大鼠癫痫持续状态后海马miRNA表达谱的研究
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摘要
目的
应用miRNA微阵列芯片技术,对大鼠癫痫持续状态(status epilepticus, SE)后海马区脑组织与正常大鼠脑组织中miRNA的表达谱进行对比研究,筛选差异表达miRNA。并对其中差异较大的miRNA在脑组织和外周血的表达量进行检测,运用生物信息学对差异表达miRNA靶基因进行预测和验证。探讨SE后相关miRNA对中枢神经系统损伤的作用机制。
方法
1.建立模型：采用6-8周龄健康雄性SD大鼠,建立氯化锂-匹罗卡品致痫大鼠SE模型。于造模成功后24小时取脑组织和外周血与正常雄性SD大鼠进行比较。
2. miRNA微阵列芯片筛选差异表达miRNA:提取大鼠脑组织海马区的miRNA,采用miRNA微阵列芯片技术研究SE后大鼠海马区脑组织与正常大鼠海马区脑组织中miRNA表达谱的差异。
3.荧光定量RT-PCR验证差异表达的miRNA:选取有明显差异表达的miRNA,采用荧光定量RT-PCR对其在脑组织海马区的表达进行验证。并对其在大鼠外周血中的表达进行检测,对比脑组织和外周血中的表达差异。
4.生物信息学分析预测靶基因：利用MiRanda软件、TargetScan软件和PicTar软件预测相关差异表达的miRNA的靶基因。
5. Western Blot检测靶基因：根据预测的结果,采用WesternBlot对相关靶基因在SE后大鼠海马区的表达进行检测。
结果
1.SE大鼠和正常大鼠海马组织差异表达miRNA:运用miRNA微阵列芯片,在SE后大鼠海马区脑组织中检测出上调的miRNA基因37个,下调的28个。其中上调大于5倍的miRNA基因为miR-34a、miR-22、miR-125a、miR-213、miR-30c、miR-26a、miR-375、miR-99a、miR-24、miR-124a、miR-101-1。表达差异最大的是miR-34a(25.86倍),差异最小的是miR-188(1.42倍)。下调大于5倍的基因有miR-21、miR-29a、Let-7e、miR-181、miR-215、miR-128a、miR-181b,其中miR-21下调最明显为27.97倍。
2.荧光定量RT-PCR验证差异表达miRNA:选择上调最明显的3个(miR-34a、miR-22和miR-125a)和下调最明显的2个(miR-21和miR-29a),采用实时荧光定量PCR对SE后大鼠脑组织海马区和外周血中差异miRNA的表达进行检测和对比。miR-34a、miR-125a和miR-22表达上调,miR-21表达下调,与芯片结果一致；miR-29a未见与芯片一致的结果。所有目标miRNA在脑组织和外周血的变化趋势均一致；miR-34a、miR-125a和miR-34a在脑组织中表达量高于外周血,miR-22和miR-21脑组织中的表达量低于外周血。
3.靶基因预测结果：利用生物信息学方法对miR-34a、miR-125a、miR-22和miR-21进行靶基因预测,结果提示miR-34a和miR-125a的上调可能调控Bcl-2,miR-21的下调可能调控Caspase-3的表达；这些靶基因都被认为与神经元凋亡有关。
4. Western-Blot检测预测靶基因的表达：对SE后大鼠海马组织的Bcl-2和Caspase-3的蛋白表达进行检测,结果与预测的一致,Bcl-2的表达下调,Caspase-3的蛋白表达上调；这些都将促进神经元凋亡。
结论
1.建立了癫痫持续状态后大鼠和正常大鼠海马区脑组织的miRNA差异表达谱。
2.发现miR-34a、miR-22、miR-125a、miR-21和miR-29a在大鼠脑组织和外周血中的变化趋势一致,有密切的相关性,为进一步将外周血检测miRNA用于相关研究提供依据。
3.miR-34a和miR-125a的靶基因可能是Bcl-2,miR-21的靶基因可能是Caspase-3,它们参与SE后神经元凋亡的调节。
Objective.
This study compared the different of miRNA expression in hippocampal region of brain tissue between the Lithium chloride pilocarpine SE model rat and the normal rat brain tissue by using the miRNA microarray chip technology. Futher, the miRNA which showed much more different between the two group were chioced and their expression in the brain tissue and in the peripheral blood were measured by real time PCR. Bio-informatics is used in predicting and examining of the target gene. Discussions also been brought on how the related miRNA injuring the central nervous system of rats after SE.
Method
1.Setted up model:Origin 6-8 weeks healthy male SD rats, then set up the Lithium chloride-pilocarpine SE model.24 hours after model setting, take the brain tissue and peripheral blood to compare with normal male SD rat's brain tissue.
2.Screened the differential expression of miRNA by using miRNA microarray chip technology:extracted miRNAs in the hippocampus of rat brain tissue. Using miRNA microchip technology to study on the miRNA expression difference between hippocampus brain tissue of SE rat and brain tissue of normal rat.
3.Verified the differential expression of miRNA Ration examination by quantitative RT-PCR:Significantly differentially expressing miRNAs were detected by quantitative RT-PCR in hippocampus brain tissue. Also tested the expression in peripheral blood of rat and compared the expression difference between hippocampus brain tissue and peripheral blood.
4.Predicted the target genes by bioinformatics analysis:Software of Miranda, TargetScan and PicTar were used to predict the target gene of significantly differentially expressing miRNAs.
5.Detected on the target genes using Western Blot:According to the prediction result, using Western Blot inspected the expression of target genes in hippocampus brain tissue of SE rats and normal rats.
Result
1. Differentially expression miRNA in hippocampus brain tissue of SE rats and normal rats:Using miRNA Microarray chip technology,37 miRNA raise up gene were found in the hippocampus brain tissue of SE rat. Among those, raise up five times higher miRNA gene is miR-34a、miR-22、miR-125a、miR-213、miR-30c、miR-26a、miR-375、miR-99a、miR-24、miR-124a、miR-101-1. miR-34a has the maximum expression difference (25.86 times) while miR-188 has the minimum expression difference (1.42 times). Lower 5 times genes are miR-21、miR-29a、Let-7e、miR-181、miR-215、miR-128a、miR-181b, the miR-21 has the sharpest lowering which is 27.97 times.
2.Validated the differentially expressed miRNAs by quantitative RT-PCR:Chose the most obviously 3 increased miRNA (miR-34a、miR-22和miR-125a) and 2 decreased (miR-21和miR-29a). By using quantitative RT-PCR, the differentially expressed miRNAs in hippocampus brain tissue and peripheral blood were detected and compared. In the five miRNA under test,the miR-34a、miR-125a and miR-22's expression was increased while miR-21 decreased which was consistent with chip test results. Then the result of miR-29a was not. All the target miRNA changing trends in the brain tissue and peripheral blood tissue were consistent. The miR-34a, miR-125a and miR-34a expression in brain tissue was higher than in peripheral blood tissue. And the miR-22 and miR-21 expression in brain tissue was lower than in the peripheral blood tissue.
3. Predicted results on target genes:By use of bioinformatics methods, miR-34a, miR-125a, miR-22 and miR-21's target genes were predicted. The results showed that the upregulation of miR-34a and miR-125a could control the expression of Bcl-2 and downturn miR-21 was likely to control the expression of Caspase-3. These target genes were considering related to neuronal apoptosis.
4.Detected the expression of the predicted target genes by using Western Blot:Tested on the protein of Bcl-2 and Caspase-3 in hippocampus brain tissue of SE rats and normal rats by using Western-Blot. The results were consistent with the prediction. Bcl-2's expression decreased while the expression of Caspase-3 protein increased. All those would promote neuronal apoptosis.
Conclusion.
1. Generated the differential expression profiles of miRNAs in SE rat's hippocampus tissue and normal rat's brain tissue.
2. Found out that miR-34a, miR-22, miR-125a, miR-21 and miR-29a in the rat brain and peripheral blood have the same changing trends and which are closely related. It provides a basis further research in this field.
3. Target genes of MiR-34a and miR-125a would be the Bcl-2 and target genes of miR-21 would be Caspase-3 which participated in the SE regulation of neuronal apoptosis.
应用miRNA微阵列芯片技术,对大鼠癫痫持续状态(status epilepticus, SE)后海马区脑组织与正常大鼠脑组织中miRNA的表达谱进行对比研究,筛选差异表达miRNA。并对其中差异较大的miRNA在脑组织和外周血的表达量进行检测,运用生物信息学对差异表达miRNA靶基因进行预测和验证。探讨SE后相关miRNA对中枢神经系统损伤的作用机制。
方法
1.建立模型：采用6-8周龄健康雄性SD大鼠,建立氯化锂-匹罗卡品致痫大鼠SE模型。于造模成功后24小时取脑组织和外周血与正常雄性SD大鼠进行比较。
2. miRNA微阵列芯片筛选差异表达miRNA:提取大鼠脑组织海马区的miRNA,采用miRNA微阵列芯片技术研究SE后大鼠海马区脑组织与正常大鼠海马区脑组织中miRNA表达谱的差异。
3.荧光定量RT-PCR验证差异表达的miRNA:选取有明显差异表达的miRNA,采用荧光定量RT-PCR对其在脑组织海马区的表达进行验证。并对其在大鼠外周血中的表达进行检测,对比脑组织和外周血中的表达差异。
4.生物信息学分析预测靶基因：利用MiRanda软件、TargetScan软件和PicTar软件预测相关差异表达的miRNA的靶基因。
5. Western Blot检测靶基因：根据预测的结果,采用WesternBlot对相关靶基因在SE后大鼠海马区的表达进行检测。
结果
1.SE大鼠和正常大鼠海马组织差异表达miRNA:运用miRNA微阵列芯片,在SE后大鼠海马区脑组织中检测出上调的miRNA基因37个,下调的28个。其中上调大于5倍的miRNA基因为miR-34a、miR-22、miR-125a、miR-213、miR-30c、miR-26a、miR-375、miR-99a、miR-24、miR-124a、miR-101-1。表达差异最大的是miR-34a(25.86倍),差异最小的是miR-188(1.42倍)。下调大于5倍的基因有miR-21、miR-29a、Let-7e、miR-181、miR-215、miR-128a、miR-181b,其中miR-21下调最明显为27.97倍。
2.荧光定量RT-PCR验证差异表达miRNA:选择上调最明显的3个(miR-34a、miR-22和miR-125a)和下调最明显的2个(miR-21和miR-29a),采用实时荧光定量PCR对SE后大鼠脑组织海马区和外周血中差异miRNA的表达进行检测和对比。miR-34a、miR-125a和miR-22表达上调,miR-21表达下调,与芯片结果一致；miR-29a未见与芯片一致的结果。所有目标miRNA在脑组织和外周血的变化趋势均一致；miR-34a、miR-125a和miR-34a在脑组织中表达量高于外周血,miR-22和miR-21脑组织中的表达量低于外周血。
3.靶基因预测结果：利用生物信息学方法对miR-34a、miR-125a、miR-22和miR-21进行靶基因预测,结果提示miR-34a和miR-125a的上调可能调控Bcl-2,miR-21的下调可能调控Caspase-3的表达；这些靶基因都被认为与神经元凋亡有关。
4. Western-Blot检测预测靶基因的表达：对SE后大鼠海马组织的Bcl-2和Caspase-3的蛋白表达进行检测,结果与预测的一致,Bcl-2的表达下调,Caspase-3的蛋白表达上调；这些都将促进神经元凋亡。
结论
1.建立了癫痫持续状态后大鼠和正常大鼠海马区脑组织的miRNA差异表达谱。
2.发现miR-34a、miR-22、miR-125a、miR-21和miR-29a在大鼠脑组织和外周血中的变化趋势一致,有密切的相关性,为进一步将外周血检测miRNA用于相关研究提供依据。
3.miR-34a和miR-125a的靶基因可能是Bcl-2,miR-21的靶基因可能是Caspase-3,它们参与SE后神经元凋亡的调节。
Objective.
This study compared the different of miRNA expression in hippocampal region of brain tissue between the Lithium chloride pilocarpine SE model rat and the normal rat brain tissue by using the miRNA microarray chip technology. Futher, the miRNA which showed much more different between the two group were chioced and their expression in the brain tissue and in the peripheral blood were measured by real time PCR. Bio-informatics is used in predicting and examining of the target gene. Discussions also been brought on how the related miRNA injuring the central nervous system of rats after SE.
Method
1.Setted up model:Origin 6-8 weeks healthy male SD rats, then set up the Lithium chloride-pilocarpine SE model.24 hours after model setting, take the brain tissue and peripheral blood to compare with normal male SD rat's brain tissue.
2.Screened the differential expression of miRNA by using miRNA microarray chip technology:extracted miRNAs in the hippocampus of rat brain tissue. Using miRNA microchip technology to study on the miRNA expression difference between hippocampus brain tissue of SE rat and brain tissue of normal rat.
3.Verified the differential expression of miRNA Ration examination by quantitative RT-PCR:Significantly differentially expressing miRNAs were detected by quantitative RT-PCR in hippocampus brain tissue. Also tested the expression in peripheral blood of rat and compared the expression difference between hippocampus brain tissue and peripheral blood.
4.Predicted the target genes by bioinformatics analysis:Software of Miranda, TargetScan and PicTar were used to predict the target gene of significantly differentially expressing miRNAs.
5.Detected on the target genes using Western Blot:According to the prediction result, using Western Blot inspected the expression of target genes in hippocampus brain tissue of SE rats and normal rats.
Result
1. Differentially expression miRNA in hippocampus brain tissue of SE rats and normal rats:Using miRNA Microarray chip technology,37 miRNA raise up gene were found in the hippocampus brain tissue of SE rat. Among those, raise up five times higher miRNA gene is miR-34a、miR-22、miR-125a、miR-213、miR-30c、miR-26a、miR-375、miR-99a、miR-24、miR-124a、miR-101-1. miR-34a has the maximum expression difference (25.86 times) while miR-188 has the minimum expression difference (1.42 times). Lower 5 times genes are miR-21、miR-29a、Let-7e、miR-181、miR-215、miR-128a、miR-181b, the miR-21 has the sharpest lowering which is 27.97 times.
2.Validated the differentially expressed miRNAs by quantitative RT-PCR:Chose the most obviously 3 increased miRNA (miR-34a、miR-22和miR-125a) and 2 decreased (miR-21和miR-29a). By using quantitative RT-PCR, the differentially expressed miRNAs in hippocampus brain tissue and peripheral blood were detected and compared. In the five miRNA under test,the miR-34a、miR-125a and miR-22's expression was increased while miR-21 decreased which was consistent with chip test results. Then the result of miR-29a was not. All the target miRNA changing trends in the brain tissue and peripheral blood tissue were consistent. The miR-34a, miR-125a and miR-34a expression in brain tissue was higher than in peripheral blood tissue. And the miR-22 and miR-21 expression in brain tissue was lower than in the peripheral blood tissue.
3. Predicted results on target genes:By use of bioinformatics methods, miR-34a, miR-125a, miR-22 and miR-21's target genes were predicted. The results showed that the upregulation of miR-34a and miR-125a could control the expression of Bcl-2 and downturn miR-21 was likely to control the expression of Caspase-3. These target genes were considering related to neuronal apoptosis.
4.Detected the expression of the predicted target genes by using Western Blot:Tested on the protein of Bcl-2 and Caspase-3 in hippocampus brain tissue of SE rats and normal rats by using Western-Blot. The results were consistent with the prediction. Bcl-2's expression decreased while the expression of Caspase-3 protein increased. All those would promote neuronal apoptosis.
Conclusion.
1. Generated the differential expression profiles of miRNAs in SE rat's hippocampus tissue and normal rat's brain tissue.
2. Found out that miR-34a, miR-22, miR-125a, miR-21 and miR-29a in the rat brain and peripheral blood have the same changing trends and which are closely related. It provides a basis further research in this field.
3. Target genes of MiR-34a and miR-125a would be the Bcl-2 and target genes of miR-21 would be Caspase-3 which participated in the SE regulation of neuronal apoptosis.
引文
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