脾肾两虚证双生子脑瘫的生物学基础研究
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摘要
目的
①通过脑瘫双生子病证结合调查,分析脑瘫的高危因素,探讨中医脾虚、肾虚证候在脑瘫中的分布规律。
②通过对脾肾两虚证脑瘫患儿的理化指标检测,分析细胞免疫、体液免疫、血清元素与脑瘫的关系,探讨中医脾肾两脏与机体免疫功能的关系。
③基于基因表达谱技术筛选4对脾肾两虚证“脑瘫-正常”同卵双生子差异表达基因,从基因表达水平探讨脾肾两虚证脑瘫的分子机制。
方法
O宏观脑瘫的病证结合研究：利用脑瘫脾肾证候量表对43对脑瘫双生子进行病证结合调查研究,探讨脑瘫的病因及脾虚、肾虚证候分布特征。
②理化指标检测：应用免疫浊度技术检测脑瘫组及正常组血清IgG、IgM、IgA、C3和C4含量,流式细胞术比较脑瘫组与正常组外周血CD3+T细胞、CD4+T细胞和CD8+T细胞百分比,原子吸收光谱法比较血清锌、铁、钙、镁及铜元素含量。
③微观特征基因的芯片筛选：借助基因芯片技术,对筛选的4对脾肾两虚证“脑瘫-正常”双生子进行基因表达谱试验,利用GO、KEGG、FatiGO+等数据库筛选脾肾两虚证脑瘫特征基因表达谱。
④芯片结果的RT-PCR验证：对基因芯片筛选到的部分差异表达基因进一步采用RT-PCR方法进行验证。
结果
①43对脑瘫双生子病证结合调查：脾肾两虚证脑瘫患儿的危险因素依次是低出生体重、缺氧窒息、早产、出生后烦躁少食等；79.59%的患儿调查到的危险因素为两种或者两种以上；证候调查结果显示多数患者以脾气虚证和肾精不足证为主导；同卵双生子具有病和证罹患的一致性,但存在着病情轻重程度的差异；筛选到4对“脑瘫-正常”双生子用于基因芯片试验。
②51例脑瘫患者理化检测结果：脾肾两虚证脑瘫组外周血CD3+T细胞、CD8+T细胞的百分比显著低于正常对照组(P<0.01)；血清IgG含量显著低于对照组(P<0.05),IgM含量显著高于对照组(P<0.01),C3含量下降显著(P<0.01)；血清锌、铁、钙和铜元素含量均显著低于对照组(P<0.01),镁元素含量差异不显著(P>0.05)。
③4对“脑瘫-正常”双生子基因表达谱结果：从4对双生子中分别筛选到2703、20、130、350个差异表达基因,GO、PATHWAY分析结果提示免疫基因的差异表达及免疫通路的异常为四对双生子的共同特征,其中细胞因子-细胞因子受体为4对双生子筛选到的差异表达基因共同注释到的通路。
④15个差异表达基因的RT-PCR验证结果：应用RT-PCR对筛选的部分差异表达基因进行验证,发现FIGN基因在脾肾两虚证脑瘫组患者中的表达显著低于正常组(P<0.05),PTGER2基因在脑瘫组患者中表达显著高于正常组(P<0.05),其它13个基因差异表达不稳定。
结论
①脾气虚证和肾精不足证是脑瘫的基础证。
②脑瘫的危险因素多样,绝大多数脑瘫患儿的高危因素在两种以上。
③脾肾两虚证脑瘫患儿存在细胞免疫和体液免疫功能异常及血清元素锌、铜、钙、铁水平低下的状态。
④脾肾两虚证脑瘫的发生涉及多个基因的异常表达,尤其是参与免疫的GO类别及免疫通路的相关基因,提示脑瘫脾肾两虚证的关键病机之一是免疫紊乱的遗传相关性。
⑤应用RT-PCR对筛选的差异基因进行验证,初步论证了FIGN、PTGER2基因的异常表达与脾肾两虚证脑瘫的关系,为该病证的深入研究奠定了基础。
Objectives
O To analyze the risk factors for cerebral palsy, and probe the distribution characteristics of spleen deficiency syndrome and kidney deficiency syndrome through the disease and syndrome survey method for cerebral palsy twins.
②To reveal the relationships between the cellular immunity, humoral immunity, serum elements with CP of spleen and kidney deficiency syndrome through checking biochemical indexes testing, and to explore the relationships between the immune function and spleen and kidney of TCM.
③To explore the molecular mechanism of CP with spleen and kidney deficiency syndrome based on applying cDNA microarray technology to four "CP-Normal" monozygotic twins.
Methods
O Investigation on combination of disease and syndrome of CP
43 CP twins were studied by the combination of disease and syndrome method based on spleen and kidney deficiency syndrome questionnaire which was made by our investigation team, and the etiology of CP and distribution characteristics of spleen deficiency syndrome and kidney deficiency syndrome were explored.
②Investigation on levels of physical and chemical indexes
Blood samples were analyzed for determining related indexes. Immunoglobulin (IgG, IgA, and IgM), C3 and C4 were analyzed using immune turbidity technology. The proportion of CD3+ T cells, CD4+ T cells and CD8+ T cells were compared by flow cytometry. The serum level of Zn, Fe, Ca, Mg and Cu were determined using atomic absorption spectroscopy method.
③Screening key genes of CP with spleen and kidney deficiency syndrome through cDNA microarray techniques
Four "CP-normal" MZ with spleen and kidney deficiency syndrome were selected as subjects of cDNA microarray test. The gene expression data were functionally annotated through several databases such as GO, KEGG, FatiGO+, etc.
④Clinical verification of cDNA microarray results
In order to exclude error and false positive results, part of differentially expressed genes key genes screened by cDNA microarray test were further verified through RT-PCR.
Results
O Investigation on combination of disease and syndrome of 43 twins cases of CP patients with spleen and kidney deficiency syndrome
The risk factors for CP with spleen and kidney deficiency syndrome were low birth weight, hypoxia asphyxia, premature birth, eat less irritability after birth, etc. 79.59% of the investigated patients had two or more risk factors for CP. Syndromes survey indicated that most of patients with spleen qi and kidney essence deficiency syndrome. There was consistency of suffering CP and spleen and kidney deficiency syndrome between MZ twins, although the differences in severity of illness were obvious.
②Investigative results of physical and chemical test in 51 cases of CP
CD3+T cells and CD8+T cell percentage was found to be significantly lower in peripheral blood of CP with spleen and kidney deficiency syndrome compared to controls (P<0.01), and CD4+/CD8+T cell ratio was significantly higher (P<0.01) in CP patients than the controls. The serum concentrations of IgG were found to be significantly lower (P<0.01), IgM significantly higher (P<0.05), and C3 significantly lower (P<0.01) in CP patients than the controls. The serum levels of elements Zn, Fe, Ca and Cu were significantly lower than the control group (P<0.01). For serum level of Mg, the differences between the groups were not significant (P>0.05).
③Gene expression profile results of 4 "CP-Normal" MZ
There were 2703,20,130 and 350 differentially expressed genes screened from four "CP-normal" MZ, respectively.GO and PATHWAY annotation results of these genes showed that immune-related genes and pathways significantly expressed in all 4 groups of cDNA microarray results, and cytokine-cytokine receptor interaction pathway was the common annotation pathway of differentially expressed genes screened from 4 chips.
④RT-PCR verification of 15 differentially expressed genes
Using RT-PCR to verify the screened differentially expressed gene, and the results preliminarily indicating that FIGN gene was significantly lower expressed in all CP patients with spleen and kidney deficiency syndrome than normal, and PTGER2 gene was significantly higher expressed in all CP patients with spleen and kidney deficiency syndrome than normal. The other 13 genes showed no expressed significance between the two groups (P>0.05).
Conclusion
O Spleen-qi deficiency syndrome and kidney essence deficiency syndrome are the basic syndromes of CP.
②There are multiple risk factors for CP, and most CP patients have two or more risk factors.
③CP patients with spleen and kidney deficiency syndrome show abnormal cellular immune function and abnormal humoral immune function. The serum levels of elements Zn, Fe, Ca and Cu were significantly lower than the normal children.
④The occurrence of CP with spleen and kidney deficiency syndrome is related to multiple differentially expressed genes, and especially the immune genes.It can be inferred that the key pathogenesis of CP with spleen and kidney deficiency syndrome is related to immune-genetic disorders.
⑤Significant expression of FIGN and PTGER2 genes according to results of RT-PCR suggests that there is a close relationship between FIGN, PTGER2 gene and CP with spleen and kidney deficiency syndrome. It will provide the basis for the disease and syndrome's further study.
①通过脑瘫双生子病证结合调查,分析脑瘫的高危因素,探讨中医脾虚、肾虚证候在脑瘫中的分布规律。
②通过对脾肾两虚证脑瘫患儿的理化指标检测,分析细胞免疫、体液免疫、血清元素与脑瘫的关系,探讨中医脾肾两脏与机体免疫功能的关系。
③基于基因表达谱技术筛选4对脾肾两虚证“脑瘫-正常”同卵双生子差异表达基因,从基因表达水平探讨脾肾两虚证脑瘫的分子机制。
方法
O宏观脑瘫的病证结合研究：利用脑瘫脾肾证候量表对43对脑瘫双生子进行病证结合调查研究,探讨脑瘫的病因及脾虚、肾虚证候分布特征。
②理化指标检测：应用免疫浊度技术检测脑瘫组及正常组血清IgG、IgM、IgA、C3和C4含量,流式细胞术比较脑瘫组与正常组外周血CD3+T细胞、CD4+T细胞和CD8+T细胞百分比,原子吸收光谱法比较血清锌、铁、钙、镁及铜元素含量。
③微观特征基因的芯片筛选：借助基因芯片技术,对筛选的4对脾肾两虚证“脑瘫-正常”双生子进行基因表达谱试验,利用GO、KEGG、FatiGO+等数据库筛选脾肾两虚证脑瘫特征基因表达谱。
④芯片结果的RT-PCR验证：对基因芯片筛选到的部分差异表达基因进一步采用RT-PCR方法进行验证。
结果
①43对脑瘫双生子病证结合调查：脾肾两虚证脑瘫患儿的危险因素依次是低出生体重、缺氧窒息、早产、出生后烦躁少食等；79.59%的患儿调查到的危险因素为两种或者两种以上；证候调查结果显示多数患者以脾气虚证和肾精不足证为主导；同卵双生子具有病和证罹患的一致性,但存在着病情轻重程度的差异；筛选到4对“脑瘫-正常”双生子用于基因芯片试验。
②51例脑瘫患者理化检测结果：脾肾两虚证脑瘫组外周血CD3+T细胞、CD8+T细胞的百分比显著低于正常对照组(P<0.01)；血清IgG含量显著低于对照组(P<0.05),IgM含量显著高于对照组(P<0.01),C3含量下降显著(P<0.01)；血清锌、铁、钙和铜元素含量均显著低于对照组(P<0.01),镁元素含量差异不显著(P>0.05)。
③4对“脑瘫-正常”双生子基因表达谱结果：从4对双生子中分别筛选到2703、20、130、350个差异表达基因,GO、PATHWAY分析结果提示免疫基因的差异表达及免疫通路的异常为四对双生子的共同特征,其中细胞因子-细胞因子受体为4对双生子筛选到的差异表达基因共同注释到的通路。
④15个差异表达基因的RT-PCR验证结果：应用RT-PCR对筛选的部分差异表达基因进行验证,发现FIGN基因在脾肾两虚证脑瘫组患者中的表达显著低于正常组(P<0.05),PTGER2基因在脑瘫组患者中表达显著高于正常组(P<0.05),其它13个基因差异表达不稳定。
结论
①脾气虚证和肾精不足证是脑瘫的基础证。
②脑瘫的危险因素多样,绝大多数脑瘫患儿的高危因素在两种以上。
③脾肾两虚证脑瘫患儿存在细胞免疫和体液免疫功能异常及血清元素锌、铜、钙、铁水平低下的状态。
④脾肾两虚证脑瘫的发生涉及多个基因的异常表达,尤其是参与免疫的GO类别及免疫通路的相关基因,提示脑瘫脾肾两虚证的关键病机之一是免疫紊乱的遗传相关性。
⑤应用RT-PCR对筛选的差异基因进行验证,初步论证了FIGN、PTGER2基因的异常表达与脾肾两虚证脑瘫的关系,为该病证的深入研究奠定了基础。
Objectives
O To analyze the risk factors for cerebral palsy, and probe the distribution characteristics of spleen deficiency syndrome and kidney deficiency syndrome through the disease and syndrome survey method for cerebral palsy twins.
②To reveal the relationships between the cellular immunity, humoral immunity, serum elements with CP of spleen and kidney deficiency syndrome through checking biochemical indexes testing, and to explore the relationships between the immune function and spleen and kidney of TCM.
③To explore the molecular mechanism of CP with spleen and kidney deficiency syndrome based on applying cDNA microarray technology to four "CP-Normal" monozygotic twins.
Methods
O Investigation on combination of disease and syndrome of CP
43 CP twins were studied by the combination of disease and syndrome method based on spleen and kidney deficiency syndrome questionnaire which was made by our investigation team, and the etiology of CP and distribution characteristics of spleen deficiency syndrome and kidney deficiency syndrome were explored.
②Investigation on levels of physical and chemical indexes
Blood samples were analyzed for determining related indexes. Immunoglobulin (IgG, IgA, and IgM), C3 and C4 were analyzed using immune turbidity technology. The proportion of CD3+ T cells, CD4+ T cells and CD8+ T cells were compared by flow cytometry. The serum level of Zn, Fe, Ca, Mg and Cu were determined using atomic absorption spectroscopy method.
③Screening key genes of CP with spleen and kidney deficiency syndrome through cDNA microarray techniques
Four "CP-normal" MZ with spleen and kidney deficiency syndrome were selected as subjects of cDNA microarray test. The gene expression data were functionally annotated through several databases such as GO, KEGG, FatiGO+, etc.
④Clinical verification of cDNA microarray results
In order to exclude error and false positive results, part of differentially expressed genes key genes screened by cDNA microarray test were further verified through RT-PCR.
Results
O Investigation on combination of disease and syndrome of 43 twins cases of CP patients with spleen and kidney deficiency syndrome
The risk factors for CP with spleen and kidney deficiency syndrome were low birth weight, hypoxia asphyxia, premature birth, eat less irritability after birth, etc. 79.59% of the investigated patients had two or more risk factors for CP. Syndromes survey indicated that most of patients with spleen qi and kidney essence deficiency syndrome. There was consistency of suffering CP and spleen and kidney deficiency syndrome between MZ twins, although the differences in severity of illness were obvious.
②Investigative results of physical and chemical test in 51 cases of CP
CD3+T cells and CD8+T cell percentage was found to be significantly lower in peripheral blood of CP with spleen and kidney deficiency syndrome compared to controls (P<0.01), and CD4+/CD8+T cell ratio was significantly higher (P<0.01) in CP patients than the controls. The serum concentrations of IgG were found to be significantly lower (P<0.01), IgM significantly higher (P<0.05), and C3 significantly lower (P<0.01) in CP patients than the controls. The serum levels of elements Zn, Fe, Ca and Cu were significantly lower than the control group (P<0.01). For serum level of Mg, the differences between the groups were not significant (P>0.05).
③Gene expression profile results of 4 "CP-Normal" MZ
There were 2703,20,130 and 350 differentially expressed genes screened from four "CP-normal" MZ, respectively.GO and PATHWAY annotation results of these genes showed that immune-related genes and pathways significantly expressed in all 4 groups of cDNA microarray results, and cytokine-cytokine receptor interaction pathway was the common annotation pathway of differentially expressed genes screened from 4 chips.
④RT-PCR verification of 15 differentially expressed genes
Using RT-PCR to verify the screened differentially expressed gene, and the results preliminarily indicating that FIGN gene was significantly lower expressed in all CP patients with spleen and kidney deficiency syndrome than normal, and PTGER2 gene was significantly higher expressed in all CP patients with spleen and kidney deficiency syndrome than normal. The other 13 genes showed no expressed significance between the two groups (P>0.05).
Conclusion
O Spleen-qi deficiency syndrome and kidney essence deficiency syndrome are the basic syndromes of CP.
②There are multiple risk factors for CP, and most CP patients have two or more risk factors.
③CP patients with spleen and kidney deficiency syndrome show abnormal cellular immune function and abnormal humoral immune function. The serum levels of elements Zn, Fe, Ca and Cu were significantly lower than the normal children.
④The occurrence of CP with spleen and kidney deficiency syndrome is related to multiple differentially expressed genes, and especially the immune genes.It can be inferred that the key pathogenesis of CP with spleen and kidney deficiency syndrome is related to immune-genetic disorders.
⑤Significant expression of FIGN and PTGER2 genes according to results of RT-PCR suggests that there is a close relationship between FIGN, PTGER2 gene and CP with spleen and kidney deficiency syndrome. It will provide the basis for the disease and syndrome's further study.
引文
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