基于差异基因cDNA文库基础上耐药性癫痫患者脑内特异性标示蛋白筛选和机制探讨
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摘要
第一部分:耐药性癫痫患者脑中差异表达基因的筛选
目的:利用基因芯片和生物信息学理论筛选耐药性癫痫患者术后脑组织中差异表达基因,通过对其功能和相互关系的分析,探讨建立耐药性癫痫患者脑内差异表达基因的cDNA文库,同步了解耐药性癫痫患者脑内是否存在耐药性癫痫新的致病基因,进一步完善对耐药性癫痫基因机制的认识。
方法:收集耐药性癫痫患者和对照组脑组织,常规病理学检查(HE染色、硝酸银染色、尼氏染色)后,抽提两组脑组织RNA,纯化mRNA,分别逆转录合成荧光分子掺入cDNA-链做探针;将含4096条人类基因PCR产物按微矩阵点样于化学涂层的栽玻片上,制成基因芯片,芯片杂交和洗片后,用ScanArray4000荧光扫描仪扫描芯片荧光信号图象,计算机分析耐药性癫痫患者和对照组脑组织差异表达的基因;生物信息学筛选出与耐药性癫痫发病相关的差异候选基因,采用RT-PCR对酪蛋白激酶2(CSNK2A1),层粘连蛋白β1(LAMB1),肌红蛋白1E(MYO1E),微管蛋白δ1(TUBD1),微管蛋白γ1(TUBG1),钙粘蛋白18,type 2(Cadherin 18 type2),微管相关蛋白1A(MAP1A),微管相关蛋白1B( MAP1B),微管相关蛋白2(MAP2),周期性依赖蛋白激酶5(CDK5),分裂素激活蛋白激酶14(MAPK14),糖原合成激酶-3β(GSK-3β)基因进行验证;实时荧光PCR(FQ-PCR)对MAP1A, MAP1B,MAP2,WDR3, CDK5 ,MAPK14 , GSK-3β, HSPBAP1, REDD1, EML5, MARK1, TRAP220 ,小脑变性相关蛋白(CDR2) mRNA水平进行检测。
结果:1、耐药性癫痫患者术后脑组织常规病理学检查提示神经元坏死、凋亡、胶质细胞增生,神经纤维增多,走行紊乱是耐药性癫痫最常见的病理改变;2、耐药性癫痫患者脑内有142条基因与对照组比效表达有显著差异(104条(73.2%)表达上调,38条(26.8%)表达下调),按生物学功能分类,发现这些差异表达的基因主要集中在信号传导(20条)、离子通道(3条)、细胞骨架基因(9条)、凋亡(7条)、细胞受体(3条)、代谢(6条)、癌基因(4条)及发育(9条)等,提示耐药性癫痫的发生可能与细胞骨架、凋亡、离子通道、代谢、免疫等。3 RT-PCR验证的12条基因结果与基因芯片一致;除MARK1外,FQ-PCR检测结果与基因芯片相符,从另一个侧面支持基因芯片检测结果。
结论: 1、耐药性癫痫发病机制可能与多个不同功能的基因组相互作用有关,而非单一基因作用;2、差异表达基因主要集中在离子通道、凋亡、细胞骨架、信号传导及其肿瘤相关基因等;3、耐药性癫痫患者脑组织中存在人类尚不清楚的耐药性癫痫新致病基因;4、基因芯片技术具有高通量、高灵敏度的优点,能发现新致病基因,但存在假阳性,需结合传统分子生物学技术验证。
第二部分:基于差异cDNA文库基础上耐药性癫痫患者脑内特异性蛋白筛选和机制研究
目的:蛋白是基因功能的执行单位,本文研究的目的就是希望在差异表达基因cDNA文库基础上通过研究其相关蛋白,筛选出耐药性癫痫患者脑内特异性,标示性的蛋白质,进而探讨耐药性癫痫患者新的发病机制,提出耐药性癫痫防治的新观点,为抗癫痫新药的开发提供新的作用靶点。
方法:收集耐药性癫痫患者和对照组颞叶标本,采用免疫组化、免疫荧光、western blot分别对细胞外信号传导激酶(extracellular signal-regulated kinase,ERK1), ERK2,磷酸化细胞外信号传导激酶1/2(P-ERK1/2),TAU蛋白、P-TAU蛋白(ser202,ser404)、糖原合成激酶-3Beta(GSK-3β)、磷酸化糖原合成激酶(ser9)(P-GSK-3β(ser9))、微管相关蛋白2(microtubular- associated protein,MAP2)、T细胞死亡相关基因51 ( T cell death-associated gene 51,TDAG51)、胰岛素样生长因子-1(Insulin-like growth factor-I,IGF-I)、MAPK14和磷酸化MAPK14(thr182 /tyr184)、CDR2总共14个蛋白的表达部位和表达量进行测定,进一步探讨其在耐药性癫痫发病机制中的作用。
结果:IGF-1、TDAG51、MAPK14、磷酸化MAPK14 (Thr180 /Tyr182)、MAP2、TAU蛋白、磷酸化TAU蛋白(ser202,ser404)、CDK5、GSK-3β、P-GSK-3β(ser9)、ERK1、ERK2、P-ERK1/2(Thr202 /Tyr204)免疫反应产物均为棕黄色点状或颗粒状沉积,神经元胞体和细胞核均有表达,部分胶质细胞也存在表达。各组脑组织间,可见着色深浅有明显差异,阴性对照组未见免疫反应产物表达。除TAU蛋白无改变和P-GSK- 3β(ser9)耐药性癫痫组降低外,癫痫患者脑组织中上述蛋白的表达较正常对照组高。CDR2见于实验组脑组织中,对照组中未见明显阳性细胞。ERK1、ERK2不同病理改变即神经元丢失组和胶质细胞增生组之间无明显改变,而P-ERK1/2(Thr202/Tyr204)在胶质细胞增生组明显高于非胶质细胞增生组。免疫荧光与免疫组化结果类似,western blot检测显示各个蛋白在相应的分子量处表达,其表达量的高低与免疫组化相符。
结论:1耐药性癫痫患者基因表达有差异,其基因的表达产物亦有类似结果;2差异表达的不是单一蛋白,而是具有相互作用的蛋白如TDAG51相关蛋白(IGF-1,MAPK14,CDR2)和TAU蛋白相关蛋白(GSK-3β,P-GSK-3β,CDK5,ERK1,ERK2,P-ERK1/2,P-MAPK14(thr182 /tyr184), MAPK14); 3研究耐药性癫痫患者脑组织中差异基因和蛋白的表达,提示耐药性癫痫新的异常发病途径,为新药开发提供理论依据。
PART ONE: SCREEN THE DIFFERENTIAL GENE EXPRESSION IN THE TEMPORAL NEOCORTEX OF PATIENTS WITH INTRACTABLE EPILEPSY
Objectives: In search for the molecular basis of drug-resistance epilepsy(DRE), we applied a genomic-transcriptomic approach and bioinformatics to identify genes involved in the pathogenesis of DRE. Understanding epileptogenesis, the process by which a normal brain becomes epileptic, may help to establish differential gene cDNA library and find out the new epilepsy associated genes, and then identify the molecular targets for drugs which could prevent epilepsy.
Methods: Using a cDNA microarray representing 4096 human genes, we identified that those genes were altered in the temporal neocortex of the patients with DRE and control tissues. Standard stains included H&E,nissl staining and modified bielschowsky silver stains. Total RNA was extracted with UNIzol reagent following the manufacturer's protocol and methods. Scans were performed with the ScanArray4000. The expression value for each gene was then calculated using ImaGene3.0 software (BioDiscovery,Inc). Each experiment was duplicated so that the mean of two ratios for each gene could be used for further analysis. To validate these results, we performed real-time fluorescence quantitative polymerase chain reaction (FQ-PCR) on optional thirteen differentially expressed genes, including MAP1A(microtubular-associated protein1A), MAP1B(microtubular- associated protein 1B),MAP2(microtubular associated protein 2),WDR3 (WD repeat domain 3),CDK5 (cyclin-dependent kinase 5),MAPK14 (mitogen-activated protein kinase 14),GSK-3β(glycogen synthase kinase 3 beta), HSPBAP1 (HSPB associated protein 1), REDD1 (regulated in development and DNA damage responses 1), EML5 (echinoderm microtubule associated protein like 5), MARK1 (microtubule affinity-regulating kinase 1), TRAP220 (thyroid hormone receptor- associated protein), CDR2 (cerebellar degeneration-related protein2)). And we also tested 12 gene by reverse transcription PCR (RT-PCR) (CSNK2A1(casein kinase 2, alpha 1),LAMB1(lamin beta1), MYO1E(myoglobin 1E), TUBD1(tublin deta1), TUBG1(tublin gama1), Cadherin 18(type2), MAP1A,MAP1B,MAP2, CDK5,MAPK14,GSK-3β).
Results: 1. Nissl-, H&E and silver- stained neurons showed that the number was significantly decreased in DRE. Patients had cortical neuronal loss and gliosis. Silver-stains showed that there were sprouting of the axon and dendrite and no senile plaques and neurofibrillary tangle formation in the neocortex of patients with DRE; 2. 142 (3.47 %) of 4096 genes significantly altered in the DRE brains. Among the 142 genes, 38(26.8%)genes were down-regulated while 104(73.2%)genes were up-regulated (>2-fold change over controls). These differentially genes included in immune, cell signal transmission, apoptosis, stress-associated, synapse plasticity, structural and cellular reorganization, and so on. Some genes had been reported in previous studies while others had never been reported. 3. Twelve of thirteen by FQ-PCR were coincidence well with the results of microarray scanning. Within the same population, Most of them were found to be significantly increased in the temporal neocortex of DRE comparing to those in the control tissue. 12 genes by RT-PCR were coincidence well with the results of genechip.
Conclusions: 1 Multiple genes were associated with DRE, but not a single gene;2 These differentially genes mainly related with immune, cell signal transmission, apoptosis, stress-associated, synapse plasticity, structural and cellular reorganization, and so on; 3 Some genes had never been reported in previous study. It was still unknown to the mechanism of DRE;4 Gene chip had the merits of high-flux and high sensitivity. However, there are some false positive. It was important to test the results by traditional molecular biological technique.
PART TWO: SCREEN THE SPECIFIC MARKED PROTEIN AND APPROACH THE MECHANISM IN THE TEMPORAL LOBE OF DRUG-RESISTANCE EPILEPSY ON THE BASE OF CDNA LIBRARY
Purpose: The protein is the gene function unit. Make use of the temporal lobe of DRE patients to detect the gene expression of candidate genes. We analyzed the relation of gene and the protein expression and clarify the possible mechanism of DRE.
Methods:Used western blot to evaluate and level of extracellular signal-regulated kinase 1(ERK1 ) , ERK2, phosphorylated- ERK1/2(P-ERK1/2),tau protein,phosphorylated-tau protein(ser202, ser404), GSK-3β, phosphorylated-GSK -3β(ser9),MAP2,T cell death- associated gene 51(TDAG51), Insulin-like growth factor-I(IGF-I),CDR2 in 40 surgically resected temporal neocortex of patients with DRE and 20 normal control. Immunohistochemistry (IHC) and immunofluorescence was also used to explore the protein expression and location in DRE.
Restuls:As compared with the control group, there appeared significant increased protein expressions of IGF-1,TDAG51,MAPK14, P-MAPK14 (Thr180/Tyr182), MAP2,P-TAU(ser202,ser404),CDK5,GSK-3β, significant decreased expressions of P-GSK-3β(ser9). ERK1,ERK2,and p-ERK in DRE was significant higher than those of controls. They were mainly expressed in the cytoplasm of neuron and glial cell. At the same time, p-ERK expression in the gliosis of DRE was higher than that in the non-gliosis. Western blot analysis showed the results of protein were coincidence with was found in DRE when compared with the normal control brain tissues by immunohistochemistry and immunofluorescence.
Conclusion:1, Our work showed that differential mRNA and protein levels may be involved in the pathophysiology of DRE and may be associated with impairment of the brain caused by frequent seizures; 2 , DRE was not caused by a single gene, but many differential genes and proteins,such as TDAG51 associated protein(IGF-1,CDR2,MAPK14, etc), tau associated protein(MAP1A,MAP1B,MAP2,CDK5,etc); 3, these differential genes and proteins expression suggested that DRE have new onset pathway and provide the theory basis of new AEDs.
目的:利用基因芯片和生物信息学理论筛选耐药性癫痫患者术后脑组织中差异表达基因,通过对其功能和相互关系的分析,探讨建立耐药性癫痫患者脑内差异表达基因的cDNA文库,同步了解耐药性癫痫患者脑内是否存在耐药性癫痫新的致病基因,进一步完善对耐药性癫痫基因机制的认识。
方法:收集耐药性癫痫患者和对照组脑组织,常规病理学检查(HE染色、硝酸银染色、尼氏染色)后,抽提两组脑组织RNA,纯化mRNA,分别逆转录合成荧光分子掺入cDNA-链做探针;将含4096条人类基因PCR产物按微矩阵点样于化学涂层的栽玻片上,制成基因芯片,芯片杂交和洗片后,用ScanArray4000荧光扫描仪扫描芯片荧光信号图象,计算机分析耐药性癫痫患者和对照组脑组织差异表达的基因;生物信息学筛选出与耐药性癫痫发病相关的差异候选基因,采用RT-PCR对酪蛋白激酶2(CSNK2A1),层粘连蛋白β1(LAMB1),肌红蛋白1E(MYO1E),微管蛋白δ1(TUBD1),微管蛋白γ1(TUBG1),钙粘蛋白18,type 2(Cadherin 18 type2),微管相关蛋白1A(MAP1A),微管相关蛋白1B( MAP1B),微管相关蛋白2(MAP2),周期性依赖蛋白激酶5(CDK5),分裂素激活蛋白激酶14(MAPK14),糖原合成激酶-3β(GSK-3β)基因进行验证;实时荧光PCR(FQ-PCR)对MAP1A, MAP1B,MAP2,WDR3, CDK5 ,MAPK14 , GSK-3β, HSPBAP1, REDD1, EML5, MARK1, TRAP220 ,小脑变性相关蛋白(CDR2) mRNA水平进行检测。
结果:1、耐药性癫痫患者术后脑组织常规病理学检查提示神经元坏死、凋亡、胶质细胞增生,神经纤维增多,走行紊乱是耐药性癫痫最常见的病理改变;2、耐药性癫痫患者脑内有142条基因与对照组比效表达有显著差异(104条(73.2%)表达上调,38条(26.8%)表达下调),按生物学功能分类,发现这些差异表达的基因主要集中在信号传导(20条)、离子通道(3条)、细胞骨架基因(9条)、凋亡(7条)、细胞受体(3条)、代谢(6条)、癌基因(4条)及发育(9条)等,提示耐药性癫痫的发生可能与细胞骨架、凋亡、离子通道、代谢、免疫等。3 RT-PCR验证的12条基因结果与基因芯片一致;除MARK1外,FQ-PCR检测结果与基因芯片相符,从另一个侧面支持基因芯片检测结果。
结论: 1、耐药性癫痫发病机制可能与多个不同功能的基因组相互作用有关,而非单一基因作用;2、差异表达基因主要集中在离子通道、凋亡、细胞骨架、信号传导及其肿瘤相关基因等;3、耐药性癫痫患者脑组织中存在人类尚不清楚的耐药性癫痫新致病基因;4、基因芯片技术具有高通量、高灵敏度的优点,能发现新致病基因,但存在假阳性,需结合传统分子生物学技术验证。
第二部分:基于差异cDNA文库基础上耐药性癫痫患者脑内特异性蛋白筛选和机制研究
目的:蛋白是基因功能的执行单位,本文研究的目的就是希望在差异表达基因cDNA文库基础上通过研究其相关蛋白,筛选出耐药性癫痫患者脑内特异性,标示性的蛋白质,进而探讨耐药性癫痫患者新的发病机制,提出耐药性癫痫防治的新观点,为抗癫痫新药的开发提供新的作用靶点。
方法:收集耐药性癫痫患者和对照组颞叶标本,采用免疫组化、免疫荧光、western blot分别对细胞外信号传导激酶(extracellular signal-regulated kinase,ERK1), ERK2,磷酸化细胞外信号传导激酶1/2(P-ERK1/2),TAU蛋白、P-TAU蛋白(ser202,ser404)、糖原合成激酶-3Beta(GSK-3β)、磷酸化糖原合成激酶(ser9)(P-GSK-3β(ser9))、微管相关蛋白2(microtubular- associated protein,MAP2)、T细胞死亡相关基因51 ( T cell death-associated gene 51,TDAG51)、胰岛素样生长因子-1(Insulin-like growth factor-I,IGF-I)、MAPK14和磷酸化MAPK14(thr182 /tyr184)、CDR2总共14个蛋白的表达部位和表达量进行测定,进一步探讨其在耐药性癫痫发病机制中的作用。
结果:IGF-1、TDAG51、MAPK14、磷酸化MAPK14 (Thr180 /Tyr182)、MAP2、TAU蛋白、磷酸化TAU蛋白(ser202,ser404)、CDK5、GSK-3β、P-GSK-3β(ser9)、ERK1、ERK2、P-ERK1/2(Thr202 /Tyr204)免疫反应产物均为棕黄色点状或颗粒状沉积,神经元胞体和细胞核均有表达,部分胶质细胞也存在表达。各组脑组织间,可见着色深浅有明显差异,阴性对照组未见免疫反应产物表达。除TAU蛋白无改变和P-GSK- 3β(ser9)耐药性癫痫组降低外,癫痫患者脑组织中上述蛋白的表达较正常对照组高。CDR2见于实验组脑组织中,对照组中未见明显阳性细胞。ERK1、ERK2不同病理改变即神经元丢失组和胶质细胞增生组之间无明显改变,而P-ERK1/2(Thr202/Tyr204)在胶质细胞增生组明显高于非胶质细胞增生组。免疫荧光与免疫组化结果类似,western blot检测显示各个蛋白在相应的分子量处表达,其表达量的高低与免疫组化相符。
结论:1耐药性癫痫患者基因表达有差异,其基因的表达产物亦有类似结果;2差异表达的不是单一蛋白,而是具有相互作用的蛋白如TDAG51相关蛋白(IGF-1,MAPK14,CDR2)和TAU蛋白相关蛋白(GSK-3β,P-GSK-3β,CDK5,ERK1,ERK2,P-ERK1/2,P-MAPK14(thr182 /tyr184), MAPK14); 3研究耐药性癫痫患者脑组织中差异基因和蛋白的表达,提示耐药性癫痫新的异常发病途径,为新药开发提供理论依据。
PART ONE: SCREEN THE DIFFERENTIAL GENE EXPRESSION IN THE TEMPORAL NEOCORTEX OF PATIENTS WITH INTRACTABLE EPILEPSY
Objectives: In search for the molecular basis of drug-resistance epilepsy(DRE), we applied a genomic-transcriptomic approach and bioinformatics to identify genes involved in the pathogenesis of DRE. Understanding epileptogenesis, the process by which a normal brain becomes epileptic, may help to establish differential gene cDNA library and find out the new epilepsy associated genes, and then identify the molecular targets for drugs which could prevent epilepsy.
Methods: Using a cDNA microarray representing 4096 human genes, we identified that those genes were altered in the temporal neocortex of the patients with DRE and control tissues. Standard stains included H&E,nissl staining and modified bielschowsky silver stains. Total RNA was extracted with UNIzol reagent following the manufacturer's protocol and methods. Scans were performed with the ScanArray4000. The expression value for each gene was then calculated using ImaGene3.0 software (BioDiscovery,Inc). Each experiment was duplicated so that the mean of two ratios for each gene could be used for further analysis. To validate these results, we performed real-time fluorescence quantitative polymerase chain reaction (FQ-PCR) on optional thirteen differentially expressed genes, including MAP1A(microtubular-associated protein1A), MAP1B(microtubular- associated protein 1B),MAP2(microtubular associated protein 2),WDR3 (WD repeat domain 3),CDK5 (cyclin-dependent kinase 5),MAPK14 (mitogen-activated protein kinase 14),GSK-3β(glycogen synthase kinase 3 beta), HSPBAP1 (HSPB associated protein 1), REDD1 (regulated in development and DNA damage responses 1), EML5 (echinoderm microtubule associated protein like 5), MARK1 (microtubule affinity-regulating kinase 1), TRAP220 (thyroid hormone receptor- associated protein), CDR2 (cerebellar degeneration-related protein2)). And we also tested 12 gene by reverse transcription PCR (RT-PCR) (CSNK2A1(casein kinase 2, alpha 1),LAMB1(lamin beta1), MYO1E(myoglobin 1E), TUBD1(tublin deta1), TUBG1(tublin gama1), Cadherin 18(type2), MAP1A,MAP1B,MAP2, CDK5,MAPK14,GSK-3β).
Results: 1. Nissl-, H&E and silver- stained neurons showed that the number was significantly decreased in DRE. Patients had cortical neuronal loss and gliosis. Silver-stains showed that there were sprouting of the axon and dendrite and no senile plaques and neurofibrillary tangle formation in the neocortex of patients with DRE; 2. 142 (3.47 %) of 4096 genes significantly altered in the DRE brains. Among the 142 genes, 38(26.8%)genes were down-regulated while 104(73.2%)genes were up-regulated (>2-fold change over controls). These differentially genes included in immune, cell signal transmission, apoptosis, stress-associated, synapse plasticity, structural and cellular reorganization, and so on. Some genes had been reported in previous studies while others had never been reported. 3. Twelve of thirteen by FQ-PCR were coincidence well with the results of microarray scanning. Within the same population, Most of them were found to be significantly increased in the temporal neocortex of DRE comparing to those in the control tissue. 12 genes by RT-PCR were coincidence well with the results of genechip.
Conclusions: 1 Multiple genes were associated with DRE, but not a single gene;2 These differentially genes mainly related with immune, cell signal transmission, apoptosis, stress-associated, synapse plasticity, structural and cellular reorganization, and so on; 3 Some genes had never been reported in previous study. It was still unknown to the mechanism of DRE;4 Gene chip had the merits of high-flux and high sensitivity. However, there are some false positive. It was important to test the results by traditional molecular biological technique.
PART TWO: SCREEN THE SPECIFIC MARKED PROTEIN AND APPROACH THE MECHANISM IN THE TEMPORAL LOBE OF DRUG-RESISTANCE EPILEPSY ON THE BASE OF CDNA LIBRARY
Purpose: The protein is the gene function unit. Make use of the temporal lobe of DRE patients to detect the gene expression of candidate genes. We analyzed the relation of gene and the protein expression and clarify the possible mechanism of DRE.
Methods:Used western blot to evaluate and level of extracellular signal-regulated kinase 1(ERK1 ) , ERK2, phosphorylated- ERK1/2(P-ERK1/2),tau protein,phosphorylated-tau protein(ser202, ser404), GSK-3β, phosphorylated-GSK -3β(ser9),MAP2,T cell death- associated gene 51(TDAG51), Insulin-like growth factor-I(IGF-I),CDR2 in 40 surgically resected temporal neocortex of patients with DRE and 20 normal control. Immunohistochemistry (IHC) and immunofluorescence was also used to explore the protein expression and location in DRE.
Restuls:As compared with the control group, there appeared significant increased protein expressions of IGF-1,TDAG51,MAPK14, P-MAPK14 (Thr180/Tyr182), MAP2,P-TAU(ser202,ser404),CDK5,GSK-3β, significant decreased expressions of P-GSK-3β(ser9). ERK1,ERK2,and p-ERK in DRE was significant higher than those of controls. They were mainly expressed in the cytoplasm of neuron and glial cell. At the same time, p-ERK expression in the gliosis of DRE was higher than that in the non-gliosis. Western blot analysis showed the results of protein were coincidence with was found in DRE when compared with the normal control brain tissues by immunohistochemistry and immunofluorescence.
Conclusion:1, Our work showed that differential mRNA and protein levels may be involved in the pathophysiology of DRE and may be associated with impairment of the brain caused by frequent seizures; 2 , DRE was not caused by a single gene, but many differential genes and proteins,such as TDAG51 associated protein(IGF-1,CDR2,MAPK14, etc), tau associated protein(MAP1A,MAP1B,MAP2,CDK5,etc); 3, these differential genes and proteins expression suggested that DRE have new onset pathway and provide the theory basis of new AEDs.
引文
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