痿肾阳虚证的医案,成都中医药大学附属医院及四川生殖医院调查收集的阳痿肾阳虚证的临床病例为研究对象。将上述搜索筛选出来的资料进行症状规范化处理,并根据数据特点和数据挖掘的技术要求建立相应的规则,构建阳痿肾阳虚证症状数据库(同时对典型非肾阳虚证症状也建立数据库,统计分析时作对照用)。运用统计学方法,包括多元回归、频次分析、聚类分析、关联规则等,结合中医药理论,就阳痿肾阳虚证的症状特点及组合规律进行逐层深入的分析。
(2)转录组学研究：将临床收集病例中选取的3例典型阳痿肾阳虚证患者和3例健康志愿者,采用基因芯片技术,探讨阳痿肾阳虚证患者的转录组学特征。抽取实验者空腹静脉血10ml,裂解红细胞,分离获得白细胞,Trizol法提取总RNA。将总RNA进行IVT体外扩增,采用cy-3标记扩增后的cDNA,单标法与agilent 4*44k人类全表达谱芯片进行杂交,洗脱、干燥、数据提取、归一化处理。SAM软件挑选差异基因,cutoff范围：P≤0.01,FC≥2。
研究结果：(1)通过数据挖掘并结合其它统计分析方法,提取了阳痿肾阳虚证22个最常见症状,并依据统计数据将其排序。这些症状可分为3类：主症4个：阳痿、腰膝酸痛、畏寒肢冷、舌脉(舌质淡胖苔白滑、脉沉细无力)；次症7个：体倦乏力、精神萎靡、腰背发冷、夜尿频多、头晕目眩、性欲减退、面色淡白；一般症状12个：尿后余沥、滑精、不育、纳差食少、遗精、阴冷、脘腹疼痛、大便溏稀、脘腹胀满、精寒、精少、消瘦。
(2)阳痿肾阳虚证患者的转录组学研究,筛选出1396个差异表达基因;这些基因的异常表达,与阳痿肾阳虚证患者的主要症状体征密切相关。这些基因主要涉及：蛋白丝氨酸/苏氨酸磷酸酶复合物、调节代谢过程、细胞内的细胞器、大分子代谢过程、转录调节活性、核糖复合物、分子功能的调控、T细胞的选择、转录辅活动、正负代谢调控过程、生物合成过程、多细胞有机体的动态平衡、生长调控,细胞代谢过程、病毒的繁殖过程、白细胞激活,等等。在差异表达基因中,10个蛋白丝氨酸/苏氨酸磷酸酶复合物相关基因表达最为突出,其中5个基因上调,5个基因下调。差异基因涉及多种功能蛋白和代谢通路。主要涉及的信号转导通路有：Alzheimer's病、代谢途径、N-糖链的合成、泛素介导的蛋白质降解、Wnt信号通路、胰岛素信号转导通路、RIG-I型样受体信号转导通路、MAPK信号转导通路、神经营养因子信号转导通路、钙信号转导通路。上述异常表达基因及相关信号通路,提示阳痿肾阳虚证患者性激素代谢低下、能量合成不足、物质代谢与免疫功能紊乱等,与其主要症状体征密切相关。
研究结论：(1)通过对古籍文献、医案及临床调查病例研究,初步揭示了阳痿肾阳虚证的症状特点规律,提出了阳痿肾阳虚证的参考诊断方法。完善了对阳痿肾阳虚证中医证候的认识。
(2)通过转录组学研究实验研究,发现10条蛋白丝氨酸/苏氨酸磷酸酶复合物相关基因表达最为突出,其中5条基因上调,5条基因下调。这与以往相关研究有一定区别,这也许能够解释阳痿肾阳虚证的发生可能与蛋白丝氨酸/苏氨酸磷酸酶复合物具有密切关系。
(3)阳痿肾阳虚证的病理生理过程复杂,涉及多种功能蛋白和代谢通路。在相关信号通路中,涉及多种信号途径,提示阳痿肾阳虚证的发生有多种信号通路参与,是多种信号通路共同参与的结果。其中,与生殖及生长发育密切相关的Wnt信号通路、对信号转导起整合作用的MAPK通路、促进蛋白质降解的泛素化通路,可能起着相对重要的病理作用。
Objective:
(1) With the technology of modern data mining, To analyze symptom characteristics of Kidney-Yang Deficiency syndrome Patients suffering from erectile dysfunction. And the symptom material are all from literature search and clinical records. (2) To explore the molecular biology of ED Kidney Yang Deficiency syndrome by microarray approach.
Methods:
(1) Literature and clinical research:study include:ED Kidney-Yang Deficiency syndrome of all relevant literature data of the "Chinese Medical Classics ",medical cases Clearly describe the ED Kidney-Yang Deficiency syndrome in Full-text Database of Chinese Academic Journals, investigation and collection of clinical cases of ED Kidney-Yang Deficiency syndrome in Affiliated Hospital of Chengdu University of Traditional Chinese Medicine and Sichuan Reproductive Hospital. Search Filter out the above symptoms data to take a normalization, and characteristics of the data requirements and data mining techniques to establish the appropriate rules, and build a database for ED Kidney-Yang Deficiency syndrome symptoms, (with a typical non-kidney yang deficiency symptoms to establish a database, statistical analysis for comparison purposes.) The use of statistical methods, including multiple regression, frequency analysis, cluster analysis, association rules, combined with Chinese medicine theory, the symptoms of ED Kidney-Yang Deficiency syndrome characteristics and composition of the regularity layers in depth analysis.
(2)Transcriptome research:Select 3 cases of typical ED Kidney-Yang Deficiency syndrome patients from clinical collected cases and 3 healthy volunteers were carried out explore the transcriptome features of ED Kidney-Yang syndrome by microarray approach. Fasting venous blood drawn experimenter 10ml, cracking red blood cells, white blood cells were isolated, Trizol extraction of total RNA, total RNA and quantitative, quality inspection. IVT will be carried out in vitro expansion of total RNA, using cy-3 labeled amplified CDNA, a single standard method and agilent 4* 44k for the entire human cDNA microarray hybridization, washed, dried, data extraction, normalization processing. SAM software selection of differentially expressed genes, cutoff range:P< 0.01, FC> 2.
Results:
(1) Rely on data mining and statistical analysis combination with other methods to extract the ED Kidney-Yang Deficiency syndrome 22 most common symptoms, and based on statistical data to sort. Among them,4 main symptoms:ED, lumbar genu ache, Chills limb cold, tongue and pulse(pale and fat tongue, thin and weak pulse); 7 secondary symptoms:body tired fatigue, listlessness, waist and back chills, nocturia, dizziness, loss of libido, pale complexion; 12 general symptoms:drop after the urine, spermatorrhoea, infertility, anorexia eat less, nocturnal emission, coldness of genitals, abdominal pain, diarrhea, abdominal distention, semen cold, less semen, thin.
(2)Selected 1396 differentially expressed genes by transcriptome research on ED Kidney-Yang Deficiency syndrome. The abnormal expression of these genes is closely related to the main symptoms and signs of ED Kidney-Yang Deficiency syndrome.These genes mainly related to:Protein serine/threonine phosphatase complex, regulation of metabolic process, intracellular organelles, macromolecular metabolic process, transcription regulator activity, ribonucleoprotein complex, regulation of molecular function, T cell selection, transcription cofactor activity, positive and negative regulation of metabolic process, biosynthetic process, multicellular organismal homeostasis, regulation of growth, cellular metabolic process, viral reproductive process, leukocyte activation, and so on.
In the differentially expressed genes,10 protein serine/threonine phosphatase complex gene expression is most prominent, of which five genes were upregulated and 5 genes were downregulated. Differences in genes involved in a variety of functional proteins and metabolic pathways. The major signaling pathway involved in are:Alzheimer's disease, metabolic pathways, N-Glycan biosynthesis, Ubiquitin mediated proteolysis, Wnt signaling pathway, Insulin signaling pathway, RIG-I-like receptor signaling pathway, MAPK signaling pathway, Neurotrophin signaling pathway, Calcium signaling pathway.The abnormal expression of genes and signaling pathways are closely related to main symptoms and signs of ED Kidney-Yang Deficiency syndrome. And it suggests that sex hormone metabolism is low, lack of energy synthesis, metabolism and immune dysfunction in those patients.
Conclusion:
(1) Through the literature, the author initially reveals the symptom characteristic, the rule of combination and the reference diagnostic method about ED Kidney-Yang Deficiency syndrome, perfects for ED Kidney-Yang Deficiency syndrome's understanding.
(2) Through the transcriptome experimental study, we found that the 10 protein serine/threonine phosphatase complex genes expression is most prominent, of which five genes were upregulated and 5 genes were downregulated, in the differentially expressed genes. This is some difference from former related research, maybe suggest ED Kidney-Yang Deficiency syndrome may occur closely related with the protein serine/threonine phosphatase complexe.
(3) ED Kidney-Yang Deficiency syndrome is a complicated pathophysiologic process involving multiple proteins and metabolic pathways. In the relevant signaling pathway, involving multiple signaling pathways, suggesting that the incidence of ED Kidney-Yang Deficiency syndrome are the results of many signal pathways cooperated. Which, Wnt signaling pathway, MAPK signaling pathway, Ubiquitin mediated proteolysis and Alzheimer's related neurodegeneration may play an important role in the foundation.
研究方法：(1)文献临床研究：以《中华医典》中所有有关的阳痿肾阳虚证的文献记载资料,中国学术期刊全文数据库中有明确描述有关阳痿肾阳虚证的医案,成都中医药大学附属医院及四川生殖医院调查收集的阳痿肾阳虚证的临床病例为研究对象。将上述搜索筛选出来的资料进行症状规范化处理,并根据数据特点和数据挖掘的技术要求建立相应的规则,构建阳痿肾阳虚证症状数据库(同时对典型非肾阳虚证症状也建立数据库,统计分析时作对照用)。运用统计学方法,包括多元回归、频次分析、聚类分析、关联规则等,结合中医药理论,就阳痿肾阳虚证的症状特点及组合规律进行逐层深入的分析。
(2)转录组学研究：将临床收集病例中选取的3例典型阳痿肾阳虚证患者和3例健康志愿者,采用基因芯片技术,探讨阳痿肾阳虚证患者的转录组学特征。抽取实验者空腹静脉血10ml,裂解红细胞,分离获得白细胞,Trizol法提取总RNA。将总RNA进行IVT体外扩增,采用cy-3标记扩增后的cDNA,单标法与agilent 4*44k人类全表达谱芯片进行杂交,洗脱、干燥、数据提取、归一化处理。SAM软件挑选差异基因,cutoff范围：P≤0.01,FC≥2。
研究结果：(1)通过数据挖掘并结合其它统计分析方法,提取了阳痿肾阳虚证22个最常见症状,并依据统计数据将其排序。这些症状可分为3类：主症4个：阳痿、腰膝酸痛、畏寒肢冷、舌脉(舌质淡胖苔白滑、脉沉细无力)；次症7个：体倦乏力、精神萎靡、腰背发冷、夜尿频多、头晕目眩、性欲减退、面色淡白；一般症状12个：尿后余沥、滑精、不育、纳差食少、遗精、阴冷、脘腹疼痛、大便溏稀、脘腹胀满、精寒、精少、消瘦。
(2)阳痿肾阳虚证患者的转录组学研究,筛选出1396个差异表达基因;这些基因的异常表达,与阳痿肾阳虚证患者的主要症状体征密切相关。这些基因主要涉及：蛋白丝氨酸/苏氨酸磷酸酶复合物、调节代谢过程、细胞内的细胞器、大分子代谢过程、转录调节活性、核糖复合物、分子功能的调控、T细胞的选择、转录辅活动、正负代谢调控过程、生物合成过程、多细胞有机体的动态平衡、生长调控,细胞代谢过程、病毒的繁殖过程、白细胞激活,等等。在差异表达基因中,10个蛋白丝氨酸/苏氨酸磷酸酶复合物相关基因表达最为突出,其中5个基因上调,5个基因下调。差异基因涉及多种功能蛋白和代谢通路。主要涉及的信号转导通路有：Alzheimer's病、代谢途径、N-糖链的合成、泛素介导的蛋白质降解、Wnt信号通路、胰岛素信号转导通路、RIG-I型样受体信号转导通路、MAPK信号转导通路、神经营养因子信号转导通路、钙信号转导通路。上述异常表达基因及相关信号通路,提示阳痿肾阳虚证患者性激素代谢低下、能量合成不足、物质代谢与免疫功能紊乱等,与其主要症状体征密切相关。
研究结论：(1)通过对古籍文献、医案及临床调查病例研究,初步揭示了阳痿肾阳虚证的症状特点规律,提出了阳痿肾阳虚证的参考诊断方法。完善了对阳痿肾阳虚证中医证候的认识。
(2)通过转录组学研究实验研究,发现10条蛋白丝氨酸/苏氨酸磷酸酶复合物相关基因表达最为突出,其中5条基因上调,5条基因下调。这与以往相关研究有一定区别,这也许能够解释阳痿肾阳虚证的发生可能与蛋白丝氨酸/苏氨酸磷酸酶复合物具有密切关系。
(3)阳痿肾阳虚证的病理生理过程复杂,涉及多种功能蛋白和代谢通路。在相关信号通路中,涉及多种信号途径,提示阳痿肾阳虚证的发生有多种信号通路参与,是多种信号通路共同参与的结果。其中,与生殖及生长发育密切相关的Wnt信号通路、对信号转导起整合作用的MAPK通路、促进蛋白质降解的泛素化通路,可能起着相对重要的病理作用。
Objective:
(1) With the technology of modern data mining, To analyze symptom characteristics of Kidney-Yang Deficiency syndrome Patients suffering from erectile dysfunction. And the symptom material are all from literature search and clinical records. (2) To explore the molecular biology of ED Kidney Yang Deficiency syndrome by microarray approach.
Methods:
(1) Literature and clinical research:study include:ED Kidney-Yang Deficiency syndrome of all relevant literature data of the "Chinese Medical Classics ",medical cases Clearly describe the ED Kidney-Yang Deficiency syndrome in Full-text Database of Chinese Academic Journals, investigation and collection of clinical cases of ED Kidney-Yang Deficiency syndrome in Affiliated Hospital of Chengdu University of Traditional Chinese Medicine and Sichuan Reproductive Hospital. Search Filter out the above symptoms data to take a normalization, and characteristics of the data requirements and data mining techniques to establish the appropriate rules, and build a database for ED Kidney-Yang Deficiency syndrome symptoms, (with a typical non-kidney yang deficiency symptoms to establish a database, statistical analysis for comparison purposes.) The use of statistical methods, including multiple regression, frequency analysis, cluster analysis, association rules, combined with Chinese medicine theory, the symptoms of ED Kidney-Yang Deficiency syndrome characteristics and composition of the regularity layers in depth analysis.
(2)Transcriptome research:Select 3 cases of typical ED Kidney-Yang Deficiency syndrome patients from clinical collected cases and 3 healthy volunteers were carried out explore the transcriptome features of ED Kidney-Yang syndrome by microarray approach. Fasting venous blood drawn experimenter 10ml, cracking red blood cells, white blood cells were isolated, Trizol extraction of total RNA, total RNA and quantitative, quality inspection. IVT will be carried out in vitro expansion of total RNA, using cy-3 labeled amplified CDNA, a single standard method and agilent 4* 44k for the entire human cDNA microarray hybridization, washed, dried, data extraction, normalization processing. SAM software selection of differentially expressed genes, cutoff range:P< 0.01, FC> 2.
Results:
(1) Rely on data mining and statistical analysis combination with other methods to extract the ED Kidney-Yang Deficiency syndrome 22 most common symptoms, and based on statistical data to sort. Among them,4 main symptoms:ED, lumbar genu ache, Chills limb cold, tongue and pulse(pale and fat tongue, thin and weak pulse); 7 secondary symptoms:body tired fatigue, listlessness, waist and back chills, nocturia, dizziness, loss of libido, pale complexion; 12 general symptoms:drop after the urine, spermatorrhoea, infertility, anorexia eat less, nocturnal emission, coldness of genitals, abdominal pain, diarrhea, abdominal distention, semen cold, less semen, thin.
(2)Selected 1396 differentially expressed genes by transcriptome research on ED Kidney-Yang Deficiency syndrome. The abnormal expression of these genes is closely related to the main symptoms and signs of ED Kidney-Yang Deficiency syndrome.These genes mainly related to:Protein serine/threonine phosphatase complex, regulation of metabolic process, intracellular organelles, macromolecular metabolic process, transcription regulator activity, ribonucleoprotein complex, regulation of molecular function, T cell selection, transcription cofactor activity, positive and negative regulation of metabolic process, biosynthetic process, multicellular organismal homeostasis, regulation of growth, cellular metabolic process, viral reproductive process, leukocyte activation, and so on.
In the differentially expressed genes,10 protein serine/threonine phosphatase complex gene expression is most prominent, of which five genes were upregulated and 5 genes were downregulated. Differences in genes involved in a variety of functional proteins and metabolic pathways. The major signaling pathway involved in are:Alzheimer's disease, metabolic pathways, N-Glycan biosynthesis, Ubiquitin mediated proteolysis, Wnt signaling pathway, Insulin signaling pathway, RIG-I-like receptor signaling pathway, MAPK signaling pathway, Neurotrophin signaling pathway, Calcium signaling pathway.The abnormal expression of genes and signaling pathways are closely related to main symptoms and signs of ED Kidney-Yang Deficiency syndrome. And it suggests that sex hormone metabolism is low, lack of energy synthesis, metabolism and immune dysfunction in those patients.
Conclusion:
(1) Through the literature, the author initially reveals the symptom characteristic, the rule of combination and the reference diagnostic method about ED Kidney-Yang Deficiency syndrome, perfects for ED Kidney-Yang Deficiency syndrome's understanding.
(2) Through the transcriptome experimental study, we found that the 10 protein serine/threonine phosphatase complex genes expression is most prominent, of which five genes were upregulated and 5 genes were downregulated, in the differentially expressed genes. This is some difference from former related research, maybe suggest ED Kidney-Yang Deficiency syndrome may occur closely related with the protein serine/threonine phosphatase complexe.
(3) ED Kidney-Yang Deficiency syndrome is a complicated pathophysiologic process involving multiple proteins and metabolic pathways. In the relevant signaling pathway, involving multiple signaling pathways, suggesting that the incidence of ED Kidney-Yang Deficiency syndrome are the results of many signal pathways cooperated. Which, Wnt signaling pathway, MAPK signaling pathway, Ubiquitin mediated proteolysis and Alzheimer's related neurodegeneration may play an important role in the foundation.
引文
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