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Please use this identifier to cite or link to this item: http://ntour.ntou.edu.tw:8080/ir/handle/987654321/34283

Title: AHR調控細胞色素P450基因的演化與生物資訊分析
Evolutionary and Bioinformatics Analysis of Cytochrome P450 Regulated by Ahr
Authors: 鄒文雄
Contributors: NTOU:Institute of Bioscience and Biotechnology
Date: 2012-08
Issue Date: 2013-10-07T02:18:54Z
Publisher: 行政院國家科學委員會
Abstract: 摘要:AHR調控細胞色素P450基因的演化與生物資訊分析 Cytochrome P450 (CYP)是一個基因家族,其蛋白質為一種含有血紅素基的 monooxygenase,此酵素可以經由氧化還原反應代謝藥物、環境毒物與和內生性化合 物。CYP P450 酵素在生物體擔任多樣性功能,從毒物代謝到生殖荷爾蒙的合成都擔任 重要的角色。目前在動物細胞系統一般認為CYP1 接受AHR(aryl hydrocarbon receptor) 調控而CYP3 接受PXR(pregnane X receptor)調控。人類的CYP3A 參與超過36%的藥物 代謝,對於藥物設計是一大挑戰。 大多數研究著重在 P450 基因的轉錄功能與其啟動子與增強子上典型的AHR 結合 序列 (XRE,5’-GCGTG-3’),本實驗室利用轉殖基因斑馬魚技術研究有驚人發現,斑 馬魚胚胎中CYP3A65 的基因特異表現竟然接受AHR2 調控,經由初步生物資訊分析竟 然發現水生魚類的CYP3 基因上游位置含有XRE 群集(cluster),而在陸生哺乳類生物沒 有這種現象;更有趣的是海豚的CYP3A 基因上游位置竟含有XRE 群集。 本實驗室的發現直接產生一個假說,那就是水生動物的 CYP3 接受AHR 調控,而 陸生動物的AHR 失去了調控CYP3 能力,轉而由PXR 擔任。而這種轉變可能是因應 不同的環境(水生與陸生)而生物體所產生的適應所致。為了驗證此假說,本研究會以 生物資訊方法廣泛收集所有陸生動物與水生動物的CYP 基因調控序列,探索XRE 序 列群集與環境適應的相關性;更進一步,本研究將會以斑馬魚胚胎與海膽胚胎作為實驗 模型,透過次世代定序、基因表現生物晶片與質譜儀,探討AHR 基因與CYP3 基因對 於肝臟轉錄體與代謝體的影響。 此研究探討 CYP3 基因調控的演化根源,對於藥物設計將有非常顯著的貢獻。
Abstract:Cytochrome P450 (CYP) represents a gene family, of which the gene product is a monooxygenase containing heme group. CYP protein is an enzyme capable of metabolizing drugs, environmental toxin and endogenous compound. The current paradigm is that CYP1 is regulated by AHR but CYP3 is regulated by PXR. And CYP3A is involved in more than the metabolism of 36% of drugs used in human. Up to now, most of the studies focus on the effect of the AHR (aryl hydrocarbon receptor)-bound XRE sequence (5’-GCGTG-3’) sequences on the strength of promoter and enhancer regions of CYP1genes. We have unexpectedly discovered CYP3A65 gene is tightly regulated by AHR2 genes in zebrafish embryo. A more extensive study on the upstream sequence of CYP3 genes revealed XRE clusters in fish but not in mammals. More interestingly, an XRE cluster was found in the upstream sequence of dolphin, a water-living mammal. The finding mentioned above leads to a hypothesis, that is, gene expression of CYP3 genes in aquatic animals could be regulated by AHR while those in terrestrial animals were regulated by PXR. The switch of gene regulator is probably is a result of environmental adaptation. To prove this hypothesis, we plan to conduct a thorough investigation on XRE clusters of the upstream sequences of all CYP genes in aquatic and terrestrial animals. Moreover, we will use embryos of zebrafish and sea urchin as the model systems to explore the transcriptome and metabolome after AHR and CYP3 are knocked down by morpholino molecules. The technology involved will include gene expression microarry, next-generation sequencing and mass spectroscopy. The research results will have an impact on the evolutionary origin of gene regulation of CYP and the drug design.
Relation: NSC101-2311-B019-001
URI: http://ntour.ntou.edu.tw/handle/987654321/34283
Appears in Collections:[生命科學暨生物科技學系] 研究計畫

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