Analysis of the biliary transcriptome in experimental biliary atresia.
Analysis of the biliary transcriptome in experimental biliary atresia.
复制标题
实验性胆道闭锁的胆道转录组分析。
DOI：
10.1016/j.gastro.2005.05.052
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发表时间：
2005
期刊：
影响因子：
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通讯作者：
Bezerra,JorgeA
中科院分区：
文献类型：
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作者：
Carvalho,Elisa;Liu,Cong;Shivakumar,Pranavkumar;Sabla,Gregg;Aronow,Bruce;Bezerra,JorgeA
背景与目的胆道闭锁发病机制的发现一直受到疾病早期患者肝外胆管组织研究能力的限制。在这里，我们使用轮状病毒诱导的胆道闭锁模型来研究整个胆道转录组，以寻找在开始和进展到胆管阻塞的不同阶段激活的分子网络。方法出生后24小时内向Balb/c小鼠腹腔注射生理盐水或轮状病毒，在3、7和14天整块显微解剖胆管和肝外胆管，产生生物素化的RNA池，并与含有45,101基因产物的微阵列杂交。结果数据过滤、聚类分析和基因表达平台的功能分配揭示了两种独特的表达模式。第一个是在闭锁的所有阶段调节免疫、酶和结构蛋白的基因的主要表达。在这种模式中，干扰素诱导因子IRF7和IRF9在损伤开始时的顺序表达，以及干扰素-γ和干扰素-γ激活的基因(STAT1、IGTP、CxCL9、CxCL10)在胆管阻塞时的顺序表达，表明了明显的促炎回路。二是调节胆道闭锁生物网络的基因的时间限制性表达，如补体成分C3ar-1和C1q-α/β。结论胆道转录组中功能相关基因的协同表达突出了主要的促炎足迹，为寻找可能在实验性胆道闭锁的胆道损伤和梗阻发病机制中发挥调节作用的基因群提供了基础。
Background & AimsDiscovery of the pathogenic mechanisms of biliary atresia has been limited by the inability to study extrahepatic biliary tissues from patients at early phases of disease. Here, we used a rotavirus-induced model of biliary atresia to investigate the entire biliary transcriptome for molecular networks activated at the onset and different phases of progression to duct obstruction.MethodsWe injected Balb/c mice with saline or rotavirus intraperitoneally within 24 hours of birth, microdissected the gallbladder and extrahepatic bile ducts en bloc 3, 7, and 14 days later, generated biotinylated RNA pools, and hybridized them against microarrays containing 45,101 gene products.ResultsData filtering, cluster analysis, and functional assignment of the gene expression platform revealed 2 unique patterns of expression. The first was an overarching expression of genes regulating immunity, enzymes, and structural proteins at all phases of atresia. Within this pattern, the sequential expression of the interferon inducers Irf7 and Irf9 at the onset of injury, and interferon-γ and interferon-γ–activated genes (Stat1, Igtp, Cxcl9, Cxcl10) at the time of duct obstruction, pointed to a prominent proinflammatory circuit. The second was the time-restricted expression of genes regulating biological networks previously unrecognized in biliary atresia, such as the complement components C3ar-1 and C1q-α/β.ConclusionsThe coordinate expression of functionally related genes in the biliary transcriptome underscores a predominant proinflammatory footprint and provides a basis for identification of gene groups that may play regulatory roles in the pathogenesis of duct injury and obstruction in experimental biliary atresia.