Transgenic Models of Ah Receptor Action

Ah 受体作用的转基因模型

• 批准号: 8258122
• 负责人: CHRISTOPHER A BRADFIELD
• 金额: $ 33.86万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-10 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258122
• 关键词: ARNT gene; Acute; Affinity; Agonist; Alleles; Animal Model; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Biological; Biological Markers; Candidate Disease Gene; Cells; Chemical Structure; Complex; Coupled; DNA; Data Set; Dependence; Development; Developmental Biology; Dioxins; Endothelial Cells; Environment; Environmental Health; Environmental Pollution; Exposure to; Gene Expression; Gene Targeting; Genetic Enhancer Element; Genetic Polymorphism; Genomics; Goals; Grant; Health Policy; Hepatocyte; Human; Individual; Ligands; Liver neoplasms; Mediating; Modeling; Mus; Outcome; Pathway interactions; Physiological; Play; Polychlorinated Biphenyls; Population; Receptor Signaling; Recombinants; Risk; Risk Assessment; Rodent; Role; Signal Pathway; Signal Transduction; Staging; Testing; Toxic effect; Toxicity Tests; Toxicology; Transcript; Transcriptional Activation; Transgenic Model; Tumor Promotion; activating transcription factor; aryl hydrocarbon receptor ligand; base; carcinogenesis; dibenzofuran; diphenyl; embryonic stem cell; environmental chemical; hazard; insight; man; mouse model; mutant; novel; pollutant; receptor; research study; response

DESCRIPTION (provided by applicant): The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the biological effects of polycyclic aromatic hydrocarbons (PAHs), halogenated-dioxins ("dioxins"), - dibenzofurans, -biphenyls (PCBs), and -diphenylethers. Because of its central role in acute toxicity, teratogenesis and carcinogenesis of a large number of environmental contaminants, mechanistic information about AHR signaling is used by regulatory agencies to establish acceptable exposure levels for these pollutants. The overarching hypothesis of this proposal is that at least three distinct AHR signaling pathways exist that are of toxicological significance to human populations and vertebrate species in general. We propose that these three pathways can be distinguished by their unique impacts on transcriptional profiles within target cell populations and that these pathways can be further defined based upon their dependence on fractional activation of the AHR, by their cellular context, and their influence on gene expression through enhancer elements known as AHREs. The goal of this proposal is to identify biomarkers that reflect exposure to agonists and their induced toxic responses. We will accomplish this through the identification of low and high affinity AHREs in the hepatocyte and endothelial cell compartments of novel recombinant mouse models. To these ends, we propose the following specific aims: Specific Aim 1: Use gene targeting in ES cells to generate recombinant alleles derived from a ligand responsive version of Ahr. Specific Aim 2: Demonstrate the importance of the cellular expression and concentration of AHR. Specific Aim 3: Classify the high and low affinity AHRE batteries using genomic approaches. Specific Aim 4: Provide evidence that environmental AHR agonists can stimulate the endogenous AHR pathway. We propose that the results of this effort will provide new models that will inform the mechanism of dioxin toxicity in humans, characterize DNA signatures of toxicity, and test a novel hypothesis that developmental toxicity arises from interference with the endogenous AHR pathway. Collectively these studies will set the stage for more accurate and informative risk assessment in man. PUBLIC HEALTH RELEVANCE: This project aims to understand the mechanisms of AHR-mediated transcriptional activation which leads to the adaptive, toxic, and developmental consequences of dioxin exposure and to search for biomarkers that are predictive of these disparate outcomes. These experiments will allow more relevant assessments of AHR-mediated dioxin toxicity as well as generate biomarkers predictive for relevant endpoints of dioxin exposure.

描述（由申请人提供）：芳基烃受体（AHR）是配体激活的转录因子，可介导多环芳族氢化碳纤维（PAHS），卤代二恶英（“ dioxins”），-dibenzofurans，-biphenyls，-biphenyls（pcbs）和-dipiphenyl的生物学作用。由于其在大量环境污染物的急性毒性，变质和致癌作用中的核心作用，因此调节机构使用有关AHR信号传导的机械信息，以建立这些污染物的可接受暴露水平。该提议的总体假设是，至少存在三种不同的AHR信号通路，这些途径对人类种群和脊椎动物物种具有毒理学意义。我们建议，这三个途径可以通过它们对目标细胞群体中转录谱的独特影响来区分，并且可以根据它们对AHR的分数激活，细胞环境以及通过称为AHRES的增强子元素对基因表达的影响来进一步定义这些途径。该提案的目的是确定反映暴露于激动剂及其诱导的有毒反应的生物标志物。我们将通过鉴定新型重组小鼠模型的肝细胞和内皮细胞室中的低亲和力AHRE来实现这一目标。对于这些目的，我们提出以下特定目的：特定目标1：使用ES细胞中的基因靶向来生成源自AHR配体响应版本的重组等位基因。特定目标2：证明AHR的细胞表达和浓度的重要性。特定目标3：使用基因组方法对高和低亲和力AHRE电池进行分类。特定目的4：提供证据表明环境AHR激动剂可以刺激内源性AHR途径。我们建议这项工作的结果将提供新的模型，以告知人类二恶英毒性的机制，表征毒性的DNA特征，并检验了一种新的假设，即发育毒性是由于干扰内源性AHR途径而产生的。这些研究总的来说，将为人类的更准确和信息丰富的风险评估奠定阶段。 公共卫生相关性：该项目旨在了解AHR介导的转录激活的机制，从而导致二恶英暴露的适应性，有毒和发育后果，并寻找可以预测这些不同结果的生物标志物。这些实验将允许对AHR介导的二恶英毒性进行更相关的评估，并为相关的二恶英暴露终点提供生物标志物的预测。