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Functional imaging: monitoring heme oxygenase-1 gene expression in vivo

机译：功能成像：监测体内血红素加氧酶-1基因表达

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Abstract: The regulation of genetic elements can be monitored in living animals using photoproteins as reporters. Heme oxygenase (HO) is the key catabolic enzyme in the heme degradation pathway. Here, HO expression serves as a model for in vivo functional imaging of transcriptional regulation of a clinically relevant gene. HO enzymatic activity is inhibited by heme analogs, metalloporphyrins, but many members of this family of compounds also activate transcription of the HO-1 promoter. The degree of transcriptional activation by twelve metalloporphyrins, differing at the central metal and porphyrin ring substituents, was evaluated in both NIH 3T3 stable lines and transgenic animals containing HO-1 promoter-luciferase gene fusions. In the correlative cell culture assays, the metalloporphyrins increased transcription form the full length HO promoter fusion to varying degrees, but none increased transcription from a truncated HO-1 promoter. These results suggested that one or both of the two distal enhancer elements located at $MIN@4 and $MIN@10 Kb upstream from transcriptional start are required for HO-1 induction by heme and its analogs. The full-length HO-1-luc fusion was then evaluated as a transgene in mice. It was possible to monitor the effects of the metalloporphyrins, SnMP and ZnPP, in living animals over time. This spatiotemporal analyses of gene expression in vivo implied that alterations in porphyrin ring substituents and the central metal may affect the extent of gene activation. These data further indicate that using photoprotein reporters, subtle differences in gene expression can be monitored in living animals. !24
机译：摘要：使用光蛋白作为报告基因，可以监测活体动物的遗传成分。血红素加氧酶（HO）是血红素降解途径中的关键分解代谢酶。在此，HO表达用作临床相关基因的转录调控的体内功能成像的模型。 HO的酶活性被血红素类似物金属卟啉抑制，但是该化合物家族的许多成员也激活HO-1启动子的转录。在NIH 3T3稳定株系和含有HO-1启动子-荧光素酶基因融合体的转基因动物中，评估了十二个金属卟啉在中央金属和卟啉环取代基上的转录激活程度。在相关的细胞培养测定中，金属卟啉以不同程度增加了全长HO启动子融合体的转录，但没有增加截短的HO-1启动子的转录。这些结果表明，位于血红素及其类似物的HO-1诱导中，位于转录起始上游$ MIN @ 4和$ MIN @ 10 Kb处的两个远端增强子元件中的一个或两个。然后将全长HO-1-luc融合体作为小鼠中的转基因进行评估。随着时间的推移，有可能监测金属卟啉，SnMP和ZnPP对活体动物的影响。这种体内基因表达的时空分析表明，卟啉环取代基和中心金属的改变可能影响基因激活的程度。这些数据进一步表明，使用光蛋白报道分子，可以在活体动物中监测基因表达的细微差异。 ！24

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