NCoR1 and developmental expression of intestinal xenobiotic processing genes

NCoR1 和肠道异生素加工基因的发育表达

基本信息

  • 批准号:
    8970343
  • 负责人:
  • 金额:
    $ 23.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-09-01 至 2017-08-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Fundamental changes in expression of xenobiotic processing genes (XPGs) such as those that encode the Phase 1, 2, and 3 proteins occur during the progression from the neonatal period to the adult. Progress has been made in understanding these changes, as the regulation of these genes has been linked in part through expression of the family of xenobiotic nuclear receptors (XNRs), which partner in relationship to the retinoid X- receptor. But explanations for these differences and the mechanisms that regulate expression of the XNRs have not been elucidated. Experiments conducted with humanized UGT1 (hUGT1) mice that express all nine of the UGT1A genes have revealed that neonatal hUGT1 mice develop dramatic hyperbilirubinemia during the early neonatal period. Two key factors result in this syndrome. First, the human UGT1A1 gene is repressed in liver and is transcriptionally blocked by the repressive actions of PXR. Second, developmental expression of intestinal UGT1A1 late in the neonatal period leads to a reduction of hyperbilirubinemia and clearance of serum bilirubin. These findings suggested that the UGT1A1 gene was actively repressed during neonatal development, and led us to examine the role of the transcriptional co-repressor protein NCoR1. In these experiments, we selectively targeted the deletion of the NCoR1 gene in either the liver (hUGT1/NCoR1Hep mice) or intestines (hUGT1/NCoR1HepIEC mice) of hUGT1 mice. Deletion of NCoR1 in liver tissue had no effect on serum bilirubin levels, but deletion of the gene in intestinal tissue completely reversed neonatal hyperbilirubinemia. Consistent with the reduction of serum bilirubin in hUGT1/NCoR1HepIEC mice was the dramatic induction of intestinal UGT1A1 gene expression. This intriguing finding led us to examine in greater detail the role of NCoR1 in early neonatal and adult expression of the XPGs in intestinal tissue. Our preliminary findings clearly indicate that the deletion of the c-repressor NCoR1 leads to induction and regulation of a series of XPGs in neonates that are different from those induced in adult intestines. Since NCoR1 represses gene transcription by forming a co-repressor complex with selective XNRs, we hypothesize that NCoR1 is controlling the repression of XPGs in a developmental fashion by forming complexes with different XNRs. To examine this hypothesis, we are going to characterize the expression patterns of the XPGs and the epigenetic events that control expression of these genes as a result of NCoR1 de-repression. These findings will allow us to identify the nuclear receptor involved in NCoR1 repression by associating gene expression patterns to known XNR function. In addition, this work will reveal the underlying mechanisms linking repression of XPG expression during neonatal development and the regulatory events that promote differential induction of these genes in adult mice. It is hopeful that this work will reveal for the first time the molecular evens that dictate developmental expression of the XPGs. These findings will be important in determining the link between toxicant exposure, metabolism and a toxic episode that is favored during neonatal development.
 描述(由申请人提供):异生素加工基因(XPG)的表达发生根本性变化,例如编码第 1、2 和 3 相蛋白的基因,发生在从新生儿期到成人的过程中。在理解这些变化方面已经取得了进展,因为这些基因的调节部分与异生核受体 (XNR) 家族的表达有关,该家族与类视黄醇 X 受体相关。但对这些差异的解释以及调节 XNR 表达的机制尚未阐明。对表达所有九个 UGT1A 基因的人源化 UGT1 (hUGT1) 小鼠进行的实验表明,新生 hUGT1 小鼠在新生儿早期会出现严重的高胆红素血症。导致这种综合征的两个关键因素。首先,人类 UGT1A1 基因在肝脏中受到抑制,并且通过 PXR 的抑制作用而在转录上被阻断。其次,新生儿后期肠道UGT1A1的发育表达导致高胆红素血症的减少和血清胆红素的清除。这些发现表明 UGT1A1 基因在新生儿发育过程中受到积极抑制,并促使我们研究转录辅助抑制蛋白 NCoR1 的作用。在这些实验中,我们选择性地删除 hUGT1 小鼠的肝脏(hUGT1/NCoR1Hep 小鼠)或肠道(hUGT1/NCoR1HepIEC 小鼠)中的 NCoR1 基因。肝组织中NCoR1的缺失对血清胆红素水平没有影响,但肠道组织中该基因的缺失完全逆转了新生儿高胆红素血症。与 hUGT1/NCoR1HepIEC 小鼠血清胆红素降低一致的是肠道 UGT1A1 基因表达的显着诱导。这一有趣的发现使我们更详细地研究了 NCoR1 在早期新生儿和成人肠道组织中 XPG 表达中的作用。我们的初步研究结果清楚地表明,c 阻遏蛋白 NCoR1 的缺失会导致新生儿中一系列 XPG 的诱导和调节,这些 XPG 与成人肠道中诱导的不同。由于NCoR1通过与选择性XNR形成共阻遏物复合物来抑制基因转录,因此我们假设NCoR1通过与不同XNR形成复合物以发育方式控制XPG的抑制。为了检验这一假设,我们将描述 XPG 的表达模式以及由于 NCoR1 去抑制而控制这些基因表达的表观遗传事件。这些发现将使我们能够通过将基因表达模式与已知的 XNR 功能相关联来识别参与 NCoR1 抑制的核受体。此外,这项工作将揭示新生儿发育过程中 XPG 表达抑制与成年小鼠中促进这些基因差异诱导的调控事件之间的潜在机制。希望这项工作将首次揭示决定 XPG 发育表达的分子事件。这些发现对于确定有毒物质暴露、代谢和新生儿发育过程中容易发生的中毒事件之间的联系非常重要。

项目成果

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Shujuan Chen其他文献

Shujuan Chen的其他文献

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{{ truncateString('Shujuan Chen', 18)}}的其他基金

The role of nuclear receptor co-repressor NCoR1 in ulcerative colitis
核受体共阻遏物NCoR1在溃疡性结肠炎中的作用
  • 批准号:
    9600568
  • 财政年份:
    2018
  • 资助金额:
    $ 23.25万
  • 项目类别:
Organ-specific Ugt1 profiling in detoxifying the anticancer drug CPT-11
抗癌药物 CPT-11 解毒过程中的器官特异性 Ugt1 分析
  • 批准号:
    8358561
  • 财政年份:
    2012
  • 资助金额:
    $ 23.25万
  • 项目类别:
Organ-specific Ugt1 profiling in detoxifying the anticancer drug CPT-11
抗癌药物 CPT-11 解毒过程中的器官特异性 Ugt1 分析
  • 批准号:
    8507662
  • 财政年份:
    2012
  • 资助金额:
    $ 23.25万
  • 项目类别:

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