NUCLEAR RECEPTOR REGULATION OF THE C ELEGANS DETOXIFICATION NETWORK

线虫解毒网络的核受体调节

• 批准号: 7959441
• 负责人: TIM H LINDBLOM
• 金额: $ 1.96万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959441
• 关键词: Arkansas; Biology; Biomedical Research; C. elegans genome; Caenorhabditis elegans; Chemicals; Computer Retrieval of Information on Scientific Projects Database; Coupled; Diet; Drug Metabolic Detoxication; Drug Metabolism Induction; Drug Prescriptions; Environment; Enzyme Gene; Enzymes; Funding; Gene Expression; Gene Family; Genes; Genetic Transcription; Genomics; Goals; Grant; Homologous Gene; Institution; Knowledge; Mediator of activation protein; Metabolic Pathway; Nuclear Receptors; Pharmaceutical Preparations; Poison; Regulation; Research; Research Personnel; Resistance; Resources; Role; Signal Transduction; Source; Toxicogenomics; United States National Institutes of Health; Xenobiotics; drug metabolism; environmental chemical; genome sequencing; insight; member; response; tool

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long term goal of this research is to understand how environmental chemical signals impact the expression of drug metabolism enzymes (DMEs). Although it is recognized that DME gene expression is upregulated in the presence of their substrates, insights into the mechanisms of this induction have only recently been obtained. The nuclear receptor (NR) PXR has been implicated as a key mediator of xenobiotic induction of DME expression in several vertebrate species. This discovery broadened the known biology attributed to the NR superfamily; namely, that NRs not only regulate transcription in response to endogenous signals but also in response to the presence of chemical signals from the environment. To date, searches for transcriptional targets for PXR and other "xenobiotic sensing" NRs have generally revealed members of DME gene families. Thus, discovery of the entire suite of genes regulated by these NRs will illuminate the various metabolic pathways elicited by xenobiotics. This knowledge, in turn, will provide the requisite information needed for the prediction of drug-drug and drug-environment interactions that often result in dramatically modified efficacy of prescription drugs. The discovery of NR regulated DME expression, coupled with the advent of genome sequencing projects and modern genomics tools, makes the use of a toxicogenomics approach to reveal the complete description of loci upregulated via NRs in response to compounds in our drugs, diet, and environment an appealing possibility. Within the C. elegans genome are more than 260 NRs including several that are closely related to PXR. Among these PXR-related NRs is NHR-8, which C. elegans requires for wild type resistance to xenobiotics. The role of NHR-8 in xenobiotic resistance suggests that like its vertebrate homolog, NHR-8 responds to the presence of xenobiotic toxic compounds by upregulating the expression of a detoxification network to remove the offending compounds.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本研究的长期目标是了解环境化学信号如何影响药物代谢酶（DME）的表达。虽然它是公认的DME基因表达上调的存在下，他们的底物，这种诱导机制的见解最近才获得。核受体（NR）PXR已被牵连作为一个关键介导的异源诱导DME表达在几种脊椎动物物种。这一发现拓宽了NR超家族的已知生物学;即NR不仅响应内源性信号调节转录，而且响应来自环境的化学信号的存在。到目前为止，搜索转录靶PXR和其他“异生物质传感”NR一般发现DME基因家族的成员。因此，发现由这些核受体调控的整套基因将阐明外源性物质引起的各种代谢途径。反过来，这些知识将提供预测药物与药物和药物与环境相互作用所需的必要信息，这些相互作用通常会导致处方药的功效显着改变。NR调节DME表达的发现，加上基因组测序项目和现代基因组学工具的出现，使得使用毒理基因组学方法来揭示通过NR上调的基因座的完整描述，以响应我们的药物，饮食和环境中的化合物成为一种有吸引力的可能性。 在C.线虫基因组中有超过260个NR，包括几个与PXR密切相关的NR。在这些PXR相关的NR中，NHR-8是C.线虫需要野生型对异生物质的抗性。NHR-8在异生物质抗性中的作用表明，与其脊椎动物同源物一样，NHR-8通过上调解毒网络的表达以去除有害化合物来响应异生物质毒性化合物的存在。