Microarray analysis of the temporal response of skeletal muscle to methylprednisolone: comparative analysis of two dosing regimens
Microarray analysis of the temporal response of skeletal muscle to methylprednisolone: comparative analysis of two dosing regimens
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DOI：
10.1152/physiolgenomics.00242.2006
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发表时间：
2007-08-20
影响因子：
4.6
通讯作者：
Jusko, William J.
中科院分区：
文献类型：
--
作者：
Almon, Richard R.;DuBois, Debra C.;Jusko, William J.
在168小时内研究了骨骼肌对慢性皮质类固醇暴露的转录反应，并与单剂量皮质类固醇后观察到的反应谱进行了比较。雄性肾上腺切除Wistar大鼠皮下植入微型泵，等速滴注0.3 mg中心点kg（-1）中心点h（-1）甲基强的松龙7天。在注射过程中，分别在10个不同时间点处死4只对照动物和40只药物治疗动物。将肝脏总rna杂交到44个Affymetrix REA230A基因芯片上。先前，我们描述了一种过滤方法，用于在急性给药后接受甲基强的松龙（MPL）治疗的大鼠组织中开发的微阵列数据集中识别感兴趣的基因。在这里，一个类似的方法涉及一系列的三个过滤器被依次应用于识别感兴趣的基因。这些过滤器的设计是为了消除在组织中不表达的探针组，不受药物调节，或不符合规定的质量控制标准。过滤消除了86%的探测集，剩下的2316个有待进一步考虑。在先前的一项研究中，653个探针组在单次（急性）剂量的药物治疗后被确定为MPL调节。两组数据的比较得出196个基因在两种给药方案中都被MPL调控。由于受体下调，预计受受体-糖皮质激素反应元件相互作用调控的基因在慢性情况下会表现出耐受性。然而，许多基因没有表现出类固醇耐受性，这表明目前关于糖皮质激素作用机制的观点不能完全解释所有的时间特征。
The transcriptional response of skeletal muscle to chronic corticosteroid exposure was examined over 168 h and compared with the response profiles observed following a single dose of corticosteroid. Male adrenalectomized Wistar rats were given a constant- rate infusion of 0.3 mg center dot kg(-1)center dot h(-1) methylprednisolone for up to 7 days via subcutaneously implanted minipumps. Four control and forty drug- treated animals were killed at ten different time points during infusion. Liver total RNAs were hybridized to 44 individual Affymetrix REA230A gene chips. Previously, we described a filtration approach for identifying genes of interest in microarray data sets developed from tissues of rats treated with methylprednisolone ( MPL) following acute dosing. Here, a similar approach involving a series of three filters was applied sequentially to identify genes of interest. These filters were designed to eliminate probe sets that were not expressed in the tissue, not regulated by the drug, or did not meet defined quality control standards. Filtering eliminated 86% of probe sets, leaving a remainder of 2,316 for further consideration. In a previous study, 653 probe sets were identified as MPL regulated following administration of a single ( acute) dose of the drug. Comparison of the two data sets yielded 196 genes identified as regulated by MPL in both dosing regimens. Because of receptor downregulation, it was predicted that genes regulated by receptor- glucocorticoid response element interactions would exhibit tolerance in chronic profiles. However, many genes did not exhibit steroid tolerance, indicating that present perspectives on the mechanism of glucocorticoid action cannot entirely explain all temporal profiles.