神经营养素3对神经细胞调亡的保护作用机制研究
摘要
神经细胞凋亡与骨科创伤、肿瘤以及多种疾病的发生与治疗密切相关。探索神经细胞凋亡的保护作用机制,可能为上述疾病提供新的治疗方案。
神经营养因子3(Neurotrophin-3, NT-3)属于神经生长因子家族,广泛存在于中枢神经系统及周围组织。NT-3的缺乏与多种神经功能障碍相关,它对于感觉神经元、交感神经元的存活与功能有重要作用,近年来备受关注。有研究发现,NT-3对谷氨酸盐介导的未成熟少突胶质细胞凋亡只有瞬时的抑制作用,其机制尚不明了。另外,NT-3可能是通过激活PI-3 kinase/Akt信号通路对培养的皮层神经元发挥一定程度的抗凋亡作用,进一步作用机制尚在研究之中。关于NT-3对于少突胶质细胞和皮层神经元以外的其他细胞调亡过程是否有类似作用尚罕见报道。因此,探讨NT-3对神经细胞凋亡的保护作用机制,对于建立安全、有效的新型治疗策略,可能具有特殊意义。
本文首先设计引物,从大鼠脑组织用RT-PCR方法扩增NT-3基因,得到长度为777bp的片断,酶切鉴定正确,测序结果与GenBank中大鼠NT-3序列完全一致。成功构建原核表达载体pRSET-A-NT-3,导入大肠杆菌BL21中,经IPTG诱导表达,SDS-PAGE电泳鉴定得到一条约34kDa的新生蛋白带,用镍柱纯化融合蛋白。与免疫佐剂联用免疫家兔制备特异性抗体,获得了1:64000的高效价特异性抗大鼠NT-3血清。为研究NT-3对神经细胞凋亡的保护作用机制提供了基础。
进一步建立6羟基多巴胺(6-OHDA)诱导PC12细胞凋亡模型,探讨NT-3对PC12细胞凋亡的作用。通过这种公认的体外神经元凋亡模型,利用MTT、TUNEL染色检测细胞存活率和凋亡率,Hoechst标记观察染色质凝聚,并测定caspase-3活性和caspase-3与PARP裂解情况。研究发现先加入NT-3孵育后细胞存活率回升、凋亡率明显降低。Annexin V-FITC/PI染色流式细胞分析验证了6-OHDA对PC12细胞产生的效应主要是诱导凋亡而不是导致细胞坏死;同时也验证了NT-3的抗凋亡作用。荧光光度测定显示NT-3使caspase-3活性显著降低。蛋白质印迹分析表明caspase-3与PARP裂解减少,Akt磷酸化增加。Hoechst染色观察到NT-3明显抑制染色质凝聚,而anti-TrkA可减弱这种抑制作用,提示NT-3对染色质凝聚的抑制作用可能与TrkA受体有关。磷脂酰肌醇3激酶(PI3-kinase)抑制剂LY294002则增加染色质凝聚,加入NT-3未能逆转该作用。这些结果提示,NT-3能够抑制6-OHDA诱导的PC12细胞凋亡,这种作用是通过PI3-kinase/Akt信号途径实现的。
本文还观察了脊髓内注射NT-3重组腺病毒对坐骨神经损伤后脊髓前角运动神经元的作用。制备大鼠坐骨神经夹伤模型,治疗组大鼠在立体定位仪上于脊髓腹角给予神经营养素3重组腺病毒(Adeno-NT-3),而对照组则给予生理盐水。术后通过CTB逆标观察脊髓相应节段运动神经元再生的数目,通过尼氏染色计数并计算运动神经元的存活百分率。发现给予Adeno-NT-3组与对照组相比,相应节段运动神经元再生数目和存活百分率明显增加,而且再生神经元增加的比例高于存活神经元。表明Adeno-NT-3对坐骨神经损伤后的脊髓前角运动神经元具有保护作用。提示NT-3在创伤诱发的神经损害中同样具有神经保护作用,其机制仍有待进一步探究。
综上所述,本文成功克隆了大鼠脑组织中NT-3基因,并在原核细胞中成功表达、纯化NT-3蛋白。进一步运用多种研究方法发现NT-3能够抑制6-OHDA诱导的PC12细胞凋亡,这种作用是通过PI3-kinase/Akt信号途径实现的。另外,在动物实验中观察到NT-3对坐骨神经损伤后脊髓前角运动神经元具有保护作用,提示NT-3在创伤诱发的神经损害中同样具有神经保护作用。因此,本文可望为将NT-3应用于神经系统肿瘤、创伤和疾病的基因治疗提供实验依据。
Neurocyte apoptosis correlates closely with nosogenesis and therapeutics of orthopedics diseases such as trauma, tumour etc. It is important to explore the mechanism of action about neuronal apoptosis protection to provide information for the therapy of these diseases.
Neurotrophin-3(NT-3) belongs to nerve growth factor family, and exists extensively in central nervous system and periphery tissue. NT-3 is an important regulator of neuronal survival, development, function, and neuronal differentiation, and has become the focus of intense interest because of its association with various neurological disorders. NT-3 was previously found to transiently protect immature oligodendrocytes from glutamate-mediated apoptosis, NT-3 has also exhibited anti-apoptotic effects on cultured cortical neurons, while the mechanism in them is not elucidated completely. Reports excluding oligodendrocytes and cortical neurons are rare. Therefore, It is significant to explore the mechanism of action about neuronal apoptosis protection to establish new strategies of gene therapy for these diseases.
Firstly, We amplified target gene by RT-PCR and cloned it into the pMD-18T vector, then analyzed its sequence and compared it with the sequence in GenBank. We got a 777 bp gene segment by RT-PCR. The DNA sequence was identical to rat NT-3 gene sequence in GenBank. It suggested that the target gene was correctly inserted into the vector. We subcloned it into pRSET-A vector and introduced it into Escherichia coli BL21. The expression was induced by IPTG, and identified by SDS-PAGE. The fusion protein was purified by niccolum purify kit. A new protein band of about 34 kDa appeared on SDS-PAGE after induction of IPTG. We immuned rabbits with immunological adjuvant for specificity antibody preparation. A specific high titer antibody of 1:64000 was gained by immuning rabbits with immunological adjuvant. All this make it possible to do further investigation.
Secondly, we treated PC12 cells with 6-hydroxydopamine (6-OHDA) which is a widely used neurotoxic agent that can be used to selectively damage dopaminergic neurons in vivo and in vitro. This treatment resulted in activation of caspases-3 and subsequent apoptosis, as detected by TUNEL staining. In addition, Akt phosphorylation was decreased. Pretreatment with NT-3 reduced the percentage of apoptotic cells and caspase-3 activity induced by 6-OHDA and suppressed the cleavage of caspase-3 and PARP with a significant decrease in cell viability. Moreover, Akt phosphorylation was enhanced and 6-OHDA-induced chromatin condensation was suppressed by NT-3. Such NT-3-evoked supression in chromatin condensation was reversed by anti-TrkA antibody receptor blockade. Further study revealed that LY294002, an inhibitor of PI3-kinase (a molecule upstream of Akt), enhanced 6-OHDA-induced apoptosis. These data indicate that NT-3 prevents 6-OHDA-induced apoptosis in PC12 cells via activation of PI3-kinase/Akt pathway.
Finally, we also observed the protective effect of recombinant adenovirus-mediated NT-3 gene(Adeno-NT3) on the survival and regeneration of motoneurons after sciatic nerve crush. In the experimental group, Adeno-NT3 was injected directly into the spinal cord parenchyma, while in the control group, isotonic Na chloride was injected instead. Nissl staining and CTB retrograde were carried out to label the survival and regeneration motoneurons respectively, and the numbers of the motoneurons of survival and regeneration were counted as well. We found that numbers of motoneurons of both survival and regeneration were significantly higher in the experimental group than that of the control group, and the ones of regeneration were more than the ones of survival in experimental group. So we made a conclusion that Adeno-NT3 can promote the survival and regeneration ability of motoneuron after sciatic nerve crush, the mechanism in it still needs further investigation.
To sum up, in this study we amplified target gene by RT-PCR and inserted it correctly into the pMD-18T vector and pRSET-A vector, and introduced it into Escherichia coli BL21. A new protein band of about 34 kDa appeared on SDS-PAGE after induction of IPTG. We used several methods to investigate the effect of NT-3 on 6-OHDA-induced apoptosis in PC12 cells . We found that NT-3 prevents apoptosis via activation of PI3-kinase/Akt pathway. We also observed the animal experiment and made a conclusion that Adeno-NT-3 can promote the survival and regeneration ability of motoneuron after sciatic nerve crush. Therefore, this study may bring a new strategy of gene therapy for orthopedics diseases such as trauma, tumour and other diseases.
神经营养因子3(Neurotrophin-3, NT-3)属于神经生长因子家族,广泛存在于中枢神经系统及周围组织。NT-3的缺乏与多种神经功能障碍相关,它对于感觉神经元、交感神经元的存活与功能有重要作用,近年来备受关注。有研究发现,NT-3对谷氨酸盐介导的未成熟少突胶质细胞凋亡只有瞬时的抑制作用,其机制尚不明了。另外,NT-3可能是通过激活PI-3 kinase/Akt信号通路对培养的皮层神经元发挥一定程度的抗凋亡作用,进一步作用机制尚在研究之中。关于NT-3对于少突胶质细胞和皮层神经元以外的其他细胞调亡过程是否有类似作用尚罕见报道。因此,探讨NT-3对神经细胞凋亡的保护作用机制,对于建立安全、有效的新型治疗策略,可能具有特殊意义。
本文首先设计引物,从大鼠脑组织用RT-PCR方法扩增NT-3基因,得到长度为777bp的片断,酶切鉴定正确,测序结果与GenBank中大鼠NT-3序列完全一致。成功构建原核表达载体pRSET-A-NT-3,导入大肠杆菌BL21中,经IPTG诱导表达,SDS-PAGE电泳鉴定得到一条约34kDa的新生蛋白带,用镍柱纯化融合蛋白。与免疫佐剂联用免疫家兔制备特异性抗体,获得了1:64000的高效价特异性抗大鼠NT-3血清。为研究NT-3对神经细胞凋亡的保护作用机制提供了基础。
进一步建立6羟基多巴胺(6-OHDA)诱导PC12细胞凋亡模型,探讨NT-3对PC12细胞凋亡的作用。通过这种公认的体外神经元凋亡模型,利用MTT、TUNEL染色检测细胞存活率和凋亡率,Hoechst标记观察染色质凝聚,并测定caspase-3活性和caspase-3与PARP裂解情况。研究发现先加入NT-3孵育后细胞存活率回升、凋亡率明显降低。Annexin V-FITC/PI染色流式细胞分析验证了6-OHDA对PC12细胞产生的效应主要是诱导凋亡而不是导致细胞坏死;同时也验证了NT-3的抗凋亡作用。荧光光度测定显示NT-3使caspase-3活性显著降低。蛋白质印迹分析表明caspase-3与PARP裂解减少,Akt磷酸化增加。Hoechst染色观察到NT-3明显抑制染色质凝聚,而anti-TrkA可减弱这种抑制作用,提示NT-3对染色质凝聚的抑制作用可能与TrkA受体有关。磷脂酰肌醇3激酶(PI3-kinase)抑制剂LY294002则增加染色质凝聚,加入NT-3未能逆转该作用。这些结果提示,NT-3能够抑制6-OHDA诱导的PC12细胞凋亡,这种作用是通过PI3-kinase/Akt信号途径实现的。
本文还观察了脊髓内注射NT-3重组腺病毒对坐骨神经损伤后脊髓前角运动神经元的作用。制备大鼠坐骨神经夹伤模型,治疗组大鼠在立体定位仪上于脊髓腹角给予神经营养素3重组腺病毒(Adeno-NT-3),而对照组则给予生理盐水。术后通过CTB逆标观察脊髓相应节段运动神经元再生的数目,通过尼氏染色计数并计算运动神经元的存活百分率。发现给予Adeno-NT-3组与对照组相比,相应节段运动神经元再生数目和存活百分率明显增加,而且再生神经元增加的比例高于存活神经元。表明Adeno-NT-3对坐骨神经损伤后的脊髓前角运动神经元具有保护作用。提示NT-3在创伤诱发的神经损害中同样具有神经保护作用,其机制仍有待进一步探究。
综上所述,本文成功克隆了大鼠脑组织中NT-3基因,并在原核细胞中成功表达、纯化NT-3蛋白。进一步运用多种研究方法发现NT-3能够抑制6-OHDA诱导的PC12细胞凋亡,这种作用是通过PI3-kinase/Akt信号途径实现的。另外,在动物实验中观察到NT-3对坐骨神经损伤后脊髓前角运动神经元具有保护作用,提示NT-3在创伤诱发的神经损害中同样具有神经保护作用。因此,本文可望为将NT-3应用于神经系统肿瘤、创伤和疾病的基因治疗提供实验依据。
Neurocyte apoptosis correlates closely with nosogenesis and therapeutics of orthopedics diseases such as trauma, tumour etc. It is important to explore the mechanism of action about neuronal apoptosis protection to provide information for the therapy of these diseases.
Neurotrophin-3(NT-3) belongs to nerve growth factor family, and exists extensively in central nervous system and periphery tissue. NT-3 is an important regulator of neuronal survival, development, function, and neuronal differentiation, and has become the focus of intense interest because of its association with various neurological disorders. NT-3 was previously found to transiently protect immature oligodendrocytes from glutamate-mediated apoptosis, NT-3 has also exhibited anti-apoptotic effects on cultured cortical neurons, while the mechanism in them is not elucidated completely. Reports excluding oligodendrocytes and cortical neurons are rare. Therefore, It is significant to explore the mechanism of action about neuronal apoptosis protection to establish new strategies of gene therapy for these diseases.
Firstly, We amplified target gene by RT-PCR and cloned it into the pMD-18T vector, then analyzed its sequence and compared it with the sequence in GenBank. We got a 777 bp gene segment by RT-PCR. The DNA sequence was identical to rat NT-3 gene sequence in GenBank. It suggested that the target gene was correctly inserted into the vector. We subcloned it into pRSET-A vector and introduced it into Escherichia coli BL21. The expression was induced by IPTG, and identified by SDS-PAGE. The fusion protein was purified by niccolum purify kit. A new protein band of about 34 kDa appeared on SDS-PAGE after induction of IPTG. We immuned rabbits with immunological adjuvant for specificity antibody preparation. A specific high titer antibody of 1:64000 was gained by immuning rabbits with immunological adjuvant. All this make it possible to do further investigation.
Secondly, we treated PC12 cells with 6-hydroxydopamine (6-OHDA) which is a widely used neurotoxic agent that can be used to selectively damage dopaminergic neurons in vivo and in vitro. This treatment resulted in activation of caspases-3 and subsequent apoptosis, as detected by TUNEL staining. In addition, Akt phosphorylation was decreased. Pretreatment with NT-3 reduced the percentage of apoptotic cells and caspase-3 activity induced by 6-OHDA and suppressed the cleavage of caspase-3 and PARP with a significant decrease in cell viability. Moreover, Akt phosphorylation was enhanced and 6-OHDA-induced chromatin condensation was suppressed by NT-3. Such NT-3-evoked supression in chromatin condensation was reversed by anti-TrkA antibody receptor blockade. Further study revealed that LY294002, an inhibitor of PI3-kinase (a molecule upstream of Akt), enhanced 6-OHDA-induced apoptosis. These data indicate that NT-3 prevents 6-OHDA-induced apoptosis in PC12 cells via activation of PI3-kinase/Akt pathway.
Finally, we also observed the protective effect of recombinant adenovirus-mediated NT-3 gene(Adeno-NT3) on the survival and regeneration of motoneurons after sciatic nerve crush. In the experimental group, Adeno-NT3 was injected directly into the spinal cord parenchyma, while in the control group, isotonic Na chloride was injected instead. Nissl staining and CTB retrograde were carried out to label the survival and regeneration motoneurons respectively, and the numbers of the motoneurons of survival and regeneration were counted as well. We found that numbers of motoneurons of both survival and regeneration were significantly higher in the experimental group than that of the control group, and the ones of regeneration were more than the ones of survival in experimental group. So we made a conclusion that Adeno-NT3 can promote the survival and regeneration ability of motoneuron after sciatic nerve crush, the mechanism in it still needs further investigation.
To sum up, in this study we amplified target gene by RT-PCR and inserted it correctly into the pMD-18T vector and pRSET-A vector, and introduced it into Escherichia coli BL21. A new protein band of about 34 kDa appeared on SDS-PAGE after induction of IPTG. We used several methods to investigate the effect of NT-3 on 6-OHDA-induced apoptosis in PC12 cells . We found that NT-3 prevents apoptosis via activation of PI3-kinase/Akt pathway. We also observed the animal experiment and made a conclusion that Adeno-NT-3 can promote the survival and regeneration ability of motoneuron after sciatic nerve crush. Therefore, this study may bring a new strategy of gene therapy for orthopedics diseases such as trauma, tumour and other diseases.
引文
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