Transcriptional expression patterns triggered by chemically distinct neuroprotective molecules.
Transcriptional expression patterns triggered by chemically distinct neuroprotective molecules.
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DOI：
10.1016/j.neuroscience.2012.09.007
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发表时间：
2012-12-13
期刊：
影响因子：
3.3
通讯作者：
Oksenberg, J. R.
中科院分区：
文献类型：
--
作者：
Pappas, D. J.;Gabatto, P. A.;Oksenberg, D.;Khankhanian, P.;Baranzini, S. E.;Gan, L.;Oksenberg, J. R.
谷氨酸介导的兴奋性毒性被认为是许多神经退行性疾病的基础。谷氨酸受体的一个亚型，即 N-甲基-D-天冬氨酸 (NMDA) 受体，已被认为是神经保护的潜在靶点。为了加深我们对这种神经保护机制的理解，我们采用了谷氨酸受体诱导的兴奋性毒性损伤的小鼠模型。来自出生后第 0 天 CD-1 小鼠的原代皮质神经元在存在或不存在神经保护分子的情况下进行培养，并暴露于 NMDA。恢复期后，通过微阵列分析测量全基因组表达。我们结合使用数据库和文本挖掘以及系统建模来识别差异表达基因内的特征。虽然分子的作用机制不同，但我们发现一组核心基因和通路的表达存在显着重叠。其中许多分子与神经元保护和存活有明确的联系，包括离子通道、转运蛋白以及信号通路，包括丝裂原激活蛋白激酶 (MAPK)、Toll 样受体 (TLR) 和缺氧诱导因子 (HIF)。在 TLR 通路中，我们还发现了干扰素调节因子 7 (IRF7) 调节基因的显着富集。 RNA 干扰敲低 Irf7 导致 NMDA 治疗后生存率降低。鉴于 IRF7 在 I 型干扰素 (IFN) 转导中发挥的重要作用，我们还测试了 I 型 IFN 是否单独发挥神经保护剂的作用，并发现 I 型 IFN 足以促进神经元存活。我们的数据表明，TLR/IRF7/IFN 轴在谷氨酸诱导的兴奋性毒性的恢复中发挥着重要作用。
Glutamate mediated excitotoxicity has been purported to underlie many neurodegenerative disorders. A subtype of glutamate receptors, namely N-methyl-D-aspartate (NMDA) receptors, has been recognized as potential targets for neuroprotection. To increase our understanding of the mechanisms that underlie this neuroprotection, we employed a mouse model of glutamate receptor induced excitotoxic injury. Primary cortical neurons derived from postnatal day-0 CD-1 mice were cultured in the presence or absence of neuroprotective molecules and exposed to NMDA. Following a recovery period, whole genome expression was measured by microarray analysis. We used a combination of database and text mining, as well as systems modeling to identify signatures within the differentially expressed genes. While molecules differed in their mechanisms of action, we found significant overlap in the expression of a core group of genes and pathways. Many of these molecules have clear links to neuronal protection and survival, including ion channels, transporters, as well as signaling pathways including the mitogen-activated protein kinase (MAPK), the Toll-like receptor (TLR), and the hypoxic inducible factor (HIF). Within the TLR pathway, we also discovered a significant enrichment of interferon regulatory factor 7 (IRF7) regulated genes. Knockdown of Irf7 by RNA interference resulted in reduced survival following NMDA treatment. Given the prominent role that IRF7 plays in the transduction of type-I interferons (IFN), we also tested whether type-I IFNs alone functioned as neuroprotective agents and found that type-I IFNs were sufficient to promote neuronal survival. Our data suggest that the TLR/IRF7/IFN axis plays a significant role in recovery from glutamate induced excitotoxicity.
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影响因子：
3.9
作者：
Hardingham GE
通讯作者：
Hardingham GE
神经炎症性脱髓鞘性疾病中的谷氨酸受体。
影响因子：
4.6
作者：
Bolton, Christopher;Paul, Carolyn
通讯作者：
Paul, Carolyn
影响因子：
3.3
作者：
Connell, B. J.;Crosby, K. M.;Saleh, T. M.
通讯作者：
Saleh, T. M.
影响因子：
4.7
作者：
Hara, T;Hamada, J;Ushio, Y
通讯作者：
Ushio, Y
影响因子：
4.8
作者：
Chen, J;Zhou, YG;Li, G
通讯作者：
Li, G