ROLE PARTITIONING BY ARYL HYDROCARBON RECEPTORS (AHR) IN CELL REGULATION AND TOX

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。子项目及 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。 总体目标是阐明基因失调和细胞毒性的环境污染物的机制。卤代芳烃（HAH）和多环芳烃（PAH）广泛存在于环境中，在低浓度下具有高毒性，并与人类和野生动物的许多健康影响有关。芳烃受体（AHR）是配体激活的转录因子，调节编码生物转化酶的基因，以响应HAH和PAH暴露。此外，许多与代谢无关的基因，包括正常细胞生理学所必需的基因，在存在和不存在外源配体的情况下也受到AHR的调节。因此，劫持AHR从其生理功能可能在细胞毒性中发挥重要作用。与哺乳动物不同的是，硬骨鱼和软骨鱼拥有两个或多个不同的旁系同源的AHR。这些蛋白质在结构、功能以及发育和组织特异性表达方面不同，但它们在细胞调节中的作用尚不清楚。研究这些AHR可能揭示新的调节功能，并提供洞察AHR配体的细胞毒性的机制。了解多个AHR旁系同源物之间的功能划分可以揭示单个哺乳动物AHR的生理作用，并提供一个有效的范式来分别测试关于哺乳动物AHR基因靶点子集的假设。我们将测试以下假设集中在软骨和硬骨鱼的AHR旁系同源物的角色划分：1）新的AHR结构不同的能力，结合配体和激活转录，2）多个AHR旁系同源物在同一生物体有不同的转录目标密切相关的细胞调控，和3）暴露于HAH破坏细胞周期调节的AHR依赖性机制。

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 overall objective is to elucidate mechanisms underlying gene dysregulation and cell toxicity by environmental contaminants. Halogenated aromatic hydrocarbons (HAH) and polycyclic aromatic hydrocarbons (PAH) are widespread in the environment, highly toxic at low concentrations, and are linked to numerous health effects in humans and wildlife. Aryl hydrocarbon receptors (AHR) are ligand-activated transcription factors that regulate genes encoding biotransformation enzymes in response to HAH and PAH exposure. Moreover, numerous genes not associated with metabolism, including those necessary for normal cell physiology, are also regulated by AHR in the presence and absence of exogenous ligands. Thus, the hijacking of AHR from its physiological functions may play a major role in cell toxicity. Unlike mammals, which possess a single AHR, bony and cartilaginous fishes possess two or more divergent paralogs of the AHR. These proteins differ in their structure, function, and developmental and tissue specific expression, however their roles in cell regulation are not known. Investigating these AHRs may reveal novel regulatory functions and provide insight to the mechanisms underlying cell toxicity by AHR ligands. Understanding partitioning of functions among multiple AHR paralogs can reveal physiological roles of the single mammalian AHR, and provide an effective paradigm to separately test hypotheses about subsets of mammalian AHR gene targets. We will test the following hypotheses centered on role partitioning by AHR paralogs in cartilaginous and bony fishes: 1) Novel AHR structures differ in their ability to bind ligands and activate transcription, 2) multiple AHR paralogs in the same organism have distinct transcriptional targets germane to cell regulation, and 3) exposure to HAHs disrupts cell cycle regulation by an AHR-dependent mechanism.