AH RECEPTOR IN NON-MAMMALIAN MODELS

描述：（改编自研究者摘要）芳烃 受体（AHR）是一种配体激活的转录因子， 卤代芳烃，如2，3，7，8-四氯二苯并-p-二恶英 （TCDD），导致改变基因表达和毒性。AHR属于 碱性-螺旋-环-螺旋/Per-ARNT-Sim（bHLH-PAS）转录因子家族 调节蛋白，其成员发挥关键作用，在发展，昼夜节律 节律性和环境稳态。然而，正常的细胞 AHR的功能尚不清楚，尽管对AHR进行了广泛的研究， 哺乳动物，包括AHR缺失小鼠。 鱼类和非哺乳类脊椎动物越来越多地被用作模型系统 在毒理学和致癌研究，在发育生物学， 环境质量的哨兵。对所得结果的正确解释 在这些模型中，需要了解以下方面的相似性和差异： 人类和鱼类之间的分子机制在过去的一段时间里，我们 鉴定了一个AHR同源物（AHR 1）以及一个新的AHR相关基因（AHR 2）， 多骨和软骨的鱼。鱼AHR 1和AHR 2都表现出特异性， 与[3 H]TCDD的高亲和力结合。系统发育分析表明，AHR基因 复制发生在脊椎动物进化的早期，这表明两个AHR 基因可能存在于其他脊椎动物，包括人类（PNAS（1997）） 94：13743）。为了充分了解TCDD对人体的影响， 确定人类是否拥有第二个AHR，如果是，它是否起作用 作为配体激活的转录因子，如AHR 1。如果AHR 2不存在， 在人类中，重要的是确定 鱼类AHR 1/AHRs和人类AHRs，以评估鱼类作为模型的价值 环境健康研究。 拟议研究的总体目标是评估 AHR依赖性信号的成分和机制的差异 在毒理学中用作模型的人与鱼之间的转导。我们将 确定AHR基因在鱼类中的多样性和功能， 作为水生动物模型，检验第二个AHR样基因存在于 人类，并比较鱼类和人类AHRs的功能。

DESCRIPTION: (Adapted from the Investigator's Abstract) The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor through which halogenated aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), cause altered gene expression and toxicity. The AHR belongs to the basic-helix-loop-helix/Per-ARNT-Sim (bHLH-PAS) family of transcriptional regulatory proteins, whose members play key roles in development, circadian rhythmicity, and environmental homeostasis. However, the normal cellular function of the AHR is not yet known, despite extensive studies of the AHR in mammals, including AHR-null mice. Fish and non-mammalian vertebrates are being used increasingly as model systems in toxicology and carcinogenesis research, in developmental biology, and as sentinels of environmental quality. Proper interpretation of results obtained in such models requires an understanding of the similarities and differences in molecular mechanisms between humans and fish. In the preceding grant period, we identified an AHR homolog (AHR1) as well as a novel AHR-related gene (AHR2) in bony and cartilaginous fish. Fish AHR1 and AHR2 both exhibit specific, high-affinity binding to [3H]TCDD. Phylogenetic analyses show that an AHR gene duplication occurred early in vertebrate evolution, suggesting that two AHR genes could exist in other vertebrates, including humans (PNAS (1997) 94:13743). To fully understand TCDD effects in humans, it is critical to establish whether humans possess a second AHR and, if so, whether it functions as a ligand-activated transcription factor like AHR1. If an AHR2 is not present in humans, it is important to determine the functional relationships between fish AHR1/AHRs and the human AHR in order to assess the value of fish as models in environmental health research. The overall objectives of the proposed research is to assess the similarities and differences in components and mechanisms of AHR-dependent signal transduction between humans and fish used as models in toxicology. We will determine the diversity and function of AHR genes in fish species commonly used as aquatic models, test the hypothesis that a second AHR-like gene exists in humans, and compare the function of fish and human AHRs.