| Budget Amount *help |
¥11,200,000 (Direct Cost: ¥11,200,000)
Fiscal Year 2001: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2000: ¥7,700,000 (Direct Cost: ¥7,700,000)
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| Research Abstract |
Three variants of routine serotonin transporter (5-HTT) mRNA, which consist of a different exon-one (exon-la, exon-1b or exon-1c) and the same exon-two to exon-five, were identified. Any promoter region, ligated to PGL-3 enhancer vector, had activities significantly higher than the empty vector in some cell lines tested, where as the activity for the exon-1c was significantly lower than the others. In COS-7 cell lines, dibutyryl-cyclic AMP (Dib-cAMP) treatment decreased the activity for the exon-lc and did not change the others. Human interferon-*** (ENF-***) treatment decreased the activity for the exon-la, did not change the one for the exon-lb and increased the one for exon-lc. In PC12 cell lines the promoter regions for exon-la and exon-lb had higher activities than the mock vector. The promoter activity for exon-l c did not differ from that of mock vector. Dib-cAMP treatment increased the activities of all of the constructs whereas human INF-α application did not change any of the
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m. In immortalized rat serotoneigic raphe neurons, RN46A, the insertion of the promoter region for exonl a, exonlb and exonlc increased the activity twelve, sixteen or three times respectively. Dib-cAMP slightly increased their activity where as murine interferon *** did not change them. These three promoter regions may play a role in transcription of 5-HTT and could offer a model of the regulation of 5-HTT production in human and further the pathogenesis of depression and other serotonin spectrum disorders.
Enhancer/silencer activity of each allelic variant of the human serotonin transporter linked polymorphic region (5HTTLPR) including newly found ones was measured in several cell lines including raphe-nucleus-derived RN46A. 5-HTTLR variants ligated in pGL-3 promote1 vector increased hiciferase activity in COS-7 cells and PC12 cells, where no significant differences among the variants were observed. In RN46A cell lines, however, 5-HTTLPRs decreased hiciferase activity to eighty to thirty percent, acting as silencers not as enhancers. Some allelic variants (15, 19, 20, and 22) showed even significantly stronger silencer activities than others in RN46A. We also examined relationship between allelic frequencies, the enhancer/silencer activities and incidents of mood disorder. The categorized genotypic or allelic frequencies was not significantly different between the mood disorder and the control. No significant difference was detected either when analyzed by silencer activities of each allelic variant.
Three variants ofmurine serotonin transporter (5-HTT) mRNA, which consist of a different exon-one (exon-la, exon-lb or exon-lc) and the same exon4wo to exon-five, were identified. Any promoter region, ligated to pGL-3 enhancer vector, had activities significantly higher than the empty vector in some cell lines tested, where as the activity for the exon-lc was significantly lower than the others. Less
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