缺氧诱导Neuroglobin上调的调控机制和以Neuroglobin为靶分子筛选神经保护药物的研究
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摘要
第一部分缺氧诱导Neuroglobin上调的调控机制
Neuroglobin (Ngb)是新近发现的神经特异性表达的携氧蛋白,主要在脊椎动物神经组织中高表达。以前的研究表明,缺氧可以诱导大脑中Ngb基因的表达的上调,而增加Ngb的表达可以进一步保护大脑免受缺血缺氧引发的损伤。然而,Ngb在缺氧条件下的调控机制尚不是很清楚。在这个研究中,我们发现小鼠Ngb基因的近端启动子约554bp的序列高度保守,并且这段区域包含几个保守的NFκB和Egr1结合位点。过表达或者干扰转录因子p65,p50,Egr1或者Sp1能够增加或者降低Ngb基因的表达。Ngb基因启动子区域转录因子结合位点突变研究以及凝胶迁移或电泳迁移率实验(EMSA)和染色体免疫沉淀实验证明了NFκB家族成员(包括p65,p50和cRel)以及Egr1和Sp1能够与Ngb基因的启动子区域结合。而且,我们研究发现一个κB3位点作为一个关键的顺式作用原件介导了缺氧条件下诱导Ngb基因启动子活性的上调。转录因子NFκB(p65),Sp1参与了调控缺氧条件下Ngb基因的表达上调。尽管我们在小鼠Ngb基因的近端启动子区域并没有发现HIF1α的保守结合位点,但是我们的结果表明HIF1α也参与了缺氧条件下Ngb基因的表达上调。因此,从这些结果中我们得出结论：转录因子NFκB,Egr1,Sp1通过与小鼠Ngb基因启动子特异性的结合参与了对Ngb基因的调控,而NFκB,Sp1以及HIF1α参与了缺氧条件下小鼠Ngb基因的调控。第二部分以Neuroglobin为靶分子筛选神经保护药物研究
中风是引起人类死亡的主要疾病之一。以前的研究表明Ngb是一个能保护神经免受缺血缺氧,氧压以及神经退行性病变的新的内源性神经保护蛋白。因此,上调Ngb的表达可能能作为一种干预和治疗中风以及相关性疾病的潜在的治疗方法。为了筛选能够上调Ngb表达的自然化合物,我们分别克隆了人以及小鼠约2kb的Ngb启动子并构建进入报告基因载体,然后进一步分别建立了人以及小鼠具有Ngb启动子报告基因的稳定表达系。为了鉴定我们的人以及小鼠的稳定表达系,我们初步筛选了一个包含约40个化合物的文库。我们发现：Polydatin, Icariin, Genipin, Genistein, Daidzein, Biochanin A, Formononetin能够在小鼠的稳定表达系中上调小鼠的Ngb基因启动子活性。而Polydatin, Genistein, Daidzein, Biochanin A, Formononetin能够在人的稳定表达细胞系中上调人的Ngb基因启动子活性。通过RT-PCR和Western blotting我们进一步确认了Polydatin, Genistein, Formononetin能够显著的上调Ngb mRNA水平和蛋白水平。而且我们的结果表明Polydatin和Formononetin能够减少OGD诱导的神经元的死亡。因此,我们的结果说明Polydatin和Formononetin可能可以作为潜在的神经保护药物,并且我们构建的人和小鼠Ngb基因报告基因表达系可以用于进一步的高通量药物筛选。
Part Ⅰ Transcriptional Regulation Mechanisms of Hypoxia-Induced Neuroglobin Gene Expression
Neuroglobin (Ngb) has been identified as a novel endogenous neuroprotectant. However, little is known about the regulation mechanisms of Ngb expression, especially under hypoxia conditions. In this study, we located the core proximal promoter of mouse Ngb gene to a554bp segment, which harbors putative conserved NFκB, Egr1binding sites. Over-expression and knock-down of transcription factors p65, p50, Egr1or Sp1increased and decreased Ngb expression, respectively. Experimental assessments with transfections of mutational Ngb gene promoter constructs, as well as EMS A and ChIP assays demonstrated that NFκB family members (p65, p50, cRel), Egr1, and Sp1bound in vitro and in vivo to the proximal promoter region of Ngb gene. Moreover, a κB3site was found as a pivotal cis-element responsible for hypoxia-induced Ngb promoter activity. NFκB (p65) and Sp1were also responsible for hypoxia-induced upregulation of Ngb expression. Although there are no conserved HREs (hypoxia-response elements) in the promoter of mouse Ngb gene, our results suggested that HIF1α is also involved in hypoxia-induced Ngb upregulation. In conclusion, we identified that NFκB, Egr1, and Sp1played important roles in regulation of basal Ngb expression via specific interactions with the mouse Ngb promoter. NFκB, Sp1and HIF1α contributed to the upregulation of mouse Ngb gene expression under hypoxic conditions. Part Ⅱ
Identifying Compounds That Upregulate Neuroglobin for Endogenous Neuroprotection
Stroke is one of the leading causes of death worldwide. Previous studies indicate that Neuroglobin is a novel neuroprotective protein that protected against hypoxic/ischemic neuron injury, oxidative injury, neurodegenerated disease. Thus, up-regulating Ngb may be a novel therapeutic approach for the intervention and treatment of stroke and related disorders. To identify natural compounds that increase Ngb expression, we developed both mouse and human reporter system that stably expressed a luciferase reporter gene directed by around2000bp of the mouse and human Ngb promoter, respectively. Preliminary validation of both reporter system using a small pool of natural compounds identified several Ngb activators:Polydatin, Icariin, Genipin, Genistein, Daidzein, Biochanin A, Formononetin for increasing mouse Ngb promoter activity; Polydatin, Genistein, Daidzein, Biochanin A, Formononetin for increasing human Ngb promoter activity. Those potential activators of the Ngb promoter were further evaluated by secondary analyses. RT-PCR and Western blotting further confirmed that Polydatin, Genistein, Formononetin were able to significantly increase Ngb mRNA levels and protein levels. Moreover, they also significantly decreased OGD-induced the rate of death of mouse primary cortical neuron. Our results suggested that Polydatin, Fonnononetin are potential neuroprotective drugs and our mouse and human reporter system could be used for high-throughput screening.
Neuroglobin (Ngb)是新近发现的神经特异性表达的携氧蛋白,主要在脊椎动物神经组织中高表达。以前的研究表明,缺氧可以诱导大脑中Ngb基因的表达的上调,而增加Ngb的表达可以进一步保护大脑免受缺血缺氧引发的损伤。然而,Ngb在缺氧条件下的调控机制尚不是很清楚。在这个研究中,我们发现小鼠Ngb基因的近端启动子约554bp的序列高度保守,并且这段区域包含几个保守的NFκB和Egr1结合位点。过表达或者干扰转录因子p65,p50,Egr1或者Sp1能够增加或者降低Ngb基因的表达。Ngb基因启动子区域转录因子结合位点突变研究以及凝胶迁移或电泳迁移率实验(EMSA)和染色体免疫沉淀实验证明了NFκB家族成员(包括p65,p50和cRel)以及Egr1和Sp1能够与Ngb基因的启动子区域结合。而且,我们研究发现一个κB3位点作为一个关键的顺式作用原件介导了缺氧条件下诱导Ngb基因启动子活性的上调。转录因子NFκB(p65),Sp1参与了调控缺氧条件下Ngb基因的表达上调。尽管我们在小鼠Ngb基因的近端启动子区域并没有发现HIF1α的保守结合位点,但是我们的结果表明HIF1α也参与了缺氧条件下Ngb基因的表达上调。因此,从这些结果中我们得出结论：转录因子NFκB,Egr1,Sp1通过与小鼠Ngb基因启动子特异性的结合参与了对Ngb基因的调控,而NFκB,Sp1以及HIF1α参与了缺氧条件下小鼠Ngb基因的调控。第二部分以Neuroglobin为靶分子筛选神经保护药物研究
中风是引起人类死亡的主要疾病之一。以前的研究表明Ngb是一个能保护神经免受缺血缺氧,氧压以及神经退行性病变的新的内源性神经保护蛋白。因此,上调Ngb的表达可能能作为一种干预和治疗中风以及相关性疾病的潜在的治疗方法。为了筛选能够上调Ngb表达的自然化合物,我们分别克隆了人以及小鼠约2kb的Ngb启动子并构建进入报告基因载体,然后进一步分别建立了人以及小鼠具有Ngb启动子报告基因的稳定表达系。为了鉴定我们的人以及小鼠的稳定表达系,我们初步筛选了一个包含约40个化合物的文库。我们发现：Polydatin, Icariin, Genipin, Genistein, Daidzein, Biochanin A, Formononetin能够在小鼠的稳定表达系中上调小鼠的Ngb基因启动子活性。而Polydatin, Genistein, Daidzein, Biochanin A, Formononetin能够在人的稳定表达细胞系中上调人的Ngb基因启动子活性。通过RT-PCR和Western blotting我们进一步确认了Polydatin, Genistein, Formononetin能够显著的上调Ngb mRNA水平和蛋白水平。而且我们的结果表明Polydatin和Formononetin能够减少OGD诱导的神经元的死亡。因此,我们的结果说明Polydatin和Formononetin可能可以作为潜在的神经保护药物,并且我们构建的人和小鼠Ngb基因报告基因表达系可以用于进一步的高通量药物筛选。
Part Ⅰ Transcriptional Regulation Mechanisms of Hypoxia-Induced Neuroglobin Gene Expression
Neuroglobin (Ngb) has been identified as a novel endogenous neuroprotectant. However, little is known about the regulation mechanisms of Ngb expression, especially under hypoxia conditions. In this study, we located the core proximal promoter of mouse Ngb gene to a554bp segment, which harbors putative conserved NFκB, Egr1binding sites. Over-expression and knock-down of transcription factors p65, p50, Egr1or Sp1increased and decreased Ngb expression, respectively. Experimental assessments with transfections of mutational Ngb gene promoter constructs, as well as EMS A and ChIP assays demonstrated that NFκB family members (p65, p50, cRel), Egr1, and Sp1bound in vitro and in vivo to the proximal promoter region of Ngb gene. Moreover, a κB3site was found as a pivotal cis-element responsible for hypoxia-induced Ngb promoter activity. NFκB (p65) and Sp1were also responsible for hypoxia-induced upregulation of Ngb expression. Although there are no conserved HREs (hypoxia-response elements) in the promoter of mouse Ngb gene, our results suggested that HIF1α is also involved in hypoxia-induced Ngb upregulation. In conclusion, we identified that NFκB, Egr1, and Sp1played important roles in regulation of basal Ngb expression via specific interactions with the mouse Ngb promoter. NFκB, Sp1and HIF1α contributed to the upregulation of mouse Ngb gene expression under hypoxic conditions. Part Ⅱ
Identifying Compounds That Upregulate Neuroglobin for Endogenous Neuroprotection
Stroke is one of the leading causes of death worldwide. Previous studies indicate that Neuroglobin is a novel neuroprotective protein that protected against hypoxic/ischemic neuron injury, oxidative injury, neurodegenerated disease. Thus, up-regulating Ngb may be a novel therapeutic approach for the intervention and treatment of stroke and related disorders. To identify natural compounds that increase Ngb expression, we developed both mouse and human reporter system that stably expressed a luciferase reporter gene directed by around2000bp of the mouse and human Ngb promoter, respectively. Preliminary validation of both reporter system using a small pool of natural compounds identified several Ngb activators:Polydatin, Icariin, Genipin, Genistein, Daidzein, Biochanin A, Formononetin for increasing mouse Ngb promoter activity; Polydatin, Genistein, Daidzein, Biochanin A, Formononetin for increasing human Ngb promoter activity. Those potential activators of the Ngb promoter were further evaluated by secondary analyses. RT-PCR and Western blotting further confirmed that Polydatin, Genistein, Formononetin were able to significantly increase Ngb mRNA levels and protein levels. Moreover, they also significantly decreased OGD-induced the rate of death of mouse primary cortical neuron. Our results suggested that Polydatin, Fonnononetin are potential neuroprotective drugs and our mouse and human reporter system could be used for high-throughput screening.
引文
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