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首页> 外文期刊>BMC Genomics >Gene expression profiling in non-human primate jejunum, ileum and colon after total-body irradiation: a comparative study of segment-specific molecular and cellular responses
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Gene expression profiling in non-human primate jejunum, ileum and colon after total-body irradiation: a comparative study of segment-specific molecular and cellular responses

机译：全身照射后非人类灵长类空肠，回肠和结肠中的基因表达谱：段特异性分子和细胞应答的比较研究

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Although extensive studies have investigated radiation-induced injuries in particular gastrointestinal (GI) segments, a systematic comparison among the different segments on the basis of mode, magnitude and mechanism has not been reported. Here, a comparative study of segment-specific molecular and cellular responses was performed on jejunum, ileum and colon obtained at three time points (4, 7 and 12?days after irradiation) from non-human primate (Rhesus macaque) models exposed to 6.7?Gy or 7.4?Gy total body irradiation (TBI). Pathway analysis on the gene expression profiles identified radiation-induced time-, dose- and segment-dependent activation of tumor necrosis factor α (TNFα) cascade, tight junction, apoptosis, cell cycle control/DNA damage repair and coagulation system signaling. Activation of these signaling pathways suggests that colon sustained the severest mucosal barrier disruption and inflammation, and jejunum the greatest DNA damage, apoptosis and endothelial dysfunction. These more pronounced alterations correlate with the high incidence of macroscopic pathologies that are observed in the colon after TBI. Compared to colon and jejunum, ileum was resistant to radiation injury. In addition to the identification a marked increase of TNFα cascade, this study also identified radiation induced strikingly up-regulated tight junction gene CLDN2 (196-fold after 7.4-Gy TBI), matrix degradation genes such as MMP7 (increased 11- and 41-fold after 6.7-Gy and 7.4-Gy TBI), and anoikis mediated gene EDA2R that mediate mucosal shedding and barrier disruption. This is the first systematic comparative study of the molecular and cellular responses to radiation injury in jejunum, ileum and colon. The strongest activation of TNFα cascades and the striking up-regulation of its down-stream matrix-dissociated genes suggest that TNFα modulation could be a target for mitigating radiation-induced mucosal barrier disruption.
机译：尽管广泛的研究已经调查了特定胃肠道（GI）部分的辐射损伤，但尚未报道根据模式，大小和机制对不同部分进行系统的比较。在这里，对从暴露于6.7的非人类灵长类动物（猕猴）模型在三个时间点（照射后4、7和12天）获得的空肠，回肠和结肠的段特异性分子和细胞应答进行了比较研究。 ？Gy或7.4？Gy全身辐射（TBI）。基因表达谱的途径分析确定了辐射诱导的肿瘤坏死因子α（TNFα）级联，紧密连接，凋亡，细胞周期控制/ DNA损伤修复和凝血系统信号传导的时间，剂量和区段依赖性活化。这些信号通路的激活表明结肠承受了最严重的粘膜屏障破坏和炎​​症，空肠具有最大的DNA损伤，凋亡和内皮功能障碍。这些更明显的改变与在TBI后在结肠中观察到的宏观病理的高发生率相关。与结肠和空肠相比，回肠对辐射损伤具有抵抗力。除了鉴定出TNFα级联的显着增加外，该研究还鉴定了辐射诱导的紧密连接基因CLDN2（在7.4-Gy TBI后为196倍），基质降解基因如MMP7（11和41-分别增加）。在6.7-Gy和7.4-Gy TBI之后折叠），而无神经素介导的基因EDA2R介导粘膜脱落和屏障破坏。这是对空肠，回肠和结肠中辐射损伤的分子和细胞反应的第一个系统比较研究。 TNFα级联的最强激活及其下游基质解离基因的显着上调表明，TNFα调节可能是减轻辐射引起的粘膜屏障破坏的靶标。

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