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首页> 外文期刊>Journal of applied toxicology >Systems biology approaches for toxicology.
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Systems biology approaches for toxicology.

机译：毒理学的系统生物学方法。

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Systems biology/toxicology involves the iterative and integrative study of perturbations by chemicals and other stressors of gene and protein expression that are linked firmly to toxicological outcome. In this review, the value of systems biology to enhance the understanding of complex biological processes such as neurodegeneration in the developing brain is explored. Exposure of the developing mammal to NMDA (N-methyl-D-aspartate) receptor antagonists perturbs the endogenous NMDA receptor system and results in enhanced neuronal cell death. It is proposed that continuous blockade of NMDA receptors in the developing brain by NMDA antagonists such as ketamine (a dissociative anesthetic) causes a compensatory up-regulation of NMDA receptors, which makes the neurons bearing these receptors subsequently more vulnerable (e.g. after ketamine washout), to the excitotoxic effects of endogenous glutamate: the up-regulation of NMDA receptors allows for the accumulation of toxic levels of intracellular Ca(2+) under normal physiological conditions. Systems biology, as applied to toxicology, provides a framework in which information can be arranged in the form of a biological model. In our ketamine model, for example, blockade of NMDA receptor up-regulation by the co-administration of antisense oligonucleotides that specifically target NMDA receptor NR1 subunit mRNA, dramatically diminishes ketamine-induced cell death. Preliminary gene expression data support the role of apoptosis as a mode of action of ketamine-induced neurotoxicity. In addition, ketamine-induced cell death is also prevented by the inhibition of NF-kappaB translocation into the nucleus. This process is known to respond to changes in the redox state of the cytoplasm and has been shown to respond to NMDA-induced cellular stress. Although comprehensive gene expression/proteomic studies and mathematical modeling remain to be carried out, biological models have been established in an iterative manner to allow for the confirmation of biological pathways underlying NMDA antagonist-induced cell death in the developing nonhuman primate and rodent. Published in 2007 John Wiley & Sons, Ltd.
机译：系统生物学/毒理学涉及对与化学和毒理学结果紧密相关的化学物质以及其他基因和蛋白质表达压力源的扰动进行的迭代和综合研究。在这篇综述中，探索了系统生物学对增进对复杂的生物过程（例如发育中的大脑中神经退行性疾病）的理解的价值。发育中的哺乳动物暴露于NMDA（N-甲基-D-天冬氨酸）受体拮抗剂会扰乱内源性NMDA受体系统，并导致神经元细胞死亡增加。有人提出，NMDA拮抗剂（如氯胺酮（一种解离性麻醉剂））持续阻断发育中的大脑中的NMDA受体会引起NMDA受体的补偿性上调，这会使带有这些受体的神经元随后变得更加脆弱（例如，在清除氯胺酮后） ，对内源性谷氨酸的兴奋毒性作用：NMDA受体的上调允许在正常生理条件下积累细胞内Ca（2+）的毒性水平。应用于毒理学的系统生物学提供了一个框架，在该框架中可以以生物学模型的形式安排信息。例如，在我们的氯胺酮模型中，通过共同施用特异靶向NMDA受体NR1亚基mRNA的反义寡核苷酸来阻断NMDA受体上调，从而大大减少了氯胺酮诱导的细胞死亡。初步的基因表达数据支持凋亡作为氯胺酮诱导的神经毒性作用的一种模式。此外，氯胺酮诱导的细胞死亡也可通过抑制NF-κB易位进入细胞核来预防。已知该过程对细胞质的氧化还原状态的变化有反应，并且已经表明对NMDA诱导的细胞应激有反应。尽管全面的基因表达/蛋白质组学研究和数学建模仍有待进行，但已经以迭代方式建立了生物学模型，以确认在发育中的非人类灵长类动物和啮齿动物中NMDA拮抗剂诱导的细胞死亡的生物学途径。出版于2007年John Wiley＆Sons，Ltd.

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