Employment of digital gene expression profiling to identify potential pathogenic and therapeutic targets of fulminant hepatic failure.
Employment of digital gene expression profiling to identify potential pathogenic and therapeutic targets of fulminant hepatic failure.
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利用数字基因表达谱来识别暴发性肝衰竭的潜在致病和治疗靶点。
DOI：
10.1186/s12967-015-0380-9
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发表时间：
2015-01-27
影响因子：
7.4
通讯作者：
Tang H
中科院分区：
文献类型：
--
作者：
Chen EQ;Bai L;Gong DY;Tang H
细胞因子代谢和活性失调是暴发性肝功能衰竭（FHF）发生发展的关键，目前已鉴定出多种不同的细胞因子。然而，确切的基因表达谱及其相互作用与FHF的关系还有待进一步阐明。本研究通过高通量测序技术检测正常和FHF小鼠肝脏的数字基因表达谱（DGEP），验证FHF治疗的候选基因和潜在靶点。采用D-氨基半乳糖（GalN）/脂多糖（LPS）诱导FHF小鼠模型。从RNA-seq数据中共检测到12727个基因，获得3551个差异表达基因（DEG）。在FHF小鼠肝脏中，许多DEG被鉴定为在代谢过程、生物合成过程、对刺激的反应和对应激的反应等中差异表达。同样，在FHF小鼠肝脏中，途径富集分析显示许多显著的DEG也在代谢途径、凋亡、趋化因子信号途径、考虑到核因子-κ B（NF-κB）在代谢调节和细胞存活与死亡之间的微妙平衡中的重要作用，选择了几个参与NF-κB通路的DEG进行实验验证。与正常对照组相比，FHF肝组织中NF-κ Bp 65及其抑制蛋白IκBα均显著升高，NF-κB靶向基因肿瘤坏死因子α（TNFα）、诱导型一氧化氮合酶（iNOS）、白细胞介素1β（IL-1β）、趋化因子CCL 3和CCL 4也显著升高。此外，NF-κB阻断后，FHF小鼠模型的肝脏病理损伤和死亡率均明显降低。本研究提供了FHF小鼠肝脏地球仪基因表达谱，并证明了NF-κB基因作为FHF治疗靶点的可能性。本文的在线版本（doi：10.1186/s12967-015-0380-9）包含补充材料，可供授权用户使用。
The dysregulated cytokine metabolism and activity are crucial to the development of fulminant hepatic failure (FHF), and many different cytokines have been identified. However, the precise gene expression profile and their interactions association with FHF are yet to be further elucidated. In this study, we detected the digital gene expression profile (DGEP) by high-throughput sequencing in normal and FHF mouse liver, and the candidate genes and potential targets for FHF therapy were verified. And the FHF mouse model was induced by D-Galactosamine (GalN)/lipopolysaccharide (LPS). Totally 12727 genes were detected, and 3551 differentially expressed genes (DEGs) were obtained from RNA-seq data in FHF mouse liver. In FHF mouse liver, many of those DEGs were identified as differentially expressed in metabolic process, biosynthetic process, response to stimulus and response to stress, etc. Similarly, pathway enrichment analysis in FHF mouse liver showed that many significantly DEGs were also enriched in metabolic pathways, apoptosis, chemokine signaling pathways, etc. Considering the important role of nuclear factor-kappa B (NF-κB) in metabolic regulation and delicate balance between cell survival and death, several DEGs involved in NF-κB pathway were selected for experimental validation. As compared to normal control, NF-κBp65 and its inhibitory protein IκBα were both significantly increased, and NF-κB targeted genes including tumor necrosis factor α(TNFα), inducible nitric oxide synthase (iNOS), interleukin-1β, chemokines CCL3 and CCL4 were also increased in hepatic tissues of FHF. In addition, after NF-κB was successfully pre-blocked, there were significant alteration of hepatic pathological damage and mortality of FHF mouse model. This study provides the globe gene expression profile of FHF mouse liver, and demonstrates the possibility of NF-κB gene as a potential therapeutic target for FHF. The online version of this article (doi:10.1186/s12967-015-0380-9) contains supplementary material, which is available to authorized users.
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